Patent Application
20230322878
The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on Jun. 29, 2023, is named 0177-0136-DIV-SL.xml and is 10,001,595 bytes in size.
The invention relates to compounds for inducing tissue formation, biomaterials and medical devices comprising such compounds, such compounds for use in medical methods and use of such compounds in non-medical methods.
Tissue regeneration forms an important part of the healing process subsequent to disease, trauma, or surgery. In situations where disease or trauma produces a tissue defect, for example a bone, cartilage, skin, vascular tissue, or eye retina defect, tissue regeneration is a central goal of recovery. It is not, however, a goal that is always or easily achieved and much research has been devoted to newer and more effective ways to promote tissue repair and regeneration. Conventional technics to achieve tissue regeneration involve the activation of tissue-specific stem cells present in adult tissues with repair and/or regenerative capabilities called mesenchymal stem cell(s) or MSC(s) using recombinant proteins called growth factors (GFs). MSCs or MSC-like cells may be found in the bone marrow, but also in tissues such as fat, umbilical cord blood, amniotic fluid, placenta, dental pulp, tendons, synovial membrane and skeletal muscle. Natural regulation of the MSCs is effected through the participation of a number of growth factors (GFs), including vascular endothelial growth factors (VEGF), which trigger angiogenesis crucial for the repair of most tissues, bone morphogenetic proteins (BMP), which induce the formation of new bone and regulate capillary stem cell activation, transforming growth factors (TGF), which induce cartilage formation, and platelet-derived growth factor-BB (PDGF-BB), which is involved in the formation of granulation tissues and the recruitment of stem cells. Naturally occurring growth factors are found within the tissues themselves and are only present in small amounts. Thus, to provide industrially useful and reproducible amounts of human growth factors, traditional technics involve the production of GFs by genetic recombination. These recombinant molecules are typically grafted onto the surface of a biocompatible material and placed, where needed, inside or on the body of a patient.
Bone
It is conventionally known that mature osteoblasts are the cells responsible for bone formation and are derived from osteoblast precursors. Differentiation of human bone marrow mesenchymal stem cells and osteoblast precursors is one of the important processes for bone regeneration. Osteoblasts differentiate from mesenchymal stem cells. Mature osteoblasts differentiate from osteoblast precursors and into osteocytes which are non-dividing cells. Upon cell activation osteoblasts begin to secrete some extracellular matrix around themselves. Calcification, i.e., deposition of insoluble calcium salts in the bone matrix, begins a short time after the matrix has been secreted. Upon termination of bone matrix synthesis, osteoblasts either undergo cell death by apoptosis or differentiate into osteocytes or bone lining cells. Mesenchymal stem cells are found in large numbers in the periosteum, the fibrous-like layer on the outside surface of bones, and in the bone marrow. During cellular differentiation of osteoblasts, the developing progenitor cells express the regulatory transcription factor Cbfa1/Runx2. A second important transcription factor required for osteoblastic differentiation is osterix. Osteoprogenitors differentiate under the influence of growth factors. Important growth factors in skeletal differentiation include bone morphogenetic proteins (BMPs), transforming growth factor beta (TGF-β) and fibroblast growth factors (FGFs). Differentiation of osteoblasts is also characterized by the expression of alkaline phosphatase as an early marker of pre-osteoblasts. As a result, acting on the differentiation cycle of mammal bone marrow mesenchymal stem cells and osteoblast precursors may have applications in bone tissue regeneration.
Osteoporosis
Osteoporosis is a progressive bone disease that is characterized by a decrease in bone mass and density which can lead to an increased risk of fracture. In osteoporosis, the bone mineral density (BMD) is reduced, bone microarchitecture deteriorates, and the amount and variety of proteins in bone are altered. Osteoporosis is defined by the World Health Organization as a bone mineral density of 2.5 standard deviations or more below the mean peak bone mass (average of young, healthy adults) as measured by dual-energy X-ray absorptiometry; the term “established osteoporosis” includes the presence of a fragility fracture. The treatment of osteoporotic fractures is often hindered by reduced bone healing and higher rates of complications. Studies in osteoporotic animal models revealed delayed callus formation and enchondral ossification, resulting in impaired biomechanical properties of the bone. The cellular sources of fracture healing are mesenchymal stem cells (MSCs). MSCs migrate to the fracture site, where they proliferate and differentiate into osteoblasts upon stimulation with osteoinductive cytokines. Molecular biological alterations of MSCs, such as decreased proliferative capacity, production of collagen I deficient matrix, preferableness of adipogenic differentiation, and impaired osteogenic differentiation have been described in osteoporotic patients. With regards to the osteoinduction of MSCs, key agents are BMPs. Of these, BMP-2 is one of the most potent osteoinductive cytokines which physiologically contributes to the early phase of fracture healing. Beyond that, BMP-2 is already clinically approved for the treatment of distinct fracture entities. The predominant role of BMP-2 in osteoinduction and bone formation led to a scientific quest regarding its involvement in the pathophysiology of osteoporosis. Osteoporotic animal models revealed inconsistent data with regard to BMP-2 expression levels. BMP-2 was found to be overexpressed in the callus of mandibles and down-regulated in MSCs derived from tibial and femoral bone. In humans, genetic polymorphisms in BMP-2 have been identified as risk factors for the development of familial osteoporosis and osteoporotic fractures. All these findings directly link the BMP pathways to osteoporosis. Other studies investigated the therapeutic potential of BMP-2 in osteoporotic animal models. The systemic administration of rhBMP-2 increased the volume of trabecular bone and stimulated bone formation in osteoporotic mice. The local application of adenoviral BMP-2 at the site of injury enhanced callus formation and improved mechanical properties of the healing bone in osteoporotic sheep. Stimulating the differentiation of MSCs and/or inducing growth factor activity, in particular of BMPs, may thus lead to the development of new osteoporosis treatments.
Cartilage
Although native chondrocytes offer little assistance to injured articular cartilage, these cells are responsible for the synthesis and turnover of the cartilage extracellular matrix (ECM), which provides an environment of nutrition diffusion for chondrocytes and provides the joint surface with biomechanical competence. Chondrogenic cells arise from pluripotential adult mesenchymal stem cells (MSCs) through a series of differentiation pathways. Subsequently, it was shown that a number of cytokines and transcription factors are involved in chondrocyte maturation and cartilage formation. Chondrogenic differentiation of MSCs is induced by various intrinsic and extrinsic factors. Growth factors play the most important role in this process. They represent a group of biologically active polypeptides produced by the body, which can stimulate cell proliferation, differentiation and maturation. In the hyaline cartilage, growth factors regulate homeostasis and integrity, as well as development. Important growth factors intervening in cartilage regeneration include TGF-β1, TGF-β3, BMP-2, BMP-4, BMP-7 and GDF-5. As a result, acting on the differentiation cycle of mammal mesenchymal stem cells and chondroblast precursors may have applications in cartilage tissue regeneration.
Muscles
Skeletal muscle is a highly complex and heterogeneous tissue serving a multitude of functions in the organism. The process of generating muscle-myogenesis-can be divided into several distinct phases. During embryonic myogenesis, mesoderm-derived structures generate the first muscle fibers of the body proper, and in subsequent waves additional fibers are generated along these template fibers. In the perinatal phase, muscle resident myogenic progenitors initially proliferate extensively but, later on, decrease as the number of myonuclei reaches a steady state and myofibrillar protein synthesis peaks. Once the muscle has matured, these progenitors will enter quiescence and henceforth reside within it as satellite cells. Adult skeletal muscle, like all renewing organs, relies on a mechanism that compensates for the turnover of terminally differentiated cells to maintain tissue homeostasis. This type of myogenesis depends on the activation of satellite cells that have the potential to differentiate into new fibers. The most comprehensively studied form of myogenesis takes place when mature muscle is damaged and large cohorts of satellite cells expand mitotically and differentiate to repair the tissue and reestablish homeostasis. Many similarities, such as common transcription factors and signaling molecules, between embryonic myogenesis and regeneration in the mature skeletal musculature have been discovered. It is now generally accepted that satellite cells are closely related to progenitors of somitic origin. The activation of the network of transcription factors that controls skeletal muscle development depends on paracrine factors that are released by adjacent tissues, such as the neural tube, notochord, surface ectoderm and lateral mesoderm. Several secreted factors have been identified that determine the spatial and temporal onset of myogenesis. However, no consensus has been reached as to whether these molecules instruct naive cells (instructive induction), amplify a pool of committed progenitors and/or enable a default differentiation pathway (permissive induction) or primarily prevent programmed cell death of muscle progenitor cells. Sonic hedgehog (SHH) and WNT signaling have been reported to have pivotal roles in the induction of myogenesis. Likewise, other signalling molecules, such as Noggin and bone morphogenetic proteins (BMPs)—which inactivate and activate receptors of the transforming growth factor-β (TGFβ) superfamily, respectively—are known to play an important part in orchestrating the activation of myogenesis. Muscle tissue degenerative diseases or disorders include, but are not limited to, myopathies, muscular atrophy, disuse atrophy, denervation atrophy, muscular dystrophies such as the Duchenne muscular dystrophy (DMD), and the Becker muscular dystrophy (BMD), fibrosis, fibrositis, muscle weakness, fatigue, cramps, fibromyalgia, or chronic muscle pain syndrome.
Vascular
The vasculature in the human body forms through two distinct processes: vasculogenesis and angiogenesis. Vasculogenesis is defined as the process of de novo blood vessel formation occurring when endothelial precursor cells (angioblasts) migrate and differentiate into endothelial cells which form the new vessel. These vascular trees are then extended through angiogenesis which is defined as the new vessel formation secondary to proliferation of endothelial cells from pre-existing vessels. Vasculogenesis as well as angiogenesis occur during the embryologic development of the circulatory system but also in the adult organism from circulating endothelial progenitor cells (derivatives of stem cells) able to contribute, albeit to varying degrees, to neovascularization. An example of where these processes can occur in adults is the revascularization following trauma, e.g., after cardiac ischemia. It is known that the ablation of the endothelial progenitor cells (EPCs) in the bone marrow leads to a significant decrease in the vasculature development which would place endothelial progenitor cells as a novel therapeutic target. The differentiation of the EPCs is a consequence of the interplay amongst different signaling molecules such as growth factors. These include FGF, VEGF, PDGF and others. Vascular endothelial growth factor (VEGF) is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate. VEGF is a sub-family of growth factors, to be specific, the platelet-derived growth factor family of cystine-knot growth factors. VEGF causes an importantsignaling cascade in endothelial cells. Binding to VEGF receptor-2 (VEGFR-2) starts a tyrosine kinase signaling cascade that stimulates the production of factors that variously stimulate vessel permeability, proliferation/survival, migration and finally differentiation into mature blood vessels. Recent reports have also indicated that different somatic cells (other than the EPCs) could be reprogrammed towards distinct endothelial cell lineages. This somatic reprogramming as well as the stimulation of EPCs differentiation, both represent promising therapeutic targets in regenerative vascular medicine.
Wound Healing
Wound healing is a complex and dynamic process of replacing devitalized and missing cellular structures and tissue layers. Upon injury to the skin, a set of complex biochemical events takes place in a closely orchestrated cascade to repair the damage and restore the protective barrier which in the normal skin is formed by the epidermis (outermost layer) and the dermis (inner or deeper layer) which exist in a steady-state equilibrium. The human adult wound healing process can be divided into 4 distinct phases: hemostasis, inflammatory, fibroblastic, and maturation (or remodeling). These phases are initiated and regulated by various secreted factors such as growth factors. In the first phase, the damaged blood vessels are sealed via different substances secreted by the platelets such as the platelet-derived growth factor (PDGF). The second phase corresponds to an inflammatory response which causes the blood vessels to become leaky thus releasing plasma and PMN's into the surrounding tissue. The neutrophils phagocytize debris and microorganisms and provide the first line of defence against infection. The cells macrophages are able to phagocytize bacteria and provide a second line of defence. They also secrete a variety of chemotactic and growth factors such as fibroblast growth factor (FGF), epidermal growth factor (EGF), transforming growth factor beta (TGF β and interleukin-1 (IL-1) which appears to direct the next stages of wound healing. The third phase involves the replacement of dermal and subdermal tissues. The fibroblasts secrete the collagen framework onto which further dermal regeneration occurs. The pericytes which regenerate the outer layers of capillaries and the endothelial cells which produce the lining are involved in the angiogenesis. The keratinocytes are responsible for the epithelialization. In the final stage of epithelializtion, contracture occurs as the keratinocytes differentiate to form the protective outer layer or stratum corneum. The last and 4th phase of wound healing involves remodeling the dermal tissues to produce greater tensile strength. The principle cells involved in this process are the fibroblasts. For a wound to heal successfully, all four phases must occur in the proper sequence and time frame. Many factors can interfere with one or more phases of this process, thus causing improper or impaired wound healing. Recent research has also shown that adult stem cells could be involved in wound healing. In particular hematopoietic progenitor cells (that give rise to mature cells in the blood) may have the ability to de-differentiate back into hematopoietic stem cells and/or trans-differentiate into non-lineage cells, such as fibroblasts. It is thought that the extent of the stem cell involvement in skin wound healing is complex as the epidermis and dermis could be reconstituted by mitotically active stem cells that reside at the apex of rete ridges (basal stem cells or BSC), the bulge of hair follicles (hair follicular stem cell or HFSC), and the papillary dermis (dermal stem cells). Moreover, the bone marrow may also contain stem cells that could play a major role in cutaneous wound healing. Therefore, activating adult stem cells as well as the different cells and growth factors intervening during the four phases of the skin wound healing process, most certainly represents a promising therapeutic target.
Tissue Closure
Wound healing not only applies to skin tissue repair but also to the closure of all tissue layers damaged e.g. in an injury or during surgery. For instance, during bone repair surgery, the different layers of tissues incised in order for the surgeon to reach the damaged bone part and repair it would all need to be closed for the overall healing process to occur. The mediation of this complex, “multi-layered” healing process, involves the participation of many different factors such as growth factors.
Neurons
For along time, the human nervous system has been considered fixed and incapable or regeneration since neurons do not divide within the central nervous system (CNS). Recently in has been discovered that neural cells can be regenerated from neural stem cells (NSCs). These are self-renewing, multipotent adult stem cells that generate the main phenotype of the nervous system. They undergo asymmetric cell division into two daughter cells, one non-specialized and one specialized. NSCs primarily differentiate into neurons, astrocytes, and oligodendrocytes. NSCs are generated throughout an adult's life via the process of neurogenesis. NSCs can be differentiated to replace lost or injured neurons or in many cases even glial cells. NSCs are stimulated to begin differentiation via exogenous cues from their microenvironment, or the neural stem cell niche. This niche defines a zone in which stem cells are retained after embryonic development for the production of new cells of the nervous system. This continual supply of new neurons and glia then provides the postnatal and adult brain with an added capacity for cellular plasticity. Critical to the maintenance of the stem cell niche are microenvironmental cues and cell-cell interactions that act to balance stem cell quiescence with proliferation and to direct neurogenesis versus gliogenesis lineage decisions. Several proteins like different growth factors are involved in the mechanisms of the neural stem cell niche as well as in the maintenance and growth of the newly formed neurons. These include the BMPs, FGFs, PDGF, VEGF, TGF βBDNF and others. Nerve growth factor (NGF) is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons (nerve cells). It also functions as a signaling molecule. While “nerve growth factor” refers to a single factor, “nerve growth factors” refers to a family of factors also known as neurotrophins. Other members of the neurotrophin family that are well recognized include Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), and Neurotrophin 4/5 (NT-4/5). NGF is critical for the survival and maintenance of sympathetic and sensory neurons. Without it, these neurons undergo apoptosis. Nerve growth factor causes axonal growth. Studies have shown that it causes also axonal branching and elongation. Several brain diseases are considered to be caused by disorders in the neural stem cell niche and especially in the precise signaling of this microenvironment. Therefore restoring correct growth factor signaling is a promising target for the treatment of brain diseases.
Eye Retina
The vertebrate retina is a light-sensitive layer of tissue, lining the inner surface of the eye. Light striking the retina initiates a cascade of chemical and electrical events that ultimately trigger nerve impulses. These are sent to various visual centers of the brain through the fibers of the optic nerve. In vertebrate embryonic development, the retina and the optic nerve originate as outgrowths of the developing brain, so the retina is considered part of the central nervous system (CNS) and is actually brain tissue. Retinal development involves a complex progression of tissue induction, proliferation of retinal progenitor cell (RPC) populations and terminal differentiation of these cells into specific functional types. Growing evidence indicates that several extrinsic cues play a critical role in the retinal cell development. One such extrinsic molecule type, bone morphogenetic protein (BMP), is a member of the transforming growth factor (TGF)-β family of signaling molecules, which are known to regulate a variety of cell functions in the developing nervous system, including neural induction, cell fate determination, apoptosis, and proliferation. BMP-2, -4, and -7 and their receptors (BMPRs) are expressed in the eye during embryogenesis and are essential for multiple aspects of retinal development. There are many inherited and acquired diseases or disorders that may affect the retina like for example the macular degeneration. It is a degenerative disease that usually affects older adults and results in a loss of vision in the center of the visual field (the macula) because of damage to the retina. Age-related macular degeneration is the leading cause of irreversible blindness in North America. Regenerating the retina via the growth factor signaling responsible for its development is thus a significant potential therapeutic target.
Kidneys
The kidney is a complex tissue consisting of several different cell types including glomerular podocytes, endothelial cells, mesangial cells, interstitial cells, tubular epithelial cells, and connecting duct cells. These cell types interact to establish a precise cellular environment that functions as an efficient tissue. Kidney diseases are currently a global public health problem, with an incidence that has reached epidemic proportions and continues to climb worldwide. Kidney failure can be associated with chronic kidney disease (CKD), which is a progressive loss in renal function over a period of months or years. Renal fibrosis, the common pathological feature of CKDs, is characterized by excessive accumulation of ECM (extracellular matrix). TGF-β (transforming growth factor-β) and BMP-7 (bone morphogenetic protein-7), two key members in the TGF-β superfamily, play important but diverse roles in CKDs (chronic kidney diseases). Both TGF-β and BMP-7 share similar downstream Smad signalling pathways, but counter-regulate each other to maintain the balance of their biological activities. During renal injury in CKDs, this balance is significantly altered because TGF-β signalling is up-regulated by inducing TGF-β1 and activating Smad3, whereas BMP-7 and its downstream Smad1/5/8 are down-regulated. In the context of renal fibrosis, Smad3 is pathogenic, whereas Smad2 and Smad7 are renoprotective. However, this counter-balancing mechanism is also altered because TGF-β1 induces Smurf2, an ubiquitin E3-ligase, to target Smad7 as well as Smad2 for degradation. Thus overexpression of renal Smad7 restores the balance of TGF-β/Smad signaling and has therapeutic effect on CKDs. It may this be that restoring the BMP-7 signaling is a potential therapeutic target in renal regenerative therapies.
Ligaments and Tendons
Tendons and ligaments (T/L) are dense connective tissues of mesodermal origin. They connect and transmit force from muscle to bone and bone to bone, respectively. Both tissues are able to store elastic energy and withstand hightensile forces, on which locomotion is entirely dependent. T/L are predominantly composed of collagen type I fibrils organized in a highly hierarchical manner that is unique for the T/L. Other collagens (types III-VI, XI, XII, XIV, and XV) and various proteoglycans (decorin, cartilage oligomeric matrix protein (COMP), byglican, lumican, fibromodulin, tenascin-C, etc.) are building the remaining T/L substance. The cellular content of T/L is dominated by tendon-specific fibroblasts named tenocytes. During embryonic development, the tendon-specific cells descend from a sub-set of mesenchymal progenitors condensed in the syndetome, a dorsolateral domain of the sclerotome. Moreover, Mesenchymal stem cells (MSCs), multipotent adult cells that give rise to tissues of mesodermal origin, have been shown to generate in vitro T/L progenitor cells. Several tendon injuries result from gradual wear and tear to the tendon from overuse or aging. Tendon healing is a complex and highly-regulated process that is initiated, sustained and eventually terminated by a large number and variety of molecules. Growth factors represent one of the most important molecule families involved in regeneration. The activity of five growth factors has been best characterized during this process: insulin-like growth factor-I (IGF-I), transforming growth factor beta (TGFbeta), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF). Stimulating the differentiation of MSCs and/or inducing growth factor activity thus represent two potentially significant therapeutic targets in T/L regeneration and healing.
Fertility and Reproduction
Reproduction (or procreation) is the biological process by which new offspring individual organisms are produced from their parents. Sexual reproduction is a biological process by which organisms create descendants that have a combination of genetic material contributed from two (usually) different members of the species. Fertility is the natural capability to produce offspring. The development and physiological functions of basic structures in the mammalian reproductive system are influenced by the tissue-specific expression of members of different growth factors families like the BMP family. The establishment of the germ line is a fundamental aspect of reproduction. Germ cell determination is induced in epiblast cells by the extraembryonic ectoderm, and is not acquired through the inheritance of preformed germ plasma. There is some strong evidence that BMP-4 and -8b play a central role in determining primordial germ cell (PGC) formation in the embryo. The genes encoding BMP-4 and -8b have overlapping expression in the extraembryonic ectoderm before gastrulation, i.e., before PGCs are seen. Thus, PGC formation requires BMP-4 expression. There is also evidence from knockout mammals that BMP-8b is required for PGC formation. Furthermore, there is increasing evidence that locally produced BMPs play a major role in the differentiation of the pituitary gonadotrope. Restoring the BMPs signaling would thus be an important factor in infertility therapies.
Hair
Tissue homeostasis and regeneration are regulated through balancing quiescence and activation of quiescent epithelial stem cells (SCs). Hair follicles (HFs) follow this process. Throughout adult life, they undergo dynamic, synchronized cycles of degeneration (catagen), quiescence (telogen), and regeneration (anagen). During telogen, which can last for months, HFSCs are quiescent and reside within a specialized microenvironment called the bulge. Within this niche, HFSCs surround the hair shaft produced in the previous cycle. Throughout telogen, the base of the bulge, called the secondary hair germ (HG), directly abuts the underlying mesenchymal dermal papillae (DP), a key signaling center for HFSCs. The telogen/anagen transition relies upon DP-HFSC crosstalk to generate the necessary threshold of activating factors. Upon activation, HFSCs in the HG are the first to proliferate and initiate HF regeneration, whereas HFSCs within the bulge become active several days later. As the new HF emerges, the DP stimulus is pushed increasingly further from niche SCs, which return to quiescence. In contrast, throughout anagen, relatively undifferentiated bulge cell progeny along the outer root sheath (ORS) accelerate proliferation as they approach the DP. This fuels a steady production of transiently amplifying matrix cells, which undergo a few divisions while in contact with DP and then terminally differentiate to form the hair and inner root sheath (IRS). At the anagen/catagen transition, matrix cells apoptosis and the DP retracts upward along with the dying/differentiating epithelial strand. As the HF reenters telogen, growth factors from the inner layer of non-SC niche cells and from surrounding dermal tissue impose a threshold, which must be overcome to initiate the next cycle. When cells in the telogen phase are not able to reenter into the anagen phase, hair stop their growth, and conditions such as hair loss emerge. As a result, acting on the differentiation cycle of mammal hair follicle mesenchymal stem cells and precursor cells may have applications in hair follicle tissue regeneration thus preventing hair-loss and activating hair-growth, preventing/treating alopecia areata, alopecia totalis, alopecia universalis, androgenic alopecia (male pattern baldness), telogen effluvium, anagen effluvium or chemotherapy-induced alopecia, but is not limited.
Skin
The skin constantly renews itself throughout adult life. Stem cells (SCs) residing in the epidermis ensure the maintenance of adult skin homeostasis, but they also participate in the repair of the epidermis after injuries. The skin protects the body from dehydration, injury and infection. The skin consists of an underlying dermis, separated by a basement membrane from the multilayered overlaying epidermis. The dermis is of mesodermal embryonic origin and contains as adult stem cells fibroblastic mesenchymal stem-cell-like cells. These cells have a multi-lineage differentiation potential, being also able to form adipose tissue or bones. The stratified epidermis is of ectodermal origin and composed of keratinocytes that differentiate to a water-impermeable stratum corneum. The terminally differentiated cells in the epidermis are shed from the skin, necessitating a continuous delivery of newly differentiating cells. The epidermis is completely renewed about every four weeks. Given that the differentiated cells cannot divide anymore, their replacement depends on epidermal stem cells. Skin stem cells are of special interest because they are easily accessible. In recent years, several products said to have a link with skin stem cells have found their way to the cosmetic products market such as AMATOKIN®, a face care product line commercialised by Voss Laboratories and said to stimulate stem cells in the skin, or Dior's CAPTURE® R60/80 XP product line used as anti-wrinkles whose mechanism is said to be based on the protection of the life force of stem cells. As a result, there is thus some potential in acting on the differentiation cycle of mammal skin mesenchymal stem cells and precursor cells with potential applications in skin tissue regeneration thus preventing wrinkles formation and generally improving skin appearance.
Blood
Blood is a bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those cells. When it reaches the lungs, gas exchange occurs wherein carbon dioxide is diffused out of the blood into the alveoli and oxygen is diffused into the blood. This oxygenated blood is pumped to the left hand side of the heart in the pulmonary vein and enters the left atrium. From here it passes through the bicuspid valve, through the ventricle and taken all around the body by the aorta. Blood contains antibodies, nutrients, oxygen and much more to help the body work. In vertebrates, it is composed of blood cells suspended in blood plasma. Plasma, which constitutes 55% of blood fluid, is mostly water (92% by volume), and contains dissipated proteins, glucose, mineral ions, hormones, carbon dioxide (plasma being the main medium for excretory product transportation), and blood cells themselves. Albumin is the main protein in plasma, and it functions to regulate the colloidal osmotic pressure of blood. Hematopoietic stem cells (HSCs) are the blood cells that give rise to all the other blood cells and are derived from the mesoderm. They are located in the red bone marrow, which is contained in the core of most bones. The HSCs give rise to the myeloid lineage (monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets, dendritic cells), and to the lymphoid lineages (T-cells, B-cells, NK-cells). The most abundant cells in the vertebrate blood are red blood cells (also called RBSs or erythrocytes). These contain hemoglobin, an iron-containing protein, which facilitates oxygen transport by reversibly binding to this respiratory gas and greatly increasing its solubility in blood. Blood cell degeneration-related diseases, conditions or disorders include, but are not limited to, Anemia, Iron-deficiency anemia, Anemia of chronic disease, Pernicious anemia, Aplastic anemia, Autoimmune hemolytic anemia, Thalassemia, Sickle cell anemia, Polycythemia vera, Vitamin deficiency anemia, Hemolytic anemia, Thrombocytopenia, Idiopathic thrombocytopenic purpura, Heparin-induced thrombocytopenia, Thrombotic thrombocytopenic purpura, Essential thrombocytosis (primary thrombocythemia), Thrombosis, Hemophilia, von Willebrand disease, Hypercoaguable state (hypercoagulable state), Deep venous thrombosis, Disseminated intravascular coagulation (DIC), Thrombocytopenia, Immune Thrombocytopenia (ITP), Drug-induced thrombocytopenia (DITP), Gestational thrombocytopenia, Thrombotic microangiopathies (TMA), Drug-induced thrombotic microangiopathies, Complement-mediated thrombotic microangiopathies, Mixed cryoglobulinemia, Eosinophilia, Eosinopenia, Idiopathic hypereosinophilic syndrome, Antiphospholipid syndrome (Hughes syndrome), Glanzmann's thrombasthenia, Wiskott-Aldrich syndrome (WAS), Leishmania infection, Toxoplasmosis, Hereditary hypogammaglobulinemia, Nonfamilial hypogammaglobulinemia, Leukopenia, Agranulocytosis, Basopenia, Bernard-Soulier syndrome (BSS), Malaria, Sepsis, or Hemolytic uremic syndrome (HUS).
Adipose Tissue
Adipose tissue is loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells (i.e. adipose tissue macrophages (ATMs)). Adipose tissue is derived from preadipocytes. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body. Pre-adipocytes are thought to be undifferentiated fibroblasts that can be stimulated to form adipocytes. The pre-adipocytes originate from mesenchymal stem cells. Areolar connective tissue is composed of adipocytes. The term “lipoblast” is used to describe the precursor of the adult cell. Adipose tissue degeneration-related diseases, conditions or disorders include, but are not limited to, Obesity, Dercum's disease (DD), Multiple symmetric lipomatosis (MSL), Familial multiple lipomatosis (FML), Upodystrophy, Lipedema, or Atherosclerosis.
Lung
The lung is the essential respiration organ in many air-breathing animals. In mammals the two lungs are located near the backbone on either side of the heart. Their principal function is to transport oxygen from the atmosphere into the bloodstream, and to release carbon dioxide from the bloodstream into the atmosphere. A large surface area is needed for this exchange of gases, which is accomplished by the mosaic of specialized cells that form millions of tiny, exceptionally thin-walled air sacs called alveoli. Lung cells include, but are not limited to, type I pneumocytes, type II pneumocytes, clara cells and goblet cells. Lung tissue degeneration-related diseases, conditions or disorders include, but are not limited to, Asthma, Chronic obstructive pulmonary disease (COPD), Chronic bronchitis, Emphysema, Cystic fibrosis, Pulmonary edema, Acute respiratory distress syndrome (ARDS), Pneumoconiosis, Interstitial lung disease (ILD), Sarcoidosis, Idiopathic pulmonary fibrosis, Pulmonary embolism (PE), Pulmonary hypertension, Pleural effusion, Pneumothorax, Mesothelioma, Granulomatosis with polyangiitis (GPA), Goodpasture syndrome (GPS), Pulmonary hyperplasia, Infant respiratory distress syndrome (IRDS), Chronic obstructive pulmonary disease (COPD), Silicosis, Sleep Apnea, Severe Acute Respiratory Syndrome (SARS), Pulmonary fibrosis, Primary ciliary dyskinesia (PCD), Pneumoconiosis (Black Lung Disease), Hypersensitivity Pneumonitis, Cryptogenic Organizing Pneumonia (Bronchiolitis Obliterans Organizing Pneumonia (BOOP)), Byssinosis, Bronchopulmonary Dysplasia, Bronchiolitis, Bronchiectasis, Asbestosis, Pertussis, Middle Eastern Respiratory Syndrome (MERS), Pneumonia, Tuberculosis, Bronchitis, Histoplasmosis, Coccidioidomycosis (Cocci), or Acute bronchitis.
The present invention thus provides compounds, compositions, microenvironments, functionalised bioactive carriers, medical devices, kits, methods and processes for the design, preparation, manufacture and/or formulation of such compounds, compositions, functionalised bioactive carriers, medical devices and kits, and methods and uses thereof for regenerating or recoding mammalian tissues.
Cellular differentiation is the process by which a cell type becomes specialized, and involves a highly controlled switch from one gene expression pattern to another. In each specific lineage, cells progress through various stages of differentiation and maturation. In the case of bone lineage, osteoblast progenitors are derived from adult bone marrow mesenchymal stem cells, followed by osteoblast precursors, mature osteoblasts and osteocytes.
Mesenchymal stem cells or MSCs are multipotent stromal cells that can differentiate into a variety of cell types including osteoblasts (bone cells), chondrocytes (cartilage cells), neurons, endothelial cells and adipocytes (fat cells). Growth factors generally modulate MSC activity through non-covalent binding to specific receptors called growth factor receptors (GFRs). Growth factors (GF) bind to serine-threonine kinase receptors on the cell surface, triggering specific intracellular pathways that activate and influence gene transcription, having effects in cell proliferation and/or differentiation. There are three or more receptors (types I, II and Ill) for GF members but only types I and II are required for binding and signalling. After binding of signal molecule, receptors are activated which leads into induction of SMAD pathway. Type I receptors phosphorylate receptor-regulated Smads (R-Smads) which form a complex with common-partner Smad (Co-Smad). This complex is translocated into the nucleus and modulates gene transcription with other transcription factors required for chondrogenic differentiation.
Modulation of such an activity may typically be performed using recombinant growth factors. However, studies indicated that prior attempts using this technology, for instance, in the field of spinal fusion, may be harmful to the patient treated and lead in certain cases to the development of tumors and other serious side-effects. The real clinical advantage over previously employed technics not involving the use of recombinant growth factors may also be questioned.
Other attempts to induce tissue formation involve the use of synthetic peptides reproducing parts of the natural sequences of growth factors. For example, these synthetic peptides have been studied for their potential use in improving bone repair. However, these peptides generally often lack sufficient biological activity and suffer from poor in-vitro and/or in-vivo stability. Furthermore, the tissue-induction activity of conventional synthetic peptides is not rapid. For example, in-vitro osteogenic differentiation of mesenchymal stem cells cultured on biomaterials using such conventional peptides is generally observed after 3 weeks of cell culture.
The present invention thus provides embodiments for:
I. Definitions
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the invention described herein. The scope of the present invention is not intended to be limited to the present description, but rather is as set forth in the appended claims.
In the claims, articles such as “a”, “an”, and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
It is also noted that the term “comprising” is intended to be open and permits but does not require the inclusion of additional elements or steps. When the term “comprising” is used herein, the terms “consisting of”, “consisting essentially of”, “consisting substantially of” and “consisting exclusively of” are thus also encompassed and disclosed.
As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise indicated, self-evident or contradictory in context (e.g. except where such number would exceed 100% of a possible value).
As used herein and unless otherwise indicated or contradictory in context, the term “with” followed by a specific number of amino acids, when used to define a particular peptide, variant or analog thereof, such as in “a peptide with three amino acids”, means that such peptide, variant or analog thereof, contains exclusively the specific number of amino acids specified after this term.
As used herein and unless otherwise indicated or contradictory in context, the term “Ci-alkyl” is intended to specifically and individually disclose any branched or unbranched radical, moiety or functional group having “i” carbon atom(s).
The carbon atom content of the various hydrocarbon-containing moieties herein may be indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety. For example, in certain embodiments, (Ca-Cb)alkyl indicates an alkyl moiety of the integer “a” to the integer “b” carbon atoms, inclusive.
At various places in the present specification, substituents of compounds of the present disclosure may be disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual sub-combination of the members of such groups and ranges. For example, in certain embodiments, the term “C1-C5 alkyl” is an abbreviation for (and thus is specifically intended to individually disclose) C1-alkyl (i.e. methyl), C2-alkyl (i.e. ethyl), C3-alkyl (i.e. 1-propyl and 2-propyl), C4-alkyl (i.e. 1-butyl, sec-butyl, iso-butyl and tert-butyl), and C5-alkyl (i.e. 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl and 1,1-dimethyl-1-propyl).
As used herein, unless indicated otherwise or contradictory in context, the terms “alkyl” and “(Ca-Cb)alkyl” refer to monovalent hydrocarbon radicals containing the requisite number of carbon atoms as described above, having straight or branched moieties or combinations thereof. As used herein, alkyl groups may be optionally substituted with between one to four substitutes. Non-limiting examples of alkyl groups include, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, etc. Of course, other alkyl groups will be readily apparent to those of skilled in the art given the benefit of the present disclosure.
Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. For example, in certain embodiments, a disclosed 0-10 range would, for example, in certain embodiments, also specifically and individually disclose the following values and ranges: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 0-1, 0-2, 0-3, 0-4, 0-5, 0-6, 0-7, 0-8, 0-9, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 5-6, 5-7, 5-8, 5-9, 5-10, 6-7, 6-8, 6-9, 6-10, 7-8, 7-9, 7-10, 8-9, 8-10, 9-10, 0-0.1, 0-0.2, 0-0.3, 0-0.4, 0-0.5, 0-0.6, 0-0.7, 0-0.8, 0-0.9, 0-1.1, 0-1.2, etc.
As used herein and unless otherwise indicated or contradictory in context, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.
In addition, it is to be understood that any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims using the appropriate disclaimer(s) or proviso(s). Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the invention (e.g., any nucleic acid or protein encoded thereby; any method of production; any method of use; etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art.
All cited sources, for example, in certain embodiments, references, publications, databases, database entries, and art cited herein, are incorporated into this application by reference in their entirety, even if not expressly stated in the citation. In case of conflicting statements of a cited source and the instant application, the statement in the instant application shall control.
As the case may be, and unless otherwise indicated or contradictory in context, macromolecules molecular weights should be understood in the present description as being number averaged molecular weights.
The peptides mentioned in the present description may not follow the usual representation conventions. For instance, the N-terminal amino acid of a peptide sequence may be the first amino acid in the sequence or the last amino acid. Likewise, the C-terminal amino acid of a peptide sequence may be the first amino acid in the sequence or the last amino acid. For example, in the peptide sequence NAIS (SEQ ID NO: 6357), “N” may be N-terminal or C-terminal, and “S” may be N-terminal or C-terminal. Consequently, for the purpose of the present disclosure, e.g. NAIS (SEQ ID NO: 6357) also covers SIAN (SEQ ID NO: 6607), SAIS (SEQ ID NO: 6360) also covers SIAS (SEQ ID NO: 6608), SPIN (SEQ ID NO: 6363) also covers NIPS (SEQ ID NO: 6609), etc.
In the present application, when reference is made to a certain peptide (e.g. a GFR-binding compound as provided herein) comprising one or more other peptide(s), said one or more other peptide(s) is(are) understood to be stably (in most cases, covalently) attached/bound to at least one part of said peptide. The attachment/binding may be located anywhere on the peptide unless indicated otherwise, contradictory in context or contradictory to general scientific rules. No specific attachment/binding location of said one or more other peptide(s) to said peptide shall be assumed unless specifically mentioned.
Peptide or polypeptide: As used herein, the term “peptide” or “polypeptide” are used interchangeably and refers to a polymer of less than or equal to 100 amino acids long, e.g., about 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 amino acids long. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers, non-naturally occurring amino acid polymers, peptide analogs, peptide variants and peptide mimetics. Conventional techniques for synthesising peptides involve the activation of the carboxylic acid function of an amino acid or of a peptide, using a coupling agent. This activated acid is then contacted with an amino acid or a peptide in which the N-terminal amino acid is not protected, thus forming an amide bond also called peptide bond. Coupling reaction conditions together with coupling agents are well known in the art and described, for instance, in Greene, “Protective Groups in Organic Synthesis”, Wiley, New York, 2007 4th edition. In addition, suitable peptide synthesis routes are described, for instance, in Hojo H., Recent progress in the chemical synthesis of proteins, Curr Opin Struct Biol. 2014; 26C:16-23 and Saranya Chandrudu, et al., Chemical Methods for Peptide and Protein Production, Molecules, 2013, 18, 4373-4388, each of which is incorporated herein by reference in its entirety. There are two main strategies for peptide synthesis i.e. liquid-phase peptide synthesis and solid-phase peptide synthesis (SPPS) which is now most commonly used for peptide synthesis. Instead of C-terminal protection with a chemical group, the C-terminus of the first amino acid is coupled to an activated solid support, such as polystyrene or polyacrylamide. This type of approach has a two-fold function: the resin acts as the C-terminal protecting group and provides a rapid method to separate the growing peptide product from the different reaction mixtures during synthesis. As with many different biological manufacturing processes, peptide synthesizers have been developed for automation and high-throughput peptide production. SPPS allows the synthesis of natural peptides which are difficult to express in bacteria, the incorporation of unnatural amino acids, peptide/protein backbone modification, and the synthesis of D-proteins, which consist of D-amino acids. Very long peptide can be accessed by using native chemical ligation to couple two peptides together with quantitative yields.
Peptide analogs: As used herein, unless indicated otherwise or contradictory in context, the term “peptide analogs” refers to polypeptide variants which differ by one or more amino acid alterations, e.g., substitutions, additions or deletions of amino acid residues that still maintain one or more of the properties of the parent or starting peptide.
Peptide variants: As used herein, unless indicated otherwise or contradictory in context, the term “peptide variants” refers to a peptide which has a certain identity with a native or reference compound sequence. In one example, the peptide variant refers to any post—administration, application, injection modified peptide. Such post—administration, application, injection modifications include, but are not limited to, phosphorylation, acetylation, glutamylation, tyrosination, palmitoylation, glycosylation, myristoylation, palmitoylation, isoprenylation, glypiation, lipoylation, phosphopantetheinylation, acylation, alkylation, amidation, arginylation, polyglutamylation, polyglycylation, butyrylation, gamma-carboxylation, glycosylation, polysialylation, malonylation, hydroxylation, iodination, nucleotide addition, oxidation, adenylylation, propionylation, pyroglutamate formation, S-glutathionylation, S-nitrosylation, succinylation, sulfation, glycation, biotinylation, pegylation, ISGylation, SUMOylation, ubiquitination, Neddylation, Pupylation, citrullination, deamidation, eliminylation, carbamylation, and racemization.
Peptido-mimetic: As used herein, unless indicated otherwise or contradictory in context, the term “peptido-mimetic” or “peptidomimetic” refers to a synthetic chemical compound which comprises amino acids but not only and that is able to mimic the biological action of a peptide, often because the mimetic has a basic structure that mimics the basic structure of the peptide and/or has the salient biological properties of that peptide. In one particular example, a peptidomimetic is a hybrid molecule containing both, at least one peptide, and at least one of a polysaccharide, a polynucleotide or a linear or branched, saturated or unsaturated, hydrocarbon chain.
Linear peptide: As used herein, unless indicated otherwise or contradictory in context, the term “linear peptide” means a peptide in which the C-terminal and the N-terminal amino acid residues do not covalently interact with each other and none of the C-terminal or the N-terminal amino acid residues covalently interacts with another amino acid residue of the peptide chain.
Cyclic peptide: As used herein, unless indicated otherwise or contradictory in context, the term “cyclic peptide” means peptide in which the C-terminal and N-terminal amino acid residues do covalently interact with each other or the C-terminal and/or the N-terminal amino acid residues covalently interact with at least one other amino acid residue of the peptide chain so as to form a ring-like structure.
Amino acid: As used herein, unless indicated otherwise or contradictory in context, the term “amino acid” refers to naturally occurring and non-naturally occurring amino acids including amino acid analogs. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, [gamma]-carboxyglutamate, and O-phosphoserine. Naturally encoded amino acids are the 20 common amino acids glycine (Gly, G), alanine (Ala, A), valine (Val, V), leucine (Leu, L), isoleucine (Ile, I), serine (Ser, S), threonine (Thr, T), phenylalanine (Phe, F), tyrosine (Tyr, Y), tryptophane (Trp, W), cysteine (Cys, C), methionine (Met, M), proline (Pro, P), aspartic acid (Asp, D), asparagine (Asn, N), glutamine (Gln, Q), glutamic acid (Glu, E), histidine (His, H), arginine (Arg, R) et lysine (Lys, K) and pyrrolysine and selenocysteine. Non-naturally occurring amino acids include, but are not limited to, the dextrogyre (D) isomers of the above-cited naturally-occurring amino acids. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid i.e., an [alpha] carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group (i.e. side chain), and which may be used in replacement thereof without substantially affecting the overall function of the peptide to which it belongs. Amino acid analogs (or non-naturally occurring amino acids) that may be suitable for implementing embodiments of the present invention include, but are not limited to, amino acids comprising a photoactivatable cross-linker, spin-labeled amino acids, fluorescent amino acids, metal binding amino acids, metal-containing amino acids, radioactive amino acids, amino acids with novel functional groups, amino acids that covalently or noncovalently interact with other molecules, photocaged and/or photoisomerizable amino acids, amino acids comprising biotin or a biotin analogue, glycosylated amino acids such as a sugar substituted serine, other carbohydrate modified amino acids, keto-containing amino acids, amino acids comprising polyethylene glycol or polyether, heavy atom substituted amino acids, chemically cleavable and/or photocleavable amino acids, amino acids with an elongated side chains as compared to natural amino acids, including but not limited to, polyethers or long chain hydrocarbons, including but not limited to, greater than about 5 or greater than about 10 carbons, carbon-linked sugar-containing amino acids, redox-active amino acids, amino thioacid containing amino acids, and amino acids comprising one or more toxic moiety. The term “AA1−” (AA roman numeral one) may be used in the description and refers to an amino acid which may be any amino acid as defined above in particular any naturally occurring and non-naturally occurring amino acids.
Amino acid side chain: As used herein, unless indicated otherwise or contradictory in context, the term “amino acid side chain” means the functional group of an amino acid that differentiates it from other amino acids. All amino acid structures have a carboxyl group, an amine group and a specific side chain.
AAII (AA roman numeral two): As used herein, unless indicated otherwise or contradictory in context, the terms “polar amino acid” or “AAII” means amino acids having a polar, non-charged group-containing side chain. Polar amino acids are protonated at physiological pH (about 7). Examples of polar amino acids include, but are not limited to, Cys (C), Asn (N), Gln (Q), Ser (S), Thr (T), or Tyr (Y).
AAIII (AA roman numeral three): As used herein, unless indicated otherwise or contradictory in context, the terms “acidic amino acid” or “AAIII” means amino acids having an acidic group-containing side chain. Acidic amino acid deprotonated forms predominate at physiological pH (about 7). Examples of acidic amino acids include, but are not limited to, Asn (N) and Glu (E).
AAIV (AA roman numeral four): As used herein, unless indicated otherwise or contradictory in context, the terms “aliphatic amino acid” or “AAIV” means amino acids having an aliphatic side chain. Examples of aliphatic amino acids include, but are not limited to, Ala (A), Leu (L), Ile (I), Gly (G), Val (V) and any analogs and derivatives thereof.
AAV (AA roman numeral five): As used herein, unless indicated otherwise or contradictory in context, the terms “apolar amino acid” or “AAV” means amino acids having an apolar side chain. Examples of apolar amino acids include, but are not limited to, Ala (A), Phe (F), Gly (G), Ile (I), Leu (L), Met (M), Pro (P), Val (V) or Trp (W).
AAVI (AA roman numeral six): As used herein, unless indicated otherwise or contradictory in context, the term “aromatic amino acid” or “AAVI” means amino acids having an aromatic group-containing side chain. Examples of aromatic amino acids include, but are not limited to, Trp (W), Tyr (Y) or Phe (F).
AAVII (AA roman numeral seven): As used herein, unless indicated otherwise or contradictory in context, the term “basic amino acid” or “AAVII” means amino acids having a basic group-containing side chain. Basic amino acid protonated forms predominate at physiological pH (about 7). Examples of basic amino acids include, but are not limited to, Arg (R), His (H), or Lys (K).
AAVIII (AA roman numeral eight): As used herein, unless indicated otherwise or contradictory in context, the term “AAVIII” means Leu (L) or Ile (I) and any analogs and derivatives thereof.
AAIX (AA roman numeral nine): As used herein, unless indicated otherwise or contradictory in context, the term “charged amino acid” or “AAIX” means amino acids having either an acidic group-containing side chain or an basic group-containing side chain. Charged amino acid charged forms predominate at physiological pH (about 7). Examples of charged amino acids include, but are not limited to, Asn (N), Glu (E), His (H), Lys (K) or Arg (R).
AAn: As used herein, unless indicated otherwise or contradictory in context, the term “AAn”, in which n is a positive integer arbitrarily chosen to identify a specific position within the primary sequence of a peptide. For instance, AA13 means the amino acid of position 13. The terms “amino acid” and “AA” are interchangeably used in the present description.
N-terminal: As used herein, unless indicated otherwise or contradictory in context, the term “N-terminal” means the amine (—NH2) function/group/moiety located at one (terminal) end of a protein or polypeptide. This functional group is the only amine group which is not engage in n amide peptide bond.
C-terminal: As used herein, unless indicated otherwise or contradictory in context, the term “C-terminal” means the carboxylate (—CO2H) function/group/moiety located at one (terminal) end of a protein or polypeptide. This functional group is the only carboxylic acid group which is not engage in n amide peptide bond.
Naturally-occurring peptide: As used herein, unless indicated otherwise or contradictory in context, the terms “naturally-occurring peptide” or “natural peptide” means a peptide which may be found in nature without human direct intervention (except for its extraction and/or isolation).
Synthetic peptide: As used herein, unless indicated otherwise or contradictory in context, the terms “synthetic peptide” or “non-natural peptide” means a peptide which may not be found in nature without human direct intervention (except for its extraction and/or isolation). For example, in certain embodiments, a synthetic peptide may have the amino acid sequence of a natural peptide except for at least one amino acid deletion or substitution relative to the natural sequence. In the case of a substitution, an amino acid from the natural sequence is replaced by another, different, naturally-occurring or non-naturally occurring amino acid. For example, in certain embodiments, a synthetic peptide may not possess a post-translational modification of the natural peptide such as the attachment of an acetate group, a phosphate group, a lipid, a carbohydrate, or the formation of a disulfide bridge.
Covalent Interaction: As used herein, unless indicated otherwise or contradictory in context, the term “interact covalently”, “covalent interaction” or “covalent bond” are interchangeably used and means a chemical bond or interaction that involves the sharing of electron pairs between atoms. Examples of such interactions are σ-bonding and π-bonding.
Non-covalent Interaction: As used herein, unless indicated otherwise or contradictory in context, the term “interact non-covalently”, “non-covalent interaction” or “non-covalent bond” are interchangeably used and means a chemical bond or interaction that does not involve the sharing of electron pairs between atoms but rather involves more dispersed variations of electromagnetic interactions between molecules or within a molecule. Non-covalent interactions can be generally classified into four categories, electrostatic interactions, π-interactions, van der Waals forces, and hydrophobic interactions.
Electrophile: As used herein, unless indicated otherwise or contradictory in context, the term “electrophile” means an organic molecule attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile. Most electrophiles are positively charged, have an atom that carries a partial positive charge, or have an atom that does not have an octet of electrons.
Nucleophile: As used herein, unless indicated otherwise or contradictory in context, the term “nucleophile” means an organic molecule that donates an electron pair to an electrophile to form a chemical bond in relation to a reaction. All molecules or ions with a free pair of electrons or at least one pi bond can act as nucleophiles.
Polysaccharide: As used herein, unless indicated otherwise or contradictory in context, the term “polysaccharide” means polymeric carbohydrate molecules composed of long chains of monosaccharide units bound together by glycosidic linkages and which upon hydrolysis provide monosaccharides or oligosaccharides. They range in structure from linear to highly branched polymers.
Polynucleotide: As used herein, the term “polynucleotide” or “nucleic acid”, which are used interchangeably, refers to the phosphate ester polymeric form of ribonucleosides (“RNA molecules”) or deoxyribonucleosides (“DNA molecules”), or any phosphoester analogs thereof, such as phosphorothioates and thioesters, in either single stranded form, or a double-stranded helix. The term “nucleic acid” includes double-stranded DNA round, inter alia, in linear (e.g., restriction fragments) or circular DNA molecules. In particular, nucleic acids as used herein refer to nucleic acids such as RNAs encoding for agonist of growth factor receptors as defined herein.
Nucleoside: As used herein, the term “nucleoside” refers to a compound containing a sugar molecule (e.g., a pentose or ribose) or derivative thereof in combination with an organic base (e.g., a purine or pyrimidine) or a derivative thereof (also referred to herein as “nucleobase”).
Nucleotide: As used herein, the term “nucleotide” refers to a nucleoside including a phosphate group.
Dendrimer: As used herein, unless indicated otherwise or contradictory in context, the term “dendrimer” means any repetitively branched molecules. Examples of dendrimers are phosphorous dendrimers, polylysine dendrimers, polypropylenimine dendrimers and PAMAM dendrimers, such as the ones described, for instance, in Scientific World Journal. 2013; 2013:732340; Curr Opin Chem Biol. 1998; 2(6):733-42; J Pept Sci. 1999; 5(5):203-20; and J Pept Sci. 2008; 14(1):2-43, which may be used for implementing embodiments of the present invention, each of which being herein incorporated by reference in its entirety.
Synthetic molecule: As used herein, unless indicated otherwise or contradictory in context, the term “synthetic molecule” means a molecule which may not be found in nature without human direct intervention (except for its extraction and/or isolation).
Synthetic polymers: As used herein, unless indicated otherwise or contradictory in context, the term “synthetic polymer” refers to a macromolecule or polymer which may not be found in nature without human direct intervention (except for its extraction and/or isolation).
Biocompatible: As used herein, unless indicated otherwise or contradictory in context, the term “biocompatible” means compatible with living cells, tissues, organs or systems posing little to no risk of injury, toxicity or rejection by the immune system.
Biologically active: As used herein, unless indicated otherwise or contradictory in context, the term “biologically active” refers to a characteristic of any substance that has activity in a biological system and/or organism. For instance, a substance that, when administered to an organism, has a biological effect on that organism, is considered to be biologically active. In particular examples, a compound, substance or pharmaceutical composition of the present disclosure may be considered biologically active even if a portion of the compound, substance or pharmaceutical composition is biologically active or mimics an activity considered biologically relevant.
Stem cells: As used herein, unless indicated otherwise or contradictory in context, the term “stem cell” refers to the term as it is generally understood in the art. For example, in certain embodiments, stem cells, regardless of their source, are cells that are capable of dividing and renewing themselves for long periods, are at least to a degree unspecialized (undifferentiated), and can give rise to (differentiate into) specialized cell types (i.e., they are progenitor or precursor cells for a variety of different, specialized cell types).
Mesenchymal stem cells: As used herein, unless indicated otherwise or contradictory in context, the term “mesenchymal stem cells” generally means multipotent adult stromal cells that can differentiate into a variety of cell types, such as osteoblasts, chondrocytes, and adipocytes.
Stem cell-like: As used herein, unless indicated otherwise or contradictory in context, the term “Stem cell-like” refers to a cell which is not a stem cell by its origin but functions as a stem cell and presents similar characteristics such as, for example, the expression of stemness markers like Stro-1 and/or is multipotent thus has the ability to differentiate into various cell types.
Progenitor cells: As used herein, unless indicated otherwise or contradictory in context, the term “progenitor cells” generally means a biological cell that, like any stem cell, has a tendency to differentiate into a specific type of cell, but is already more specific than a stem cell and is pushed to differentiate into its “target” cell. Stem cells can generally replicate indefinitely, whereas progenitor cells can divide only a limited number of times.
Adult stem cells: As used herein, unless indicated otherwise or contradictory in context, the term “adult stem cells” means undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells, they can be found in juvenile as well as adult animals and human bodies.
Differentiation: As used herein, unless indicated otherwise or contradictory in context, the term “differentiation” refers to the process by which a less specialized cell becomes a more specialized cell type and involves a switch from one gene expression pattern to another.
Differentiated cells: As used herein, unless indicated otherwise or contradictory in context, the term “differentiated cells” generally means any cell of a specific lineage at the exception of cells containing stem cell specific markers.
Non-terminally differentiated: As used herein, unless indicated otherwise or contradictory in context, the term “non-terminally differentiated”, when used in relation to a cell, refers to a differentiated cell as defined herein which has not reached its final state of differentiation. For example, in certain embodiments, in the Osteoblast cell lineage, a non-terminally differentiated cell is any differentiated cell of the lineage at the exception of an osteocyte.
Terminally differentiated: As used herein, unless indicated otherwise or contradictory in context, the term “terminally differentiated”, when used in relation to a cell, refers to a differentiated cell as defined herein which has reached its final state of differentiation. For example, in certain embodiments, in the Osteoblast cell lineage, a terminally differentiated cell is an osteocyte.
Methods for obtaining stem cells: Methods for obtaining such stem cells and providing initial culture conditions, such as a liquid culture or semi-solid culture medium, are known in the art. The cells are initially expanded in vivo or in vitro, by contacting the source of the stem cells with a suitable reagent that expands or enriches such cells in the tissue source or in culture. Preferably, adult stem cells are isolated from a tissue source and then expanded or enriched in vitro by exposure to a suitable agent. Cells are obtained from an individual by any suitable method for obtaining a cell sample from an animal, including, but not limited, to, collection of bone marrow collection of a bodily fluid (e.g., blood), collection of umbilical cord blood, tissue punch, and tissue dissection, including particularly, but not limited to, any biopsies of skin, intestine, cornea, spinal cord, brain tissue, scalp, stomach, breast, lung (e.g., including lavage and bronchioschopy), fine needle aspirates of the bone marrow, amniotic fluid, placenta and yolk sac.
Osteogenesis: As used herein, unless indicated otherwise or contradictory in context, the term “osteogenesis” refers to the process by which bone is produced. An entity, molecule, compound, association, combination or composition may be said to be “osteogenic” when it has an effect on the development, growth, or repair of bone. This process involves the participation of stem cells.
Chondrogenesis: As used herein, unless indicated otherwise or contradictory in context, the term “chondrogenesis” refers to the process by which cartilage is produced. An entity, molecule, compound, association, combination or composition may be said to be “chondrogenic” when it has an effect on the development, growth, or repair of cartilage. This process involves the participation of stem cells.
Endothelialization: As used herein, unless indicated otherwise or contradictory in context, the term “endothelialization” or “re-endothelialization” refers to the process that maintains or restores normal vascular homeostasis and regulates neointimal hyperplasia. In native tissue, the endothelium maintains vessel integrity with dynamic mechanisms that prevent thrombosis and intimal hyperplasia. The endothelial progenitor cells are an important component of the response to vascular injury, having the potential to accelerate vascular repair through rapid re-endothelialization. For example, drug-eluting stents are generally implanted during angioplasty into patients suffering from atherosclerosis and resulting in stenosis or restenosis. In drug-eluting stents, the drug is typically coated onto a metal alloy framework and is mainly employed to inhibit neointimal growth (due to proliferation of smooth muscle cells) which would cause restenosis. Because much of the neointimal hyperplasia seems to be caused by inflammation, immunosuppressive and antiproliferative drugs are conventionally used. Drugs such as sirolimus and paclitaxel are currently used. Re-endothelialization in drug-eluting stents is generally delayed which can increase the risk for late stent thrombosis which thus may also require the administration of antiplatelet drugs such as Clopidogrel and aspirin.
Vascularization/angiogenesis: As used herein, unless indicated otherwise or contradictory in context, the term “vascularization/angiogenesis” refers to a physiological process through which new blood vessels are produced from pre-existing vessels. This process involves the participation of stem cells.
Wound healing: As used herein, unless indicated otherwise or contradictory in context, the term “wound healing” refers to a process whereby the skin (or another organ-tissue) repairs itself after injury. This process involves the participation of stem cells.
Skin repair: As used herein, unless indicated otherwise or contradictory in context, the term “skin repair” means the reparation of the dermis through the participation of stem cells. These active cells produce collagenous fibers and ground substance. Blood vessels soon grow into the dermis, restoring circulation.
Neuron-regeneration: As used herein, unless indicated otherwise or contradictory in context, the term “neuron-regeneration” or “neuroregeneration” refers to the regrowth or repair of nervous tissues, cells or cell products involving the participation of stem cells. Such mechanisms may include generation of new neurons, glia, axons, myelin, or synapses.
Tissue closure: As used herein, unless indicated otherwise or contradictory in context, the term “tissue closure” refers to the closure of all tissue layers damaged e.g. in an injury or during surgery. For instance, during bone repair surgery, the different layers of tissues incised in order for the surgeon to reach the damaged bone part and repair it would all need to be closed for the overall healing process to occur.
Cell lineage: As used herein, unless indicated otherwise or contradictory in context, the term “cell lineage” refers to the developmental history of a particular cell from its primary state in the fertilized egg or embryo through to its fully differentiated state. The different steps and phases involved in the development of a cell produces many intermediate cells which may be referred to as progenitor or precursor cells in the present application and form an integral part of the cell lineage.
Osteoblast cell lineage: As used herein, unless indicated otherwise or contradictory in context, the term “osteoblast cell lineage” refers to bone cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, osteoblasts, osteocytes or any precursors thereof.
Chondrocytic cell lineage: As used herein, unless indicated otherwise or contradictory in context, the term “chondrocytic cell lineage” refers to cartilage cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells,
Muscle cell lineage: As used herein, unless indicated otherwise or contradictory in context, the term “muscle cell lineage” refers to muscle cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, myoblasts, myocytes or any precursors thereof.
Vascular cell lineage: As used herein, unless indicated otherwise or contradictory in context, the term “vascular cell lineage” refers to vascular cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, angioblast, pericytes and endothelial cells or any precursors thereof.
Neuronal cell lineage: As used herein, unless indicated otherwise or contradictory in context, the term “neuron lineage” refers to brain cells at any stage of their development and thus include, but are not limited to, neural stem cells, neuroblast, neurocyte and neuroglial cells or any precursors thereof.
Retinal cell lineage: As used herein, unless indicated otherwise or contradictory in context, the term “retinal cell lineage” refers to eye retina cells at any stage of their development and thus include, but are not limited to, photoreceptor, bipolar cells, rod and cone cells or any precursors thereof.
Renal cell lineage: As used herein, unless indicated otherwise or contradictory in context, the term “renal cell lineage” refers to renal cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, podocytes, or any precursors thereof.
Ligament and tendon cell lineage: As used herein, unless indicated otherwise or contradictory in context, the term “ligament and tendon cell lineage” or “L/T cell lineage” refers to bone or cartilage cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, fibroblasts, fibrocytes, or any precursors thereof.
Fibroblast lineage: As used herein, unless indicated otherwise or contradictory in context, the term “fibroblast lineage” refers to skin cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, fibroblasts, keratinocytes, Merkel cells, melanocytes, Langerhans cells, and any precursor cells thereof.
Reproduction system lineage: As used herein, unless indicated otherwise or contradictory in context, the term “reproduction system lineage” refers to Sertoli cells, Leydig cell and Germ cell at any stage of their development, in particular, mesenchymal stem cells.
Blood cell lineages (myeloid lineage and lymphoid lineage): As used herein, unless indicated otherwise or contradictory in context, the term “blood cell lineages” refers to blood cells at any stage of their development from the myeloid or from the lymphoid lineage, and thus include, but are not limited to, hematopoietic stem cells (HSC), myeloid progenitors, lymphoid progenitors, mast cells, myeloblasts, monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes, thrombocytes, dendritic cells, small lymphocytes, T-lymphocytes (T-cells), B-lymphocytes (B-cells), natural killer (NK)-cells, and any precursor cells thereof.
Adipocyte lineage: As used herein, unless indicated otherwise or contradictory in context, the term “adipocyte cell lineage” refers to adipocyte cells at any stage of their development and thus include, but are not limited to, mesenchymal stem cells, areolar connective cells, adipocytes, pre-adipocytes/lipoblasts, and any precursor cells thereof.
Lung cell Lineages: As used herein, unless indicated otherwise or contradictory in context, the term “lung cell Lineage” refers to lung cells at any stage of their development and thus include, but are not limited to, epithelial cells, erythrocytes, alveolar cells and any precursor cells thereof.
Ratio: As used herein, unless indicated otherwise or contradictory in context, the term “ratio”, when used in relation to GFR-binding compound with respect to the bioactive carrier in the pharmaceutical association or composition disclosed herein, refers to the (molar, weight or part as specified) ratio between the quantity of GFR-binding compound and the quantity of bioactive carrier. The ratio may be a molar ratio, a weight ratio or a part ratio and will be specified as needed on a case by case basis. Quantity units may conventionally be mole, millimole, gram, milligram or parts. For example, in certain embodiments, it is convenient to express the relative quantity between GFR-binding compounds and bioactive carriers using densities. It shall be understood that this ratio may be varied according to the cell type to be treated.
Density: As used herein, unless indicated otherwise or contradictory in context, the term “density”, when used in relation to GFR-binding compound with respect to the bioactive carrier in the pharmaceutical composition disclosed herein, refers to the quantity of GFR-binding compounds, expressed in e.g. mole, millimole, gram, or milligram, with respect to one standardised surface unit e.g. squared millimetre (mm2), squared micrometre (μm2), or squared nanometre (nm2)). For example, in certain embodiments, the ratio between a GFR-binding compound and a bioactive carrier in the pharmaceutical association or composition disclosed herein may be expressed in pmol per mm2 or pmol/mm2.
Recoding: As used herein, unless indicated otherwise or contradictory in context, the term “recoding”, when used in relation to a cell (in particular a mesenchymal stem cell or progenitor stem cell), refers to the action of contacting (in-vitro, ex-vivo or in-vivo) a stem cell to be treated with a suitable extracellular micro-environment (e.g. containing a peptide, variant or analog thereof, peptidomimetic, a biomaterial, a medical device, or a medical or cosmetic composition as defined herein) thus providing appropriate extracellular signals so that the cell may undergo efficient differentiation into a more specialised cell type.
Recoding therapy: As used herein, unless indicated otherwise or contradictory in context, the term “recoding therapy” refers to a therapy that promotes efficient stem cell differentiation in an aim to regenerate mammalian tissues.
Extracellular micro-environment: As used herein, unless indicated otherwise or contradictory in context, the term “extracellular micro-environment” refers to the environment surrounding (in functional proximity with) a specific stem cell which is characterized by biophysical, mechanical and biochemical properties specific for each tissue and is able to regulate cell behavior. Modification of the extracellular micro-environment of a specific mesenchymal stem cell using, for instance, a peptide, variant or analog thereof, peptidomimetic, a biomaterial, a medical device, or a medical or cosmetic composition as defined herein, allows for the efficient differentiation of this cell into a more specialised cell type.
Physiologically functional cell: As used herein, unless indicated otherwise or contradictory in context, the term “physiologically functional cell” refers to a cell which is able to perform normally all of the cell functions associated with a particular cell type and necessary for the normal physiology of a cell. These functions include all of the intracellular molecular mechanisms but also all of the activities necessary for a normal communication between the cell and its microenvironment. One method which may be used to verify if a cell is physiologically functional is the grafting of the cell, after the introduction of fluorescent markers, in other mammalian model organisms such as mouse models. The cell is grafted in the tissue corresponding to its cell type. The cell characteristics and normal functions are monitored after a period of time with various methods such as in vivo microscopy or histological staining. The term “functional” when used in relation to a molecule, compound or substance refers to a biological molecule in a form in which it exhibits a property and/or activity by which it is characterized.
Shorter period of time: As used herein, unless indicated otherwise or contradictory in context, the term “shorter period of time”, when used in relation to differentiation or recoding duration, means substantially shorter to provide a substantial benefit for the treated patient in comparison with existing treatments. In certain embodiments, a shorter period of time includes at least 1.5-fold, at least 2-fold, at least 2.5-fold, at least 3-fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold or at least 10-fold reduction with respect to an existing treatment.
Exogenous: As used herein, unless indicated otherwise or contradictory in context, the term “exogenous” refers to a substance coming from outside a living system such as a cell, an organ, or an individual organism. For example, in certain embodiments, exogenous factors in medicine include pathogens and therapeutics. DNA introduced into a cell via transfection or viral infection may be considered as an exogenous factor. Carcinogens are also commonly referred to as exogenous factors.
Endogenous: As used herein, unless indicated otherwise or contradictory in context, the term “endogenous” refers to substances that originate from within an organism, tissue, or cell.
Intracellular: As used herein, unless indicated otherwise or contradictory in context, the term “intracellular” generally means “Inside the cell”. In vertebrates, such as animals, the cell membrane is the barrier between the inside of the cell and the outside of the cell (the extracellular milieu). Thus, treatments and therapies in which at least one substance, compound, pharmaceutical association, combination or composition penetrates the cell wall of a cell to be treated in order to produce/deliver its (effective) biological effect are considered as intracellular treatments and therapies.
Extracellular: As used herein, unless indicated otherwise or contradictory in context, the term “extracellular” means “outside the cell”. In vertebrates, such as animals, the cell membrane is the barrier between the inside of the cell (the intracellular milieu) and the outside of the cell. Thus, treatments and therapies in which no substance, compound, pharmaceutical association, combination or composition requires penetration of the cell membrane in order to produce/deliver its (effective) biological effect (e.g. by interacting with trans-membrane receptors) are considered as extracellular treatments and therapies. In other words, a therapy using a plurality of substances in order to provide the desired biological effect wherein one or more of these substances require the entry into the intracellular compartment to provide (or deliver) its biological effect is not considered as an extracellular therapy in the sense of the present disclosure.
In vitro: As used herein, unless indicated otherwise or contradictory in context, the term “in vitro” refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, in a Petri dish, etc., rather than within an organism (e.g., animal, plant, or microbe).
In vivo: As used herein, unless indicated otherwise or contradictory in context, the term “in vivo” refers to events that occur within an organism (e.g., animal, plant, or microbe or cell or tissue thereof).
Ex vivo: As used herein, unless indicated otherwise or contradictory in context, the term “ex vivo” refers to events that occur in an external environment on tissues sourced from an organism (e.g., animal, plant, or microbe) in an attempt to replicate natural living conditions outside such an organism.
Patient/subject: As used herein, unless indicated otherwise or contradictory in context, the term “patient” or “subject”, which are used interchangeably, refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans) and/or plants. As used herein, patients/subjects include those individuals who may seek or be in need of treatment, requires treatment, is receiving treatment, will receive treatment, or a subject who is under care by a trained professional for a particular disease or condition.
Purified: As used herein, unless indicated otherwise or contradictory in context, the term “purify,” “purified,” “purification” means to make substantially pure or clear from unwanted components, material defilement, admixture or imperfection.
Targeted Cells: As used herein, unless indicated otherwise or contradictory in context, the term “targeted cells” refers to any one or more cells of interest. The cells may be found in vitro, in vivo, in situ or in the tissue or organ of an organism. The organism may be an animal, preferably a mammal, more preferably a human and most preferably a patient.
Molecule length: As used herein, unless indicated otherwise or contradictory in context, the term molecule or peptide “length” or “size” means the longest 2D or 3D distance which may possibly be measured within the molecule. For cyclic molecules, “length” or “size” means the longest measurable distance across the cyclic structure. Throughout the present disclosure, when a molecule size or length is given (in general using the nanometre, nm, unit), the following procedures were used to calculate them:
Root Mean Square Deviation: As used herein, unless indicated otherwise or contradictory in context, the term “Root Mean Square Deviation” or “RMSD” is well known in the art and means the square root of the arithmetic mean of the square of the distances between certain matched atoms. One can represent a molecular conformation as a vector whose components are the Cartesian coordinates of the molecule's atoms. Therefore, a conformation for a molecule with N atoms can be represented as a 3N-dimensional vector of real numbers. To calculate the RMSD of a pair of peptides or peptidomimetics (e.g. x and y), each one of them must be represented as a 3N-length (assuming N atoms) vector of coordinates. The RMSD is therefore the square root of the arithmetic mean of the square of the distances between corresponding atoms of x and y. It is a measure of the average atomic displacement between the conformations of the two structures:
In other words, the RMSD is the measure of the average distance between the atoms (usually the backbone atoms) of superimposed polypeptides or peptidomimetics. In the study of globular protein conformations, one customarily measures the similarity in three-dimensional structure by the RMSD of the Ca atomic coordinates after optimal rigid body superposition.
The RMSD value of a given peptide or peptidomimetic with respect to a specifically selected reference structure (hereinafter may also be referred to as “PEPREF”) may be calculated using various methods all well know by the skilled person. However, for the purpose of the present disclosure and for the avoidance of doubts, the RMSD of a given peptide or peptidomimetic as used in the present disclosure is obtained precisely using the following procedure:
STEP 1: Creating a 3-dimensional model of (i.e. obtaining 3D structure coordinates for) a peptide or peptidomimetic for which the RMSD is to be calculated, by:
STEP 1.1: Obtaining a set of polypeptide 3D structure coordinates based on the alignment with the sequence of a peptide or peptidomometic for which the RMSD value is to be calculated, using the BLAST algorithm according to the following procedure:
The set of pdf files contains the polypeptide 3D structure coordinates of the 10 structures having the highest sequence homology with the peptide or peptidomometic for which the RMSD value is to be calculated.
STEP 1.2: Performing the structural alignment of the set of 3D structure coordinates obtained in STEP 1.1, thereby obtaining a set of aligned polypeptide 3D structure coordinates, by using STAMP (Structural Alignment of Multiple Proteins Version 4.2) according to the following procedure:
STEP 1.3: Modelling the sequence of peptide or peptidomometic for which the RMSD value is to be calculated against the set of aligned polypeptide 3D structure coordinates obtained in STEP 1.2, thereby obtaining a set of 3D structure coordinates for the peptide or peptidomometic for which the RMSD value is to be calculated, using SCWRL (reference: “SCWRL and MollDE: computer programs for side-chain conformation prediction and homology modeling”, Nature Protocols VOL3 NO. 12 2008, Qiang Wang et al.; which is hereby incorporated by reference in its entirety) according to the following procedure:
STEP 1.4: Minimizing the free energy (ΔG) of the set of 3D structure coordinates for the peptide or peptidomometic for which the RMSD value is to be calculated obtained in STEP 1.3 using GROMACS (Reference: Hess B, Kutzner C, Van Der Spoel D, Lindahl E (2008). “GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation”. J Chem Theory Comput 4 (2): 435; which is hereby incorporated by reference in its entirety) according to the following procedure:
STEP 2: Calculating the RMSD of the peptide or peptidomimetic for which the RMSD value is to be calculated by comparing the 3D structure coordinates of the peptide or peptidomimetic obtained in STEP 1.4 with the 3D structure coordinates of PEPREF to obtain the lowest possible RMSD value using FATCAT (Flexible structure AlignmenT by Chaining Aligned fragment pairs allowing Twists) according to the following procedure:
3D structure coordinates of PEPREF: As used herein, unless indicated otherwise or contradictory in context, the 3D structure coordinates of PEPREF are as follows:
Structure coordinates: As used herein, unless indicated otherwise or contradictory in context, the “structure coordinates” refers to Cartesian coordinates derived from mathematical equations related to the patterns obtained on diffraction of a monochromatic beam of X-rays by the atoms (scattering centers) of a protein, protein complex or peptide in crystal form. The diffraction data are used to calculate an electron density map of the repeating unit of the crystal. The electron density maps are then used to establish the positions of the individual atoms of the molecule or molecular complex.
STAMP: STAMP (Structural Alignment of Multiple Proteins) is a tool for aligning protein sequences based on a three-dimensional structure. Its algorithm minimizes the Ca distance between aligned residues of each molecule by applying globally optimal rigid-body rotations and translations. This program provides some information on the equivalence of the residues between the selected models.
SCWRL: This program predicts and optimizes the protein side-chain conformations. It is using the backbone of a support protein and a backbone-dependent rotamer library. The possible conformations are explored by minimizing the steric hindrance between the side-chains and between the side-chains and the backbone.
GROMACS: GROMACS is a molecular dynamics package. The “gmx rms” tool included in GROMACS compares two structures by computing the root mean square deviation (RMSD).
II. Growth Factor Receptor-Binding Compounds
In one aspect, the present disclosure provides for growth factor receptor-binding compounds having the ability to induce stem cell differentiation and promote tissue regeneration.
As used herein, the term “growth factor receptor-binding compound”, “GFR-binding compound” or “GFRBC” refers to an exogenous or endogenous compound, molecule or substance having an (binding) affinity for a growth factor receptor as defined herein, and optionally comprising the ability to associate or combine with a bioactive carrier as defined herein.
There are many ways to test, measure and present the binding affinity of a given substance for a given receptor, but for the purpose of the present disclosure, and for the avoidance of any doubts, the (binding) affinity values of a given GFR-binding compound to a given GFR are provided using the method of fluorescence anisotropy. In this method, a GFR-binding compound is fluorescently labelled using technics well established in the art. Binding of the resulting labelled compound to a growth factor receptor results in a fluctuation of fluorescence anisotropy which is used to construct an affinity binding curve from which the GFR-binding compound binding affinity value is derived. Using this technique, binding affinity values are given in the form of dissociation constants Kd. In certain embodiments, GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 1 (one) picomolar (pM). In certain embodiments, GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 1 (one) nanomolar (nM). In certain embodiments, GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 10 (ten) nanomolar (nM). In certain embodiments, GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 100 (one hundred) nanomolar (nM). In certain embodiments, GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 1 (one) micromolar (μM). In certain embodiments, GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 10 (ten) micromolar (μM). In certain embodiments, GFR-binding compounds of the present disclosure have Kd values as measured by fluorescence anisotropy of more than 100 (one hundred) micromolar (μM).
A GFR-binding compound is said to possess the ability to associate or combine with a bioactive carrier if it comprises a functional chemical element, function or group allowing for the covalent or non-covalent assembly of the GFR-binding compound and the bioactive carrier. Such a functional chemical element, function or group, also referred to as a bioactive carrier-affinity-containing group or bioactive carrier-high-affinity-containing group, include, but is not limited to, a thiol-containing compound, a cysteine-containing compound, a cysteine, or a GTPGP (SEQ ID NO: 6610) or a WWFWG (SEQ ID NO: 6611) peptide fragment.
Growth factor receptor: As used herein, unless indicated otherwise or contradictory in context, the term “growth factor receptor” or “GFR” is a receptor which binds to growth factors which are naturally occurring substances capable of stimulating, for instance, cellular growth, proliferation, healing, and cellular differentiation. Suitable as growth factor receptors for implementing embodiments of the present invention include epidermal growth factor receptors (EGFR), fibroblast growth factor receptors (FGFR), vascular endothelial growth factor receptors (VEGFR), nerve growth factor receptors (NGFR), Insulin receptor family, Trk receptor family, Eph receptor family, AXL receptor family, LTK receptor family, TIE receptor family, ROR receptor family, DDR receptor family, RET receptor family, KLG receptor family, RYK receptor family, MuSK receptor family, hepatocyte growth factor receptors (HGFR), somatomedin or insulin-like growth factor receptors (SGFR), platelet-derived growth factor receptors (PDGFR), transforming growth factor beta (TGF-β) superfamily proteins such as AMH, ARTN, BMP10, BMP15, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, GDF1, GDF10, GDF11, GDF15, GDF2, GDF3, GDF3A, GDF5, GDF6, GDF7, GDF8, GDF9, GDNF, INHA, INHBA, INHBB, INHBC, INHBE, LEFTY1, LEFTY2, MSTN, NODAL, NRTN, PSPN, TGFB1, TGFB2 and TGFB3, and any combination thereof.
Growth factor: As used herein, unless indicated otherwise or contradictory in context, the term “growth factor” refers to any substance(s) having the ability to bind to a growth factor receptor and produce (a) biological effect(s) or reaction(s), such as promoting the growth of tissues, by activating such a growth factor receptor. Exemplary growth factors include, but are not limited to, platelet-derived growth factor (PDGF), platelet-derived angiogenesis factor (PDAF), vascular endotheial growth factor (VEGF), platelet-derived epidermal growth factor (PDEGF), transforming growth factor beta (TGF-β), transforming growth factor A (TGF-A), epidermal growth factor (EGF), fibroblast growth factor (FGF), acidic fibroblast growth factor (FGF-A), basic fibroblast growth factor (FGF-B), insulin-like growth factors 1 and 2 (IGF-1 and IGF-2), keratinocyte growth factor (KGF), tumor necrosis factor (TNF), fibroblast growth factor (FGF) and interleukin-1 (IL-1), Keratinocyte Growth Factor-2 (KGF-2), and combinations thereof.
Activation of growth factor receptors: As used herein, unless indicated otherwise or contradictory in context, the term “activating” or “activation of”, when used in relation to a growth factor receptor, refers to the phosphorylation of the tyrosine kinase domain of such a growth factor receptor.
In one aspect, the present disclosure provides a GFR-binding compound having mesenchymal stem cell and progenitor cell commitment and/or differentiation and/or maturation capacities resulting in tissue regeneration.
In one example, said GFR-binding compound has a molecular weight of less than 4,000 Daltons. In one particular example, said GFR-binding compound has a molecular weight of less than 3,000 Daltons. In one particular example, said GFR-binding compound has a molecular weight comprised between 600 and 4,000 Daltons. In one particular example, said GFR-binding compound has a molecular weight comprised between 800 and 4,000 Daltons. In one particular example, said GFR-binding compound has a molecular weight comprised between 600 and 3,000 Daltons. In one particular example, said GFR-binding compound has a molecular weight comprised between 800 and 3,000 Daltons. Between 800 and 3,000 Daltons is particularly preferred.
In one particular example, the growth factor receptor involved in the interaction with said GFR-binding compound is an epidermal growth factor receptor. In one particular example, the growth factor receptor involved in the interaction with said GFR-binding compound is a fibroblast growth factor receptor. In one particular example, the growth factor receptor involved in the interaction with said GFR-binding compound is a vascular endothelial growth factor receptor. In one particular example, the growth factor receptor involved in the interaction with said GFR-binding compound is a nerve growth factor receptor. In one particular example, the growth factor receptor involved in the interaction with said GFR-binding compound is a hepatocyte growth factor receptor. In one particular example, the growth factor receptor involved in the interaction with said GFR-binding compound is a somatomedin or insulin-like growth factor receptor. In one particular example, the growth factor receptor involved in the interaction with said GFR-binding compound is a platelet-derived growth factor receptor. In one particular example, the growth factor receptor involved in the interaction with said GFR-binding compound is a protein from the transforming growth factor beta (TGF-β) superfamily.
In one particular example, the growth factor receptor(s) involved in the interaction with said GFR-binding compound is (are) preferably selected from epidermal growth factor receptors, fibroblast growth factor receptors, vascular endothelial growth factor receptors, nerve growth factor receptors, hepatocyte growth factor receptors, somatomedin or insulin-like growth factor receptors, platelet-derived growth factor receptors, and transforming growth factor beta (TGF-β) superfamily proteins.
In one particular example, said GFR-binding compound is a peptide, or a variant or analog thereof, exclusively consisting of (or constituted of) between 8-30 amino acids, in particular between 8-25 amino acids or between 8-22 amino acids, more particularly between 18-22 amino acids, even more particularly between 19-21 or 20 amino acids; wherein the RMSD value of the three dimensional (3D) atomic coordinates of said GFR-binding compound with respect to PEPREF is 2.45 Å (Angstroms) or less, in particular is 2 Å or less, and more particularly is 1.79 Å or less, and wherein PEPREF is the set of 3D atomic coordinates already defined herein (hereinafter also referred to as “wherein the RMSD is 2.45 Å or less” for the sake of conciseness).
In one particular example, said GFR-binding compound is a peptide, or a variant or analog thereof, exclusively consisting of (or constituted of) between 8-30 amino acids; wherein the RMSD value of the three dimensional (3D) atomic coordinates of said GFR-binding compound with respect to PEPREF is 2.45 Å (Angstroms) or less, in particular is 2 Å, or less, and more particularly is 1.79 Å or less, and wherein PEPREF is the set of 3D atomic coordinates already defined herein.
In one particular example, said GFR-binding compound is a peptide, or a variant or analog thereof, exclusively consisting of (or constituted of) between 8-30 amino acids, in particular between 8-25 amino acids or between 8-22 amino acids, more particularly between 18-22 amino acids, even more particularly between 19-21 or 20 amino acids; wherein the RMSD value of the three dimensional (3D) atomic coordinates of said GFR-binding compound with respect to PEPREF is 2.45 Å (Angstroms) or less, in particular is 2 Å or less, and more particularly is 1.79 Å or less, and wherein PEPREF is the set of 3D atomic coordinates already defined herein.
In one particular example, said GFR-binding compound is a peptide, or a variant or analog thereof, exclusively consisting of (or constituted of) between 8-25 amino acids; wherein the RMSD value of the three dimensional (3D) atomic coordinates of said GFR-binding compound with respect to PEPREF is 2.45 Å (Angstroms) or less, in particular is 2 Å or less, and more particularly is 1.79 Å or less, and wherein PEPREF is the set of 3D atomic coordinates already defined herein.
In one particular example, said GFR-binding compound is a peptide, or a variant or analog thereof, exclusively consisting of (or constituted of) between 8-22 amino acids; wherein the RMSD value of the three dimensional (3D) atomic coordinates of said GFR-binding compound with respect to PEPREF is 2.45 Å (Angstroms) or less, in particular is 2 Å or less, and more particularly is 1.79 Å or less, and wherein PEPREF is the set of 3D atomic coordinates already defined herein.
In one particular example, said GFR-binding compound is a peptide, or a variant or analog thereof, exclusively consisting of (or constituted of) between 18-22 amino acids; wherein the RMSD value of the three dimensional (3D) atomic coordinates of said GFR-binding compound with respect to PEPREF is 2.45 Å (Angstroms) or less, in particular is 2 Å or less, and more particularly is 1.79 Å or less, and wherein PEPREF is the set of 3D atomic coordinates already defined herein.
In one particular example, said GFR-binding compound is a peptide, or a variant or analog thereof, exclusively consisting of (or constituted of) between 19-21 amino acids; wherein the RMSD value of the three dimensional (3D) atomic coordinates of said GFR-binding compound with respect to PEPREF is 2.45 Å (Angstroms) or less, in particular is 2 Å or less, and more particularly is 1.79 Å or less, and wherein PEPREF is the set of 3D atomic coordinates already defined herein.
In one particular example, said GFR-binding compound is a peptide, or a variant or analog thereof, exclusively consisting of (or constituted of) 20 amino acid; wherein the RMSD value of the three dimensional (3D) atomic coordinates of said GFR-binding compound with respect to PEPREF is 2.45 Å (Angstroms) or less, in particular is 2 Å or less, and more particularly is 1.79 Å or less, and wherein PEPREF is the set of 3D atomic coordinates already defined herein.
In one particular example, said GFR-binding compound is a peptide, or a variant or analog thereof, exclusively consisting of (or constituted of) between 8-18 amino acids; wherein the RMSD value of the three dimensional (3D) atomic coordinates of said GFR-binding compound with respect to PEPREF is 2.45 Å (Angstroms) or less, in particular is 2 Å or less, and more particularly is 1.79 Å or less, and wherein PEPREF is the set of 3D atomic coordinates already defined herein.
In one particular example, said GFR-binding compound is a peptide, or a variant or analog thereof, exclusively consisting of (or constituted of) between 22-30 amino acids; wherein the RMSD value of the three dimensional (3D) atomic coordinates of said GFR-binding compound with respect to PEPREF is 2.45 Å (Angstroms) or less, in particular is 2 Å or less, and more particularly is 1.79 Å or less, and wherein PEPREF is the set of 3D atomic coordinates already defined herein.
In one particular example, said GFR-binding compound is a peptidomimetic as defined herein, comprising (consecutively or non-consecutively) between 8-30 amino acids, in particular between 8-25 amino acids or between 8-22 amino acids, more particularly between 18-22 amino acids, even more particularly between 19-21 or 20; wherein said GFR-binding compound has a molecular weight comprised between 600 and 4,000 Daltons (in particular, between 800-4,000 Da, 600-3,000 Da, more particularly between 800-3,000 Da); In one aspect, the present disclosure provides a GFR-binding compound, wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, having growth factor receptor-binding capability or capabilities, having a molecular weight of between 600-4,000 Da, 600-3,000 Da, or 800-4,000 Da, in particular between 800 and 3,000 Da; and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a GFR-binding compound, wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, having growth factor receptor-binding capability or capabilities, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with four amino acids (PEP1); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a GFR-binding compound, wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with eight amino acids (PEP12); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a GFR-binding compound, wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with four amino acids (PEP1); wherein said GFR-binding compound further comprises a peptide with three amino acids (PEP3); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a GFR-binding compound, wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with eight amino acids (PEP12); wherein said GFR-binding compound further comprises a peptide with three amino acids (PEP3); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a GFR-binding compound, wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with four amino acids (PEP1); wherein said GFR-binding compound further comprises a peptide with five amino acids (PEP5); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a GFR-binding compound, wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with eight amino acids (PEP12); wherein said GFR-binding compound further comprises a peptide with five amino acids (PEP5); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a GFR-binding compound, wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with four amino acids (PEP1); wherein said GFR-binding compound further comprises a peptide with between six and twelve amino acids (PEP9); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a GFR-binding compound, wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with eight amino acids (PEP12); wherein said GFR-binding compound further comprises a peptide with between six and twelve amino acids (PEP9); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a GFR-binding compound, wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with four amino acids (PEP1); wherein said GFR-binding compound further comprises a peptide with three amino acids (PEP3), an amino acid or a peptide with between two and seven amino acids (PEP7); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a GFR-binding compound, wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with four amino acids (PEP12); wherein said GFR-binding compound further comprises a peptide with three amino acids (PEP3), an amino acid or a peptide with between two and seven amino acids (PEP7); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a GFR-binding compound, wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with four amino acids (PEP1); wherein said GFR-binding compound further comprises a peptide with five amino acids (PEP5), an amino acid or a peptide with between two and seven amino acids (PEP7); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a GFR-binding compound, wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with four amino acids (PEP12); wherein said GFR-binding compound further comprises a peptide with five amino acids (PEP5), an amino acid or a peptide with between two and seven amino acids (PEP7); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a GFR-binding compound, wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, having the following general formula (I) (hereinafter may also be referred to as compound (I) or peptide (I)):
PEP(C)−PEP12 (I)
wherein PEP12 is a peptide with 8 amino acids of formula PEP1-AA17-PEP11 as defined herein; wherein one end of PEP(C) interacts covalently with PEP12 via one end of PEP1; wherein PEP(C) is a peptide with at least 5 amino acids, in particular a peptide with between 5 and 12 amino acids; and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a GFR-binding compound of general formula (I), wherein PEP(C) comprises PEP3; and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a GFR-binding compound of general formula (I), wherein PEP(C) comprises PEP5; and wherein the RMSD is 2.45 Å or less. In one particular example, PEP(C) is PEP5.
In one aspect, the present disclosure provides a GFR-binding compound of general formula (I), wherein PEP(C) comprises PEP9; and wherein the RMSD is 2.45 Å or less. In one particular example, PEP(C) is PEP9.
In one aspect, the present disclosure provides a GFR-binding compound of general formula (I), wherein PEP(C) comprises PEP3 and PEP7; and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a GFR-binding compound of general formula (I), wherein PEP(C) comprises PEP5 and PEP7; and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a GFR-binding compound, wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, having the following general formula (II) (hereinafter may also be referred to as compound (II) or peptide (II)):
PEP7−PEP5−PEP12 (II)
wherein PEP12 is a peptide with 8 amino acids of formula PEP1-AA17-PEP11 as defined herein; wherein PEP5 is a peptide with five amino acids as defined herein; wherein PEP7 is an amino acid or a peptide with between two and seven amino acids as defined herein; wherein one end of PEP5 interacts covalently with one end of PEP12 via one end of PEP1; wherein another end of PEP5 interacts covalently with one end of PEP7 via AA7; and wherein the RMSD is 2.45 Å or less.
In certain embodiments, PEP1 is selected from the group consisting of SAIS (SEQ ID NO: 6360), SSLS (SEQ ID NO: 6365), NAIS (SEQ ID NO: 6357), SATS (SEQ ID NO: 6361), SPIS (SEQ ID NO: 6364), EPIS (SEQ ID NO: 6353), SPIN (SEQ ID NO: 6363), KPLS (SEQ ID NO: 6356), EPLP (SEQ ID NO: 6354), EPLT (SEQ ID NO: 6355), SNIT (SEQ ID NO: 6362), RSVK (SEQ ID NO: 6359) and RPVQ (SEQ ID NO: 6358).
In certain embodiments, PEP3 is selected from the group consisting of VPT, VPE, APT, TPT, VPA, APV, VPQ, VSQ, SRV and TQV.
In certain embodiments, PEP5 is a peptide of general formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, VPE, APT, TPT, VPA, APV, VPQ, VSO, SRV and TQV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H; and wherein AA12 is selected from the group consisting of L, M, T, E, Q and H. In one particular example, PEP5 is selected from the group consisting of VPTEL (SEQ ID NO: 6421), VPEKM (SEQ ID NO: 6406), APTKL (SEQ ID NO: 6369), APTQL (SEQ ID NO: 6372), VPTKL (SEQ ID NO: 6423), TPTKM (SEQ ID NO: 6388), VPARL (SEQ ID NO: 6401), VPTRL (SEQ ID NO: 6427), APVKT (SEQ ID NO: 6379), VPQAL (SEQ ID NO: 6410), VSODL (SEQ ID NO: 6429), VPQDL (SEQ ID NO: 6411), VPTEE (SEQ ID NO: 6420), VPTGQ (SEQ ID NO: 6422), SRVHH (SEQ ID NO: 6382) and TQVQL (SEQ ID NO: 6393).
In certain embodiments, PEP7 is an amino acid or a peptide with between two and seven amino acids of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606); wherein wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AAI as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R; wherein AA7 is absent or is selected from the group consisting of S, T, C, E, Q, P and R, and wherein at least one of AA, AA2, AA3, AA4, AA5, AA6 or AA7 is not absent. In one particular example, PEP7 is selected from the group consisting of KIPKAXX (SEQ ID NO: 6445), GIPEPXX (SEQ ID NO: 6440), SIPKAXX (SEQ ID NO: 6450), HVTKPTX (SEQ ID NO: 6443), YVPKPXX (SEQ ID NO: 6454), TVPKPXX (SEQ ID NO: 6453), AVPKAXX (SEQ ID NO: 6439), KVGKAXX (SEQ ID NO: 6446), KASKAXX (SEQ ID NO: 6444), GSAGPXX (SEQ ID NO: 6441), AAPASXX (SEQ ID NO: 6436), STPPTXX (SEQ ID NO: 6452), HVPKPXX (SEQ ID NO: 6442), RVPSTXX (SEQ ID NO: 6449), ASAAPXX (SEQ ID NO: 6437), ASASPXX (SEQ ID NO: 6438), NDEGLEX (SEQ ID NO: 6447), SSVKXQP (SEQ ID NO: 6451) and RNVQXRP (SEQ ID NO: 6448), wherein X is C or S throughout the present description.
In certain embodiments, PEP9 is a peptide of general formula PEP7-PEP5; wherein PEP5 is a peptide of formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, VPE, APT, TPT, VPA, APV, VPQ, VSO, SRV and TQV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H; and wherein AA12 is selected from the group consisting of L, M, T, E, Q and H; wherein PEP7 is an amino acid or a peptide with between two and seven amino acids of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606); wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AAI as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R; wherein AA7 is absent or is selected from the group consisting of S, T, C, E, Q, P and R. In one particular example, PEP9 is selected from the group consisting of KIPKAXXVPTEL (SEQ ID NO: 6535), GIPEPXXVPEKM (SEQ ID NO: 6491), SIPKAXXVPTEL (SEQ ID NO: 6563), HVTKPTXAPTKL (SEQ ID NO: 6511), YVPKPXXAPTKL (SEQ ID NO: 6583), TVPKPXXAPTQL (SEQ ID NO: 6575), AVPKAXXAPTKL (SEQ ID NO: 6479), KVGKAXXVPTKL (SEQ ID NO: 6543), KASKAXXVPTKL (SEQ ID NO: 6527), GSAGPXXTPTKM (SEQ ID NO: 6497), AAPASXXVPARL (SEQ ID NO: 6458), STPPTXXVPTRL (SEQ ID NO: 6573), HVPKPXXAPTKL (SEQ ID NO: 6503), RVPSTXXAPVKT (SEQ ID NO: 6550), ASAAPXXVPQAL (SEQ ID NO: 6468), ASASPXXVSQDL (SEQ ID NO: 6478), ASASPXXVPQDL (SEQ ID NO: 6476), NDEGLEXVPTEE (SEQ ID NO: 6545), NDEGLEXVPTGQ (SEQ ID NO: 6546), SSVKXQPSRVHH (SEQ ID NO: 6565) and RNVQXRPTQVQL (SEQ ID NO: 6548), wherein X is C or S throughout the present description.
In certain embodiments, PEP12 is a peptide of general formula PEP1-AA17-PEP11; wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T); wherein PEP1 is selected from the group consisting of SAIS (SEQ ID NO: 6360), SSLS (SEQ ID NO: 6365), NAIS (SEQ ID NO: 6357), SATS (SEQ ID NO: 6361), SPIS (SEQ ID NO: 6364), EPIS (SEQ ID NO: 6353), SPIN (SEQ ID NO: 6363), KPLS (SEQ ID NO: 6356), EPLP (SEQ ID NO: 6354), EPLT (SEQ ID NO: 6355), SNIT (SEQ ID NO: 6362), RSVK (SEQ ID NO: 6359) and RPVQ (SEQ ID NO: 6358).
In particular, in certain embodiments, the pair PEP3:PEP1 is selected from the group consisting of VPT:SAIS (SEQ ID NO: 6360), VPE:SAIS (SEQ ID NO: 6360), APT:SAIS (SEQ ID NO: 6360), TPT:SAIS (SEQ ID NO: 6360), VPA:SAIS (SEQ ID NO: 6360), APV:SAIS (SEQ ID NO: 6360), VPQ:SAIS (SEQ ID NO: 6360), VSQ:SAIS (SEQ ID NO: 6360), SRV:SAIS (SEQ ID NO: 6360), TQV:SAIS (SEQ ID NO: 6360), VPE:SSLS (SEQ ID NO: 6365), VPT:SSLS (SEQ ID NO: 6365), APT:SSLS (SEQ ID NO: 6365), TPT:SSLS (SEQ ID NO: 6365), VPA:SSLS (SEQ ID NO: 6365), APV:SSLS (SEQ ID NO: 6365), VPQ:SSLS (SEQ ID NO: 6365), VSQ:SSLS (SEQ ID NO: 6365), SRV:SSLS (SEQ ID NO: 6365), TQV:SSLS (SEQ ID NO: 6365), APT:NAIS (SEQ ID NO: 6357), VPT:NAIS (SEQ ID NO: 6357), VPE:NAIS (SEQ ID NO: 6357), TPT:NAIS (SEQ ID NO: 6357), VPA:NAIS (SEQ ID NO: 6357), APV:NAIS (SEQ ID NO: 6357), VPQ:NAIS (SEQ ID NO: 6357), VSQ:NAIS (SEQ ID NO: 6357), SRV:NAIS (SEQ ID NO: 6357), TQV:NAIS (SEQ ID NO: 6357), APT:SATS (SEQ ID NO: 6361), VPT:SATS (SEQ ID NO: 6361), VPE:SATS (SEQ ID NO: 6361), TPT:SATS (SEQ ID NO: 6361), VPA:SATS (SEQ ID NO: 6361), APV:SATS (SEQ ID NO: 6361), VPQ:SATS (SEQ ID NO: 6361), VSQ:SATS (SEQ ID NO: 6361), SRV:SATS (SEQ ID NO: 6361), TQV:SATS (SEQ ID NO: 6361), VPT:SPIS (SEQ ID NO: 6364), VPE:SPIS (SEQ ID NO: 6364), APT:SPIS (SEQ ID NO: 6364), TPT:SPIS (SEQ ID NO: 6364), VPA:SPIS (SEQ ID NO: 6364), APV:SPIS (SEQ ID NO: 6364), VPQ:SPIS (SEQ ID NO: 6364), VSQ:SPIS (SEQ ID NO: 6364), SRV:SPIS (SEQ ID NO: 6364), TQV:SPIS (SEQ ID NO: 6364), VPT:EPIS (SEQ ID NO: 6353), VPE:EPIS (SEQ ID NO: 6353), APT:EPIS (SEQ ID NO: 6353), TPT:EPIS (SEQ ID NO: 6353), VPA:EPIS (SEQ ID NO: 6353), APV:EPIS (SEQ ID NO: 6353), VPQ:EPIS (SEQ ID NO: 6353), VSQ:EPIS (SEQ ID NO: 6353), SRV:EPIS (SEQ ID NO: 6353), TQV:EPIS (SEQ ID NO: 6353), TPT:SPIN (SEQ ID NO: 6363), VPT:SPIN (SEQ ID NO: 6363), VPE:SPIN (SEQ ID NO: 6363), APT:SPIN (SEQ ID NO: 6363), VPA:SPIN (SEQ ID NO: 6363), APV:SPIN (SEQ ID NO: 6363), VPQ:SPIN (SEQ ID NO: 6363), VSQ:SPIN (SEQ ID NO: 6363), SRV:SPIN (SEQ ID NO: 6363), TQV:SPIN (SEQ ID NO: 6363), APV:KPLS (SEQ ID NO: 6356), VPT:KPLS (SEQ ID NO: 6356), VPE:KPLS (SEQ ID NO: 6356), APT:KPLS (SEQ ID NO: 6356), TPT:KPLS (SEQ ID NO: 6356), VPA:KPLS (SEQ ID NO: 6356), VPQ:KPLS (SEQ ID NO: 6356), VSQ:KPLS (SEQ ID NO: 6356), SRV:KPLS (SEQ ID NO: 6356), TQV:KPLS (SEQ ID NO: 6356), VPQ:EPLP (SEQ ID NO: 6354), VPT:EPLP (SEQ ID NO: 6354), VPE:EPLP (SEQ ID NO: 6354), APT:EPLP (SEQ ID NO: 6354), TPT:EPLP (SEQ ID NO: 6354), VPA:EPLP (SEQ ID NO: 6354), APV:EPLP (SEQ ID NO: 6354), VSQ:EPLP (SEQ ID NO: 6354), SRV:EPLP (SEQ ID NO: 6354), TQV:EPLP (SEQ ID NO: 6354), VSQ:EPLT (SEQ ID NO: 6355), VPT:EPLT (SEQ ID NO: 6355), VPE:EPLT (SEQ ID NO: 6355), APT:EPLT (SEQ ID NO: 6355), TPT:EPLT (SEQ ID NO: 6355), VPA:EPLT (SEQ ID NO: 6355), APV:EPLT (SEQ ID NO: 6355), VPQ:EPLT (SEQ ID NO: 6355), SRV:EPLT (SEQ ID NO: 6355), TQV:EPLT (SEQ ID NO: 6355), VPT:SNIT (SEQ ID NO: 6362), VPE:SNIT (SEQ ID NO: 6362), APT:SNIT (SEQ ID NO: 6362), TPT:SNIT (SEQ ID NO: 6362), VPA:SNIT (SEQ ID NO: 6362), APV:SNIT (SEQ ID NO: 6362), VPQ:SNIT (SEQ ID NO: 6362), VSQ:SNIT (SEQ ID NO: 6362), SRV:SNIT (SEQ ID NO: 6362), TQV:SNIT (SEQ ID NO: 6362), SRV:RSVK (SEQ ID NO: 6359), VPT:RSVK (SEQ ID NO: 6359), VPE:RSVK (SEQ ID NO: 6359), APT:RSVK (SEQ ID NO: 6359), TPT:RSVK (SEQ ID NO: 6359), VPA:RSVK (SEQ ID NO: 6359), APV:RSVK (SEQ ID NO: 6359), VPQ:RSVK (SEQ ID NO: 6359), VSQ:RSVK (SEQ ID NO: 6359), TQV:RSVK (SEQ ID NO: 6359), TQV:RPVQ (SEQ ID NO: 6358), VPT:RPVQ (SEQ ID NO: 6358), VPE:RPVQ (SEQ ID NO: 6358), APT:RPVQ (SEQ ID NO: 6358), TPT:RPVQ (SEQ ID NO: 6358), VPA:RPVQ (SEQ ID NO: 6358), APV:RPVQ (SEQ ID NO: 6358), VPQ:RPVQ (SEQ ID NO: 6358), VSQ:RPVQ (SEQ ID NO: 6358) and SRV:RPVQ (SEQ ID NO: 6358).
In particular, in certain embodiments, the pair PEP5:PEP1 is selected from the group consisting of VPTKM (SEQ ID NO: 6424):SAIS (SEQ ID NO: 6360), VPTKL (SEQ ID NO: 6423):SAIS (SEQ ID NO: 6360), VPTQL (SEQ ID NO: 6426):SAIS (SEQ ID NO: 6360), VPTRL (SEQ ID NO: 6427):SAIS (SEQ ID NO: 6360), VPTKT (SEQ ID NO: 6425):SAIS (SEQ ID NO: 6360), VPTAL (SEQ ID NO: 6418):SAIS (SEQ ID NO: 6360), VPTDL (SEQ ID NO: 6419):SAIS (SEQ ID NO: 6360), VPEKM (SEQ ID NO: 6406):SAIS (SEQ ID NO: 6360), APTKL (SEQ ID NO: 6369):SAIS (SEQ ID NO: 6360), APTOL (SEQ ID NO: 6372):SAIS (SEQ ID NO: 6360), TPTKM (SEQ ID NO: 6388):SAIS (SEQ ID NO: 6360), VPARL (SEQ ID NO: 6401):SAIS (SEQ ID NO: 6360), APVKT (SEQ ID NO: 6379):SAIS (SEQ ID NO: 6360), VPQAL (SEQ ID NO: 6410):SAIS (SEQ ID NO: 6360), VSODL (SEQ ID NO: 6429):SAIS (SEQ ID NO: 6360), VPQDL (SEQ ID NO: 6411):SAIS (SEQ ID NO: 6360), SRVHH (SEQ ID NO: 6382):SAIS (SEQ ID NO: 6360), TQVQL (SEQ ID NO: 6393):SAIS (SEQ ID NO: 6360), VPEEL (SEQ ID NO: 6404):SSLS (SEQ ID NO: 6365), VPEKL (SEQ ID NO: 6405):SSLS (SEQ ID NO: 6365), VPEQL (SEQ ID NO: 6408):SSLS (SEQ ID NO: 6365), VPEKM (SEQ ID NO: 6406):SSLS (SEQ ID NO: 6365), VPERL (SEQ ID NO: 6409):SSLS (SEQ ID NO: 6365), VPEKT (SEQ ID NO: 6407):SSLS (SEQ ID NO: 6365), VPEAL (SEQ ID NO: 6402):SSLS (SEQ ID NO: 6365), VPEDL (SEQ ID NO: 6403):SSLS (SEQ ID NO: 6365), VPTEL (SEQ ID NO: 6421):SSLS (SEQ ID NO: 6365), APTKL (SEQ ID NO: 6369):SSLS (SEQ ID NO: 6365), APTQL (SEQ ID NO: 6372):SSLS (SEQ ID NO: 6365), VPTKL (SEQ ID NO: 6423):SSLS (SEQ ID NO: 6365), TPTKM (SEQ ID NO: 6388):SSLS (SEQ ID NO: 6365), VPARL (SEQ ID NO: 6401):SSLS (SEQ ID NO: 6365), VPTRL (SEQ ID NO: 6427)SSLS (SEQ ID NO: 6365), APVKT (SEQ ID NO: 6379):SSLS (SEQ ID NO: 6365), VPQAL (SEQ ID NO: 6410):SSLS (SEQ ID NO: 6365), VSODL (SEQ ID NO: 6429):SSLS (SEQ ID NO: 6365), VPQDL (SEQ ID NO: 6411):SSLS (SEQ ID NO: 6365), VPTEE (SEQ ID NO: 6420):SSLS (SEQ ID NO: 6365), VPTGQ (SEQ ID NO: 6422)SSLS (SEQ ID NO: 6365), SRVHH (SEQ ID NO: 6382):SSLS (SEQ ID NO: 6365), TQVQL (SEQ ID NO: 6393):SSLS (SEQ ID NO: 6365), APTEL (SEQ ID NO: 6368):NAIS (SEQ ID NO: 6357), APTKM (SEQ ID NO: 6370):NAIS (SEQ ID NO: 6357), APTKL (SEQ ID NO: 6369):NAIS (SEQ ID NO: 6357), APTRL (SEQ ID NO: 6373):NAIS (SEQ ID NO: 6357), APTKT (SEQ ID NO: 6371):NAIS (SEQ ID NO: 6357), APTAL (SEQ ID NO: 6366):NAIS (SEQ ID NO: 6357), APTDL (SEQ ID NO: 6367):NAIS (SEQ ID NO: 6357), VPTEL (SEQ ID NO: 6421):NAIS (SEQ ID NO: 6357), VPEKM (SEQ ID NO: 6406):NAIS (SEQ ID NO: 6357), VPTKL (SEQ ID NO: 6423):NAIS (SEQ ID NO: 6357), TPTKM (SEQ ID NO: 6388):NAIS (SEQ ID NO: 6357), VPARL (SEQ ID NO: 6401):NAIS (SEQ ID NO: 6357), VPTRL (SEQ ID NO: 6427):NAIS (SEQ ID NO: 6357), APVKT (SEQ ID NO: 6379):NAIS (SEQ ID NO: 6357), VPQAL (SEQ ID NO: 6410):NAIS (SEQ ID NO: 6357), VSODL (SEQ ID NO: 6429):NAIS (SEQ ID NO: 6357), VPQDL (SEQ ID NO: 6411):NAIS (SEQ ID NO: 6357), VPTEE (SEQ ID NO: 6420):NAIS (SEQ ID NO: 6357), VPTGQ (SEQ ID NO: 6422):NAIS (SEQ ID NO: 6357), SRVHH (SEQ ID NO: 6382):NAIS (SEQ ID NO: 6357), TQVQL (SEQ ID NO: 6393):NAIS (SEQ ID NO: 6357), APTEL (SEQ ID NO: 6368):SATS (SEQ ID NO: 6361), APTKM (SEQ ID NO: 6370):SATS (SEQ ID NO: 6361), APTKL (SEQ ID NO: 6369):SATS (SEQ ID NO: 6361), APTQL (SEQ ID NO: 6372):SATS (SEQ ID NO: 6361), APTRL (SEQ ID NO: 6373):SATS (SEQ ID NO: 6361), APTKT (SEQ ID NO: 6371):SATS (SEQ ID NO: 6361), APTAL (SEQ ID NO: 6366):SATS (SEQ ID NO: 6361), APTDL (SEQ ID NO: 6367):SATS (SEQ ID NO: 6361), VPTEL (SEQ ID NO: 6421):SATS (SEQ ID NO: 6361), VPEKM (SEQ ID NO: 6406):SATS (SEQ ID NO: 6361), VPTKL (SEQ ID NO: 6423):SATS (SEQ ID NO: 6361), TPTKM (SEQ ID NO: 6388):SATS (SEQ ID NO: 6361), VPARL (SEQ ID NO: 6401):SATS (SEQ ID NO: 6361), VPTRL (SEQ ID NO: 6427):SATS (SEQ ID NO: 6361), APVKT (SEQ ID NO: 6379):SATS (SEQ ID NO: 6361), VPQAL (SEQ ID NO: 6410):SATS (SEQ ID NO: 6361), VSODL (SEQ ID NO: 6429):SATS (SEQ ID NO: 6361), VPQDL (SEQ ID NO: 6411):SATS (SEQ ID NO: 6361), VPTEE (SEQ ID NO: 6420):SATS (SEQ ID NO: 6361), VPTGQ (SEQ ID NO: 6422):SATS (SEQ ID NO: 6361), SRVHH (SEQ ID NO: 6382):SATS (SEQ ID NO: 6361), TQVQL (SEQ ID NO: 6393):SATS (SEQ ID NO: 6361), VPTEL (SEQ ID NO: 6421):SPIS (SEQ ID NO: 6364), VPTKM (SEQ ID NO: 6424):SPIS (SEQ ID NO: 6364), VPTKL (SEQ ID NO: 6423):SPIS (SEQ ID NO: 6364), VPTQL (SEQ ID NO: 6426):SPIS (SEQ ID NO: 6364), VPTRL (SEQ ID NO: 6427):SPIS (SEQ ID NO: 6364), VPTKT (SEQ ID NO: 6425):SPIS (SEQ ID NO: 6364), VPTAL (SEQ ID NO: 6418):SPIS (SEQ ID NO: 6364), VPTDL (SEQ ID NO: 6419):SPIS (SEQ ID NO: 6364), VPEKM (SEQ ID NO: 6406):SPIS (SEQ ID NO: 6364), APTKL (SEQ ID NO: 6369):SPIS (SEQ ID NO: 6364), APTOL (SEQ ID NO: 6372):SPIS (SEQ ID NO: 6364), TPTKM (SEQ ID NO: 6388):SPIS (SEQ ID NO: 6364), VPARL (SEQ ID NO: 6401):SPIS (SEQ ID NO: 6364), APVKT (SEQ ID NO: 6379):SPIS (SEQ ID NO: 6364), VPQAL (SEQ ID NO: 6410):SPIS (SEQ ID NO: 6364), VSODL (SEQ ID NO: 6429):SPIS (SEQ ID NO: 6364), VPQDL (SEQ ID NO: 6411):SPIS (SEQ ID NO: 6364), SRVHH (SEQ ID NO: 6382):SPIS (SEQ ID NO: 6364), TQVQL (SEQ ID NO: 6393):SPIS (SEQ ID NO: 6364), VPTEL (SEQ ID NO: 6421):EPIS (SEQ ID NO: 6353), VPTKM (SEQ ID NO: 6424):EPIS (SEQ ID NO: 6353), VPTKL (SEQ ID NO: 6423):EPIS (SEQ ID NO: 6353), VPTQL (SEQ ID NO: 6426):EPIS (SEQ ID NO: 6353), VPTRL (SEQ ID NO: 6427):EPIS (SEQ ID NO: 6353), VPTKT (SEQ ID NO: 6425):EPIS (SEQ ID NO: 6353), VPTAL (SEQ ID NO: 6418):EPIS (SEQ ID NO: 6353), VPTDL (SEQ ID NO: 6419):EPIS (SEQ ID NO: 6353), VPEKM (SEQ ID NO: 6406):EPIS (SEQ ID NO: 6353), APTKL (SEQ ID NO: 6369):EPIS (SEQ ID NO: 6353), APTQL (SEQ ID NO: 6372):EPIS (SEQ ID NO: 6353), TPTKM (SEQ ID NO: 6388):EPIS (SEQ ID NO: 6353), VPARL (SEQ ID NO: 6401):EPIS (SEQ ID NO: 6353), APVKT (SEQ ID NO: 6379):EPIS (SEQ ID NO: 6353), VPQAL (SEQ ID NO: 6410):EPIS (SEQ ID NO: 6353), VSODL (SEQ ID NO: 6429):EPIS (SEQ ID NO: 6353), VPQDL (SEQ ID NO: 6411):EPIS (SEQ ID NO: 6353), SRVHH (SEQ ID NO: 6382):EPIS (SEQ ID NO: 6353), TQVQL (SEQ ID NO: 6393):EPIS (SEQ ID NO: 6353), TPTEL (SEQ ID NO: 6386):SPIN (SEQ ID NO: 6363), TPTKM (SEQ ID NO: 6388):SPIN (SEQ ID NO: 6363), TPTKL (SEQ ID NO: 6387):SPIN (SEQ ID NO: 6363), TPTQL (SEQ ID NO: 6390):SPIN (SEQ ID NO: 6363), TPTRL (SEQ ID NO: 6391):SPIN (SEQ ID NO: 6363), TPTKT (SEQ ID NO: 6389):SPIN (SEQ ID NO: 6363), TPTAL (SEQ ID NO: 6384):SPIN (SEQ ID NO: 6363), TPTDL (SEQ ID NO: 6385):SPIN (SEQ ID NO: 6363), VPTEL (SEQ ID NO: 6421):SPIN (SEQ ID NO: 6363), VPEKM (SEQ ID NO: 6406):SPIN (SEQ ID NO: 6363), APTKL (SEQ ID NO: 6369):SPIN (SEQ ID NO: 6363), APTQL (SEQ ID NO: 6372):SPIN (SEQ ID NO: 6363), VPTKL (SEQ ID NO: 6423):SPIN (SEQ ID NO: 6363), VPARL (SEQ ID NO: 6401):SPIN (SEQ ID NO: 6363), VPTRL (SEQ ID NO: 6427):SPIN (SEQ ID NO: 6363), APVKT (SEQ ID NO: 6379):SPIN (SEQ ID NO: 6363), VPQAL (SEQ ID NO: 6410):SPIN (SEQ ID NO: 6363), VSODL (SEQ ID NO: 6429):SPIN (SEQ ID NO: 6363), VPQDL (SEQ ID NO: 6411):SPIN (SEQ ID NO: 6363), VPTEE (SEQ ID NO: 6420):SPIN (SEQ ID NO: 6363), VPTGQ (SEQ ID NO: 6422):SPIN (SEQ ID NO: 6363), SRVHH (SEQ ID NO: 6382):SPIN (SEQ ID NO: 6363), TQVQL (SEQ ID NO: 6393):SPIN (SEQ ID NO: 6363), VPAEL (SEQ ID NO: 6396):SPIS (SEQ ID NO: 6364), VPAKM (SEQ ID NO: 6398):SPIS (SEQ ID NO: 6364), VPAKL (SEQ ID NO: 6397):SPIS (SEQ ID NO: 6364), VPAQL (SEQ ID NO: 6400):SPIS (SEQ ID NO: 6364), VPAKT (SEQ ID NO: 6399):SPIS (SEQ ID NO: 6364), VPAAL (SEQ ID NO: 6394):SPIS (SEQ ID NO: 6364), VPADL (SEQ ID NO: 6395):SPIS (SEQ ID NO: 6364), VPTEE (SEQ ID NO: 6420):SPIS (SEQ ID NO: 6364), VPTGQ (SEQ ID NO: 6422):SPIS (SEQ ID NO: 6364), APVEL (SEQ ID NO: 6376):KPLS (SEQ ID NO: 6356), APVKM (SEQ ID NO: 6378):KPLS (SEQ ID NO: 6356), APVKL (SEQ ID NO: 6377):KPLS (SEQ ID NO: 6356), APVQL (SEQ ID NO: 6380):KPLS (SEQ ID NO: 6356), APVRL (SEQ ID NO: 6381):KPLS (SEQ ID NO: 6356), APVAL (SEQ ID NO: 6374):KPLS (SEQ ID NO: 6356), APVDL (SEQ ID NO: 6375):KPLS (SEQ ID NO: 6356), VPTEL (SEQ ID NO: 6421):KPLS (SEQ ID NO: 6356), VPEKM (SEQ ID NO: 6406):KPLS (SEQ ID NO: 6356), APTKL (SEQ ID NO: 6369):KPLS (SEQ ID NO: 6356), APTQL (SEQ ID NO: 6372):KPLS (SEQ ID NO: 6356), VPTKL (SEQ ID NO: 6423):KPLS (SEQ ID NO: 6356), TPTKM (SEQ ID NO: 6388):KPLS (SEQ ID NO: 6356), VPARL (SEQ ID NO: 6401):KPLS (SEQ ID NO: 6356), VPTRL (SEQ ID NO: 6427):KPLS (SEQ ID NO: 6356), VPQAL (SEQ ID NO: 6410):KPLS (SEQ ID NO: 6356), VSQDL (SEQ ID NO: 6429):KPLS (SEQ ID NO: 6356), VPQDL (SEQ ID NO: 6411):KPLS (SEQ ID NO: 6356), VPTEE (SEQ ID NO: 6420):KPLS (SEQ ID NO: 6356), VPTGQ (SEQ ID NO: 6422):KPLS (SEQ ID NO: 6356), SRVHH (SEQ ID NO: 6382):KPLS (SEQ ID NO: 6356), TQVQL (SEQ ID NO: 6393):KPLS (SEQ ID NO: 6356), VPQEL (SEQ ID NO: 6412):EPLP (SEQ ID NO: 6354), VPQKM (SEQ ID NO: 6414):EPLP (SEQ ID NO: 6354), VPQKL (SEQ ID NO: 6413):EPLP (SEQ ID NO: 6354), VPQQL (SEQ ID NO: 6416):EPLP (SEQ ID NO: 6354), VPQRL (SEQ ID NO: 6417):EPLP (SEQ ID NO: 6354), VPQKT (SEQ ID NO: 6415):EPLP (SEQ ID NO: 6354), VPQDL (SEQ ID NO: 6411):EPLP (SEQ ID NO: 6354), VPTEL (SEQ ID NO: 6421):EPLP (SEQ ID NO: 6354), VPEKM (SEQ ID NO: 6406):EPLP (SEQ ID NO: 6354), APTKL (SEQ ID NO: 6369):EPLP (SEQ ID NO: 6354), APTOL (SEQ ID NO: 6372):EPLP (SEQ ID NO: 6354), VPTKL (SEQ ID NO: 6423):EPLP (SEQ ID NO: 6354), TPTKM (SEQ ID NO: 6388):EPLP (SEQ ID NO: 6354), VPARL (SEQ ID NO: 6401):EPLP (SEQ ID NO: 6354), VPTRL (SEQ ID NO: 6427):EPLP (SEQ ID NO: 6354), APVKT (SEQ ID NO: 6379):EPLP (SEQ ID NO: 6354), VSODL (SEQ ID NO: 6429):EPLP (SEQ ID NO: 6354), VPTEE (SEQ ID NO: 6420):EPLP (SEQ ID NO: 6354), VPTGQ (SEQ ID NO: 6422):EPLP (SEQ ID NO: 6354), SRVHH (SEQ ID NO: 6382):EPLP (SEQ ID NO: 6354), TQVQL (SEQ ID NO: 6393):EPLP (SEQ ID NO: 6354), VSQEL (SEQ ID NO: 6430):EPLT (SEQ ID NO: 6355), VSQKM (SEQ ID NO: 6432):EPLT (SEQ ID NO: 6355), VSQKL (SEQ ID NO: 6431):EPLT (SEQ ID NO: 6355), VSQQL (SEQ ID NO: 6434):EPLT (SEQ ID NO: 6355), VSQRL (SEQ ID NO: 6435):EPLT (SEQ ID NO: 6355), VSQKT (SEQ ID NO: 6433):EPLT (SEQ ID NO: 6355), VSQAL (SEQ ID NO: 6428):EPLT (SEQ ID NO: 6355), VSODL (SEQ ID NO: 6429):EPLT (SEQ ID NO: 6355), VPTEL (SEQ ID NO: 6421):EPLT (SEQ ID NO: 6355), VPEKM (SEQ ID NO: 6406):EPLT (SEQ ID NO: 6355), APTKL (SEQ ID NO: 6369):EPLT (SEQ ID NO: 6355), APTQL (SEQ ID NO: 6372):EPLT (SEQ ID NO: 6355), VPTKL (SEQ ID NO: 6423):EPLT (SEQ ID NO: 6355), TPTKM (SEQ ID NO: 6388):EPLT (SEQ ID NO: 6355), VPARL (SEQ ID NO: 6401):EPLT (SEQ ID NO: 6355), VPTRL (SEQ ID NO: 6427):EPLT (SEQ ID NO: 6355), APVKT (SEQ ID NO: 6379):EPLT (SEQ ID NO: 6355), VPQAL (SEQ ID NO: 6410):EPLT (SEQ ID NO: 6355), VPTEE (SEQ ID NO: 6420):EPLT (SEQ ID NO: 6355), VPTGQ (SEQ ID NO: 6422):EPLT (SEQ ID NO: 6355), SRVHH (SEQ ID NO: 6382):EPLT (SEQ ID NO: 6355), TQVQL (SEQ ID NO: 6393):EPLT (SEQ ID NO: 6355), VPQEL (SEQ ID NO: 6412):EPLT (SEQ ID NO: 6355), VPQKM (SEQ ID NO: 6414):EPLT (SEQ ID NO: 6355), VPQKL (SEQ ID NO: 6413):EPLT (SEQ ID NO: 6355), VPQQL (SEQ ID NO: 6416):EPLT (SEQ ID NO: 6355), VPQRL (SEQ ID NO: 6417):EPLT (SEQ ID NO: 6355), VPQKT (SEQ ID NO: 6415):EPLT (SEQ ID NO: 6355), VPQDL (SEQ ID NO: 6411):EPLT (SEQ ID NO: 6355), VPTGQ (SEQ ID NO: 6422):SNIT (SEQ ID NO: 6362), VPEKM (SEQ ID NO: 6406):SNIT (SEQ ID NO: 6362), APTKL (SEQ ID NO: 6369):SNIT (SEQ ID NO: 6362), APTQL (SEQ ID NO: 6372):SNIT (SEQ ID NO: 6362), TPTKM (SEQ ID NO: 6388):SNIT (SEQ ID NO: 6362), VPARL (SEQ ID NO: 6401):SNIT (SEQ ID NO: 6362), APVKT (SEQ ID NO: 6379):SNIT (SEQ ID NO: 6362), VPQAL (SEQ ID NO: 6410):SNIT (SEQ ID NO: 6362), VSODL (SEQ ID NO: 6429):SNIT (SEQ ID NO: 6362), VPQDL (SEQ ID NO: 6411):SNIT (SEQ ID NO: 6362), SRVHH (SEQ ID NO: 6382):SNIT (SEQ ID NO: 6362), TQVQL (SEQ ID NO: 6393):SNIT (SEQ ID NO: 6362), SRVQL (SEQ ID NO: 6383):RSVK (SEQ ID NO: 6359), VPTEL (SEQ ID NO: 6421):RSVK (SEQ ID NO: 6359), VPEKM (SEQ ID NO: 6406):RSVK (SEQ ID NO: 6359), APTKL (SEQ ID NO: 6369):RSVK (SEQ ID NO: 6359), APTQL (SEQ ID NO: 6372):RSVK (SEQ ID NO: 6359), VPTKL (SEQ ID NO: 6423):RSVK (SEQ ID NO: 6359), TPTKM (SEQ ID NO: 6388):RSVK (SEQ ID NO: 6359), VPARL (SEQ ID NO: 6401):RSVK (SEQ ID NO: 6359), VPTRL (SEQ ID NO: 6427):RSVK (SEQ ID NO: 6359), APVKT (SEQ ID NO: 6379):RSVK (SEQ ID NO: 6359), VPQAL (SEQ ID NO: 6410):RSVK (SEQ ID NO: 6359), VSODL (SEQ ID NO: 6429):RSVK (SEQ ID NO: 6359), VPQDL (SEQ ID NO: 6411):RSVK (SEQ ID NO: 6359), VPTEE (SEQ ID NO: 6420):RSVK (SEQ ID NO: 6359), VPTGQ (SEQ ID NO: 6422):RSVK (SEQ ID NO: 6359), TQVQL (SEQ ID NO: 6393):RSVK (SEQ ID NO: 6359), TQVHH (SEQ ID NO: 6392):RPVQ (SEQ ID NO: 6358), VPTEL (SEQ ID NO: 6421):RPVQ (SEQ ID NO: 6358), VPEKM (SEQ ID NO: 6406):RPVQ (SEQ ID NO: 6358), APTKL (SEQ ID NO: 6369):RPVQ (SEQ ID NO: 6358), APTQL (SEQ ID NO: 6372):RPVQ (SEQ ID NO: 6358), VPTKL (SEQ ID NO: 6423):RPVQ (SEQ ID NO: 6358), TPTKM (SEQ ID NO: 6388):RPVQ (SEQ ID NO: 6358), VPARL (SEQ ID NO: 6401):RPVQ (SEQ ID NO: 6358), VPTRL (SEQ ID NO: 6427):RPVQ (SEQ ID NO: 6358), APVKT (SEQ ID NO: 6379):RPVQ (SEQ ID NO: 6358), VPQAL (SEQ ID NO: 6410):RPVQ (SEQ ID NO: 6358), VSODL (SEQ ID NO: 6429):RPVQ (SEQ ID NO: 6358), VPQDL (SEQ ID NO: 6411):RPVQ (SEQ ID NO: 6358), VPTEE (SEQ ID NO: 6420):RPVQ (SEQ ID NO: 6358), VPTGQ (SEQ ID NO: 6422):RPVQ (SEQ ID NO: 6358) and SRVHH (SEQ ID NO: 6382):RPVQ (SEQ ID NO: 6358).
In particular, in certain embodiments, the pair PEP7:PEP1 is selected from the group consisting of GIPEPXX (SEQ ID NO: 6440):SAIS (SEQ ID NO: 6360), HVTKPTX (SEQ ID NO: 6443):SAIS (SEQ ID NO: 6360), YVPKPXX (SEQ ID NO: 6454):SAIS (SEQ ID NO: 6360), TVPKPXX (SEQ ID NO: 6453):SAIS (SEQ ID NO: 6360), AVPKAXX (SEQ ID NO: 6439):SAIS (SEQ ID NO: 6360), KVGKAXX (SEQ ID NO: 6446):SAIS (SEQ ID NO: 6360), KASKAXX (SEQ ID NO: 6444):SAIS (SEQ ID NO: 6360), GSAGPXX (SEQ ID NO: 6441):SAIS (SEQ ID NO: 6360), AAPASXX (SEQ ID NO: 6436):SAIS (SEQ ID NO: 6360), STPPTXX (SEQ ID NO: 6452):SAIS (SEQ ID NO: 6360), HVPKPXX (SEQ ID NO: 6442):SAIS (SEQ ID NO: 6360), RVPSTXX (SEQ ID NO: 6449):SAIS (SEQ ID NO: 6360), ASAAPXX (SEQ ID NO: 6437):SAIS (SEQ ID NO: 6360), ASASPXX (SEQ ID NO: 6438):SAIS (SEQ ID NO: 6360), SSVKXQP (SEQ ID NO: 6451):SAIS (SEQ ID NO: 6360), RNVQXRP (SEQ ID NO: 6448):SAIS (SEQ ID NO: 6360), KIPKAXX (SEQ ID NO: 6445):SSLS (SEQ ID NO: 6365), SIPKAXX (SEQ ID NO: 6450):SSLS (SEQ ID NO: 6365), HVTKPTX (SEQ ID NO: 6443):SSLS (SEQ ID NO: 6365), YVPKPXX (SEQ ID NO: 6454):SSLS (SEQ ID NO: 6365), TVPKPXX (SEQ ID NO: 6453):SSLS (SEQ ID NO: 6365), AVPKAXX (SEQ ID NO: 6439):SSLS (SEQ ID NO: 6365), KVGKAXX (SEQ ID NO: 6446):SSLS (SEQ ID NO: 6365), KASKAXX (SEQ ID NO: 6444):SSLS (SEQ ID NO: 6365), GSAGPXX (SEQ ID NO: 6441):SSLS (SEQ ID NO: 6365), AAPASXX (SEQ ID NO: 6436):SSLS (SEQ ID NO: 6365), STPPTXX (SEQ ID NO: 6452):SSLS (SEQ ID NO: 6365), HVPKPXX (SEQ ID NO: 6442):SSLS (SEQ ID NO: 6365), RVPSTXX (SEQ ID NO: 6449):SSLS (SEQ ID NO: 6365), ASAAPXX (SEQ ID NO: 6437):SSLS (SEQ ID NO: 6365), ASASPXX (SEQ ID NO: 6438):SSLS (SEQ ID NO: 6365), NDEGLEX (SEQ ID NO: 6447):SSLS (SEQ ID NO: 6365), SSVKXQP (SEQ ID NO: 6451):SSLS (SEQ ID NO: 6365), RNVQXRP (SEQ ID NO: 6448):SSLS (SEQ ID NO: 6365), KIPKAXX (SEQ ID NO: 6445):NAIS (SEQ ID NO: 6357), GIPEPXX (SEQ ID NO: 6440):NAIS (SEQ ID NO: 6357), SIPKAXX (SEQ ID NO: 6450):NAIS (SEQ ID NO: 6357), AVPKAXX (SEQ ID NO: 6439):NAIS (SEQ ID NO: 6357), KVGKAXX (SEQ ID NO: 6446):NAIS (SEQ ID NO: 6357), KASKAXX (SEQ ID NO: 6444):NAIS (SEQ ID NO: 6357), GSAGPXX (SEQ ID NO: 6441):NAIS (SEQ ID NO: 6357), AAPASXX (SEQ ID NO: 6436):NAIS (SEQ ID NO: 6357), STPPTXX (SEQ ID NO: 6452):NAIS (SEQ ID NO: 6357), RVPSTXX (SEQ ID NO: 6449):NAIS (SEQ ID NO: 6357), ASAAPXX (SEQ ID NO: 6437):NAIS (SEQ ID NO: 6357), ASASPXX (SEQ ID NO: 6438):NAIS (SEQ ID NO: 6357), NDEGLEX (SEQ ID NO: 6447):NAIS (SEQ ID NO: 6357), SSVKXQP (SEQ ID NO: 6451):NAIS (SEQ ID NO: 6357), RNVQXRP (SEQ ID NO: 6448):NAIS (SEQ ID NO: 6357), KIPKAXX (SEQ ID NO: 6445):SATS (SEQ ID NO: 6361), GIPEPXX (SEQ ID NO: 6440):SATS (SEQ ID NO: 6361), SIPKAXX (SEQ ID NO: 6450):SATS (SEQ ID NO: 6361), HVTKPTX (SEQ ID NO: 6443):SATS (SEQ ID NO: 6361), YVPKPXX (SEQ ID NO: 6454):SATS (SEQ ID NO: 6361), TVPKPXX (SEQ ID NO: 6453):SATS (SEQ ID NO: 6361), KVGKAXX (SEQ ID NO: 6446):SATS (SEQ ID NO: 6361), KASKAXX (SEQ ID NO: 6444):SATS (SEQ ID NO: 6361), GSAGPXX (SEQ ID NO: 6441):SATS (SEQ ID NO: 6361), AAPASXX (SEQ ID NO: 6436):SATS (SEQ ID NO: 6361), STPPTXX (SEQ ID NO: 6452):SATS (SEQ ID NO: 6361), HVPKPXX (SEQ ID NO: 6442):SATS (SEQ ID NO: 6361), RVPSTXX (SEQ ID NO: 6449):SATS (SEQ ID NO: 6361), ASAAPXX (SEQ ID NO: 6437):SATS (SEQ ID NO: 6361), ASASPXX (SEQ ID NO: 6438):SATS (SEQ ID NO: 6361), NDEGLEX (SEQ ID NO: 6447):SATS (SEQ ID NO: 6361), SSVKXQP (SEQ ID NO: 6451):SATS (SEQ ID NO: 6361), RNVQXRP (SEQ ID NO: 6448):SATS (SEQ ID NO: 6361), KIPKAXX (SEQ ID NO: 6445):SPIS (SEQ ID NO: 6364), GIPEPXX (SEQ ID NO: 6440):SPIS (SEQ ID NO: 6364), SIPKAXX (SEQ ID NO: 6450):SPIS (SEQ ID NO: 6364), HVTKPTX (SEQ ID NO: 6443):SPIS (SEQ ID NO: 6364), YVPKPXX (SEQ ID NO: 6454):SPIS (SEQ ID NO: 6364), TVPKPXX (SEQ ID NO: 6453):SPIS (SEQ ID NO: 6364), AVPKAXX (SEQ ID NO: 6439):SPIS (SEQ ID NO: 6364), KASKAXX (SEQ ID NO: 6444):SPIS (SEQ ID NO: 6364), GSAGPXX (SEQ ID NO: 6441):SPIS (SEQ ID NO: 6364), AAPASXX (SEQ ID NO: 6436):SPIS (SEQ ID NO: 6364), STPPTXX (SEQ ID NO: 6452):SPIS (SEQ ID NO: 6364), HVPKPXX (SEQ ID NO: 6442):SPIS (SEQ ID NO: 6364), RVPSTXX (SEQ ID NO: 6449):SPIS (SEQ ID NO: 6364), ASAAPXX (SEQ ID NO: 6437):SPIS (SEQ ID NO: 6364), ASASPXX (SEQ ID NO: 6438):SPIS (SEQ ID NO: 6364), SSVKXQP (SEQ ID NO: 6451):SPIS (SEQ ID NO: 6364), RNVQXRP (SEQ ID NO: 6448):SPIS (SEQ ID NO: 6364), KIPKAXX (SEQ ID NO: 6445):EPIS (SEQ ID NO: 6353), GIPEPXX (SEQ ID NO: 6440):EPIS (SEQ ID NO: 6353), SIPKAXX (SEQ ID NO: 6450):EPIS (SEQ ID NO: 6353), HVTKPTX (SEQ ID NO: 6443):EPIS (SEQ ID NO: 6353), YVPKPXX (SEQ ID NO: 6454):EPIS (SEQ ID NO: 6353), TVPKPXX (SEQ ID NO: 6453):EPIS (SEQ ID NO: 6353), AVPKAXX (SEQ ID NO: 6439):EPIS (SEQ ID NO: 6353), KVGKAXX (SEQ ID NO: 6446):EPIS (SEQ ID NO: 6353), GSAGPXX (SEQ ID NO: 6441):EPIS (SEQ ID NO: 6353), AAPASXX (SEQ ID NO: 6436):EPIS (SEQ ID NO: 6353), STPPTXX (SEQ ID NO: 6452):EPIS (SEQ ID NO: 6353), HVPKPXX (SEQ ID NO: 6442):EPIS (SEQ ID NO: 6353), RVPSTXX (SEQ ID NO: 6449):EPIS (SEQ ID NO: 6353), ASAAPXX (SEQ ID NO: 6437):EPIS (SEQ ID NO: 6353), ASASPXX (SEQ ID NO: 6438):EPIS (SEQ ID NO: 6353), SSVKXQP (SEQ ID NO: 6451):EPIS (SEQ ID NO: 6353), RNVQXRP (SEQ ID NO: 6448):EPIS (SEQ ID NO: 6353), KIPKAXX (SEQ ID NO: 6445):SPIN (SEQ ID NO: 6363), GIPEPXX (SEQ ID NO: 6440):SPIN (SEQ ID NO: 6363), SIPKAXX (SEQ ID NO: 6450):SPIN (SEQ ID NO: 6363), HVTKPTX (SEQ ID NO: 6443):SPIN (SEQ ID NO: 6363), YVPKPXX (SEQ ID NO: 6454):SPIN (SEQ ID NO: 6363), TVPKPXX (SEQ ID NO: 6453):SPIN (SEQ ID NO: 6363), AVPKAXX (SEQ ID NO: 6439):SPIN (SEQ ID NO: 6363), KVGKAXX (SEQ ID NO: 6446):SPIN (SEQ ID NO: 6363), KASKAXX (SEQ ID NO: 6444):SPIN (SEQ ID NO: 6363), AAPASXX (SEQ ID NO: 6436):SPIN (SEQ ID NO: 6363), STPPTXX (SEQ ID NO: 6452):SPIN (SEQ ID NO: 6363), HVPKPXX (SEQ ID NO: 6442):SPIN (SEQ ID NO: 6363), RVPSTXX (SEQ ID NO: 6449):SPIN (SEQ ID NO: 6363), ASAAPXX (SEQ ID NO: 6437):SPIN (SEQ ID NO: 6363), ASASPXX (SEQ ID NO: 6438):SPIN (SEQ ID NO: 6363), NDEGLEX (SEQ ID NO: 6447):SPIN (SEQ ID NO: 6363), SSVKXQP (SEQ ID NO: 6451):SPIN (SEQ ID NO: 6363), RNVQXRP (SEQ ID NO: 6448):SPIN (SEQ ID NO: 6363), KVGKAXX (SEQ ID NO: 6446):SPIS (SEQ ID NO: 6364), NDEGLEX (SEQ ID NO: 6447):SPIS (SEQ ID NO: 6364), KIPKAXX (SEQ ID NO: 6445):KPLS (SEQ ID NO: 6356), GIPEPXX (SEQ ID NO: 6440):KPLS (SEQ ID NO: 6356), SIPKAXX (SEQ ID NO: 6450):KPLS (SEQ ID NO: 6356), HVTKPTX (SEQ ID NO: 6443):KPLS (SEQ ID NO: 6356), YVPKPXX (SEQ ID NO: 6454):KPLS (SEQ ID NO: 6356), TVPKPXX (SEQ ID NO: 6453):KPLS (SEQ ID NO: 6356), AVPKAXX (SEQ ID NO: 6439):KPLS (SEQ ID NO: 6356), KVGKAXX (SEQ ID NO: 6446):KPLS (SEQ ID NO: 6356), KASKAXX (SEQ ID NO: 6444):KPLS (SEQ ID NO: 6356), GSAGPXX (SEQ ID NO: 6441):KPLS (SEQ ID NO: 6356), AAPASXX (SEQ ID NO: 6436):KPLS (SEQ ID NO: 6356), STPPTXX (SEQ ID NO: 6452):KPLS (SEQ ID NO: 6356), HVPKPXX (SEQ ID NO: 6442):KPLS (SEQ ID NO: 6356), ASAAPXX (SEQ ID NO: 6437):KPLS (SEQ ID NO: 6356), ASASPXX (SEQ ID NO: 6438):KPLS (SEQ ID NO: 6356), NDEGLEX (SEQ ID NO: 6447):KPLS (SEQ ID NO: 6356), SSVKXQP (SEQ ID NO: 6451):KPLS (SEQ ID NO: 6356), RNVQXRP (SEQ ID NO: 6448):KPLS (SEQ ID NO: 6356), KIPKAXX (SEQ ID NO: 6445):EPLP (SEQ ID NO: 6354), GIPEPXX (SEQ ID NO: 6440):EPLP (SEQ ID NO: 6354), SIPKAXX (SEQ ID NO: 6450):EPLP (SEQ ID NO: 6354), HVTKPTX (SEQ ID NO: 6443):EPLP (SEQ ID NO: 6354), YVPKPXX (SEQ ID NO: 6454):EPLP (SEQ ID NO: 6354), TVPKPXX (SEQ ID NO: 6453):EPLP (SEQ ID NO: 6354), AVPKAXX (SEQ ID NO: 6439):EPLP (SEQ ID NO: 6354), KVGKAXX (SEQ ID NO: 6446):EPLP (SEQ ID NO: 6354), KASKAXX (SEQ ID NO: 6444):EPLP (SEQ ID NO: 6354), GSAGPXX (SEQ ID NO: 6441):EPLP (SEQ ID NO: 6354), AAPASXX (SEQ ID NO: 6436):EPLP (SEQ ID NO: 6354), STPPTXX (SEQ ID NO: 6452):EPLP (SEQ ID NO: 6354), HVPKPXX (SEQ ID NO: 6442):EPLP (SEQ ID NO: 6354), RVPSTXX (SEQ ID NO: 6449):EPLP (SEQ ID NO: 6354), ASASPXX (SEQ ID NO: 6438):EPLP (SEQ ID NO: 6354), NDEGLEX (SEQ ID NO: 6447):EPLP (SEQ ID NO: 6354), SSVKXQP (SEQ ID NO: 6451):EPLP (SEQ ID NO: 6354), RNVQXRP (SEQ ID NO: 6448):EPLP (SEQ ID NO: 6354), KIPKAXX (SEQ ID NO: 6445):EPLT (SEQ ID NO: 6355), GIPEPXX (SEQ ID NO: 6440):EPLT (SEQ ID NO: 6355), SIPKAXX (SEQ ID NO: 6450):EPLT (SEQ ID NO: 6355), HVTKPTX (SEQ ID NO: 6443):EPLT (SEQ ID NO: 6355), YVPKPXX (SEQ ID NO: 6454):EPLT (SEQ ID NO: 6355), TVPKPXX (SEQ ID NO: 6453):EPLT (SEQ ID NO: 6355), AVPKAXX (SEQ ID NO: 6439):EPLT (SEQ ID NO: 6355), KVGKAXX (SEQ ID NO: 6446):EPLT (SEQ ID NO: 6355), KASKAXX (SEQ ID NO: 6444):EPLT (SEQ ID NO: 6355), GSAGPXX (SEQ ID NO: 6441):EPLT (SEQ ID NO: 6355), AAPASXX (SEQ ID NO: 6436):EPLT (SEQ ID NO: 6355), STPPTXX (SEQ ID NO: 6452):EPLT (SEQ ID NO: 6355), HVPKPXX (SEQ ID NO: 6442):EPLT (SEQ ID NO: 6355), RVPSTXX (SEQ ID NO: 6449):EPLT (SEQ ID NO: 6355), ASAAPXX (SEQ ID NO: 6437):EPLT (SEQ ID NO: 6355), ASASPXX (SEQ ID NO: 6438):EPLT (SEQ ID NO: 6355), NDEGLEX (SEQ ID NO: 6447):EPLT (SEQ ID NO: 6355), SSVKXQP (SEQ ID NO: 6451):EPLT (SEQ ID NO: 6355), RNVQXRP (SEQ ID NO: 6448):EPLT (SEQ ID NO: 6355), NDEGLEX (SEQ ID NO: 6447):SNIT (SEQ ID NO: 6362), GIPEPXX (SEQ ID NO: 6440):SNIT (SEQ ID NO: 6362), HVTKPTX (SEQ ID NO: 6443):SNIT (SEQ ID NO: 6362), YVPKPXX (SEQ ID NO: 6454):SNIT (SEQ ID NO: 6362), TVPKPXX (SEQ ID NO: 6453):SNIT (SEQ ID NO: 6362), AVPKAXX (SEQ ID NO: 6439):SNIT (SEQ ID NO: 6362), GSAGPXX (SEQ ID NO: 6441):SNIT (SEQ ID NO: 6362), AAPASXX (SEQ ID NO: 6436):SNIT (SEQ ID NO: 6362), HVPKPXX (SEQ ID NO: 6442):SNIT (SEQ ID NO: 6362), RVPSTXX (SEQ ID NO: 6449):SNIT (SEQ ID NO: 6362), ASAAPXX (SEQ ID NO: 6437):SNIT (SEQ ID NO: 6362), ASASPXX (SEQ ID NO: 6438):SNIT (SEQ ID NO: 6362), SSVKXQP (SEQ ID NO: 6451):SNIT (SEQ ID NO: 6362), RNVQXRP (SEQ ID NO: 6448):SNIT (SEQ ID NO: 6362), RNVQXRP (SEQ ID NO: 6448):RSVK (SEQ ID NO: 6359), KIPKAXX (SEQ ID NO: 6445):RSVK (SEQ ID NO: 6359), GIPEPXX (SEQ ID NO: 6440):RSVK (SEQ ID NO: 6359), SIPKAXX (SEQ ID NO: 6450):RSVK (SEQ ID NO: 6359), HVTKPTX (SEQ ID NO: 6443):RSVK (SEQ ID NO: 6359), YVPKPXX (SEQ ID NO: 6454):RSVK (SEQ ID NO: 6359), TVPKPXX (SEQ ID NO: 6453):RSVK (SEQ ID NO: 6359), AVPKAXX (SEQ ID NO: 6439):RSVK (SEQ ID NO: 6359), KVGKAXX (SEQ ID NO: 6446):RSVK (SEQ ID NO: 6359), KASKAXX (SEQ ID NO: 6444):RSVK (SEQ ID NO: 6359), GSAGPXX (SEQ ID NO: 6441):RSVK (SEQ ID NO: 6359), AAPASXX (SEQ ID NO: 6436):RSVK (SEQ ID NO: 6359), STPPTXX (SEQ ID NO: 6452):RSVK (SEQ ID NO: 6359), HVPKPXX (SEQ ID NO: 6442):RSVK (SEQ ID NO: 6359), RVPSTXX (SEQ ID NO: 6449):RSVK (SEQ ID NO: 6359), ASAAPXX (SEQ ID NO: 6437):RSVK (SEQ ID NO: 6359), ASASPXX (SEQ ID NO: 6438):RSVK (SEQ ID NO: 6359), NDEGLEX (SEQ ID NO: 6447):RSVK (SEQ ID NO: 6359), SSVKXQP (SEQ ID NO: 6451):RPVQ (SEQ ID NO: 6358), KIPKAXX (SEQ ID NO: 6445):RPVQ (SEQ ID NO: 6358), GIPEPXX (SEQ ID NO: 6440):RPVQ (SEQ ID NO: 6358), SIPKAXX (SEQ ID NO: 6450):RPVQ (SEQ ID NO: 6358), HVTKPTX (SEQ ID NO: 6443):RPVQ (SEQ ID NO: 6358), YVPKPXX (SEQ ID NO: 6454):RPVQ (SEQ ID NO: 6358), TVPKPXX (SEQ ID NO: 6453):RPVQ (SEQ ID NO: 6358), AVPKAXX (SEQ ID NO: 6439):RPVQ (SEQ ID NO: 6358), KVGKAXX (SEQ ID NO: 6446):RPVQ (SEQ ID NO: 6358), KASKAXX (SEQ ID NO: 6444):RPVQ (SEQ ID NO: 6358), GSAGPXX (SEQ ID NO: 6441):RPVQ (SEQ ID NO: 6358), AAPASXX (SEQ ID NO: 6436):RPVQ (SEQ ID NO: 6358), STPPTXX (SEQ ID NO: 6452):RPVQ (SEQ ID NO: 6358), HVPKPXX (SEQ ID NO: 6442):RPVQ (SEQ ID NO: 6358), RVPSTXX (SEQ ID NO: 6449):RPVQ (SEQ ID NO: 6358), ASAAPXX (SEQ ID NO: 6437):RPVQ (SEQ ID NO: 6358), ASASPXX (SEQ ID NO: 6438):RPVQ (SEQ ID NO: 6358) and NDEGLEX (SEQ ID NO: 6447):RPVQ (SEQ ID NO: 6358).
In particular, in certain embodiments, the pair PEP9:PEP1 is selected from the group consisting of GIPEPXXVPTKM (SEQ ID NO: 6493):SAIS (SEQ ID NO: 6360), HVTKPTXVPTKL (SEQ ID NO: 6519):SAIS (SEQ ID NO: 6360), YVPKPXXVPTKL (SEQ ID NO: 6589):SAIS (SEQ ID NO: 6360), TVPKPXXVPTQL (SEQ ID NO: 6581):SAIS (SEQ ID NO: 6360), AVPKAXXVPTKL (SEQ ID NO: 6485):SAIS (SEQ ID NO: 6360), KVGKAXXVPTKL (SEQ ID NO: 6543):SAIS (SEQ ID NO: 6360), KASKAXXVPTKL (SEQ ID NO: 6527):SAIS (SEQ ID NO: 6360), GSAGPXXVPTKM (SEQ ID NO: 6501):SAIS (SEQ ID NO: 6360), AAPASXXVPTRL (SEQ ID NO: 6461):SAIS (SEQ ID NO: 6360), STPPTXXVPTRL (SEQ ID NO: 6573):SAIS (SEQ ID NO: 6360), HVPKPXXVPTKL (SEQ ID NO: 6509):SAIS (SEQ ID NO: 6360), RVPSTXXVPTKT (SEQ ID NO: 6555):SAIS (SEQ ID NO: 6360), ASAAPXXVPTAL (SEQ ID NO: 6469):SAIS (SEQ ID NO: 6360), ASASPXXVPTDL (SEQ ID NO: 6477):SAIS (SEQ ID NO: 6360), GIPEPXXVPEKM (SEQ ID NO: 6491):SAIS (SEQ ID NO: 6360), HVTKPTXAPTKL (SEQ ID NO: 6511):SAIS (SEQ ID NO: 6360), YVPKPXXAPTKL (SEQ ID NO: 6583):SAIS (SEQ ID NO: 6360), TVPKPXXAPTQL (SEQ ID NO: 6575):SAIS (SEQ ID NO: 6360), AVPKAXXAPTKL (SEQ ID NO: 6479):SAIS (SEQ ID NO: 6360), GSAGPXXTPTKM (SEQ ID NO: 6497):SAIS (SEQ ID NO: 6360), AAPASXXVPARL (SEQ ID NO: 6458):SAIS (SEQ ID NO: 6360), HVPKPXXAPTKL (SEQ ID NO: 6503):SAIS (SEQ ID NO: 6360), RVPSTXXAPVKT (SEQ ID NO: 6550):SAIS (SEQ ID NO: 6360), ASAAPXXVPQAL (SEQ ID NO: 6468):SAIS (SEQ ID NO: 6360), ASASPXXVSQDL (SEQ ID NO: 6478):SAIS (SEQ ID NO: 6360), ASASPXXVPQDL (SEQ ID NO: 6476):SAIS (SEQ ID NO: 6360), SSVKXQPSRVHH (SEQ ID NO: 6565):SAIS (SEQ ID NO: 6360), RNVQXRPTQVQL (SEQ ID NO: 6548):SAIS (SEQ ID NO: 6360), KIPKAXXVPEEL (SEQ ID NO: 6533):SSLS (SEQ ID NO: 6365), SIPKAXXVPEEL (SEQ ID NO: 6561):SSLS (SEQ ID NO: 6365), HVTKPTXVPEKL (SEQ ID NO: 6517):SSLS (SEQ ID NO: 6365), YVPKPXXVPEKL (SEQ ID NO: 6587):SSLS (SEQ ID NO: 6365), TVPKPXXVPEQL (SEQ ID NO: 6579):SSLS (SEQ ID NO: 6365), AVPKAXXVPEKL (SEQ ID NO: 6483):SSLS (SEQ ID NO: 6365), KVGKAXXVPEKL (SEQ ID NO: 6541):SSLS (SEQ ID NO: 6365), KASKAXXVPEKL (SEQ ID NO: 6525):SSLS (SEQ ID NO: 6365), GSAGPXXVPEKM (SEQ ID NO: 6499):SSLS (SEQ ID NO: 6365), AAPASXXVPERL (SEQ ID NO: 6459):SSLS (SEQ ID NO: 6365), STPPTXXVPERL (SEQ ID NO: 6571):SSLS (SEQ ID NO: 6365), HVPKPXXVPEKL (SEQ ID NO: 6507):SSLS (SEQ ID NO: 6365), RVPSTXXVPEKT (SEQ ID NO: 6553):SSLS (SEQ ID NO: 6365), ASAAPXXVPEAL (SEQ ID NO: 6467):SSLS (SEQ ID NO: 6365), ASASPXXVPEDL (SEQ ID NO: 6475):SSLS (SEQ ID NO: 6365), KIPKAXXVPTEL (SEQ ID NO: 6535):SSLS (SEQ ID NO: 6365), SIPKAXXVPTEL (SEQ ID NO: 6563):SSLS (SEQ ID NO: 6365), HVTKPTXAPTKL (SEQ ID NO: 6511):SSLS (SEQ ID NO: 6365), YVPKPXXAPTKL (SEQ ID NO: 6583):SSLS (SEQ ID NO: 6365), TVPKPXXAPTQL (SEQ ID NO: 6575):SSLS (SEQ ID NO: 6365), AVPKAXXAPTKL (SEQ ID NO: 6479):SSLS (SEQ ID NO: 6365), KVGKAXXVPTKL (SEQ ID NO: 6543):SSLS (SEQ ID NO: 6365), KASKAXXVPTKL (SEQ ID NO: 6527):SSLS (SEQ ID NO: 6365), GSAGPXXTPTKM (SEQ ID NO: 6497):SSLS (SEQ ID NO: 6365), AAPASXXVPARL (SEQ ID NO: 6458):SSLS (SEQ ID NO: 6365), STPPTXXVPTRL (SEQ ID NO: 6573):SSLS (SEQ ID NO: 6365), HVPKPXXAPTKL (SEQ ID NO: 6503):SSLS (SEQ ID NO: 6365), RVPSTXXAPVKT (SEQ ID NO: 6550):SSLS (SEQ ID NO: 6365), ASAAPXXVPQAL (SEQ ID NO: 6468):SSLS (SEQ ID NO: 6365), ASASPXXVSQDL (SEQ ID NO: 6478):SSLS (SEQ ID NO: 6365), ASASPXXVPQDL (SEQ ID NO: 6476):SSLS (SEQ ID NO: 6365), NDEGLEXVPTEE (SEQ ID NO: 6545):SSLS (SEQ ID NO: 6365), NDEGLEXVPTGQ (SEQ ID NO: 6546):SSLS (SEQ ID NO: 6365), SSVKXQPSRVHH (SEQ ID NO: 6565):SSLS (SEQ ID NO: 6365), RNVQXRPTQVQL (SEQ ID NO: 6548):SSLS (SEQ ID NO: 6365), KIPKAXXAPTEL (SEQ ID NO: 6529):NAIS (SEQ ID NO: 6357), GIPEPXXAPTKM (SEQ ID NO: 6487):NAIS (SEQ ID NO: 6357), SIPKAXXAPTEL (SEQ ID NO: 6557):NAIS (SEQ ID NO: 6357), AVPKAXXAPTKL (SEQ ID NO: 6479):NAIS (SEQ ID NO: 6357), KVGKAXXAPTKL (SEQ ID NO: 6537):NAIS (SEQ ID NO: 6357), KASKAXXAPTKL (SEQ ID NO: 6521):NAIS (SEQ ID NO: 6357), GSAGPXXAPTKM (SEQ ID NO: 6495):NAIS (SEQ ID NO: 6357), AAPASXXAPTRL (SEQ ID NO: 6455):NAIS (SEQ ID NO: 6357), STPPTXXAPTRL (SEQ ID NO: 6567):NAIS (SEQ ID NO: 6357), RVPSTXXAPTKT (SEQ ID NO: 6549):NAIS (SEQ ID NO: 6357), ASAAPXXAPTAL (SEQ ID NO: 6463):NAIS (SEQ ID NO: 6357), ASASPXXAPTDL (SEQ ID NO: 6471):NAIS (SEQ ID NO: 6357), KIPKAXXVPTEL (SEQ ID NO: 6535):NAIS (SEQ ID NO: 6357), GIPEPXXVPEKM (SEQ ID NO: 6491):NAIS (SEQ ID NO: 6357), SIPKAXXVPTEL (SEQ ID NO: 6563):NAIS (SEQ ID NO: 6357), KVGKAXXVPTKL (SEQ ID NO: 6543):NAIS (SEQ ID NO: 6357), KASKAXXVPTKL (SEQ ID NO: 6527):NAIS (SEQ ID NO: 6357), GSAGPXXTPTKM (SEQ ID NO: 6497):NAIS (SEQ ID NO: 6357), AAPASXXVPARL (SEQ ID NO: 6458):NAIS (SEQ ID NO: 6357), STPPTXXVPTRL (SEQ ID NO: 6573):NAIS (SEQ ID NO: 6357), RVPSTXXAPVKT (SEQ ID NO: 6550):NAIS (SEQ ID NO: 6357), ASAAPXXVPQAL (SEQ ID NO: 6468):NAIS (SEQ ID NO: 6357), ASASPXXVSQDL (SEQ ID NO: 6478):NAIS (SEQ ID NO: 6357), ASASPXXVPQDL (SEQ ID NO: 6476):NAIS (SEQ ID NO: 6357), NDEGLEXVPTEE (SEQ ID NO: 6545):NAIS (SEQ ID NO: 6357), NDEGLEXVPTGQ (SEQ ID NO: 6546):NAIS (SEQ ID NO: 6357), SSVKXQPSRVHH (SEQ ID NO: 6565):NAIS (SEQ ID NO: 6357), RNVQXRPTQVQL (SEQ ID NO: 6548):NAIS (SEQ ID NO: 6357), KIPKAXXAPTEL (SEQ ID NO: 6529):SATS (SEQ ID NO: 6361), GIPEPXXAPTKM (SEQ ID NO: 6487):SATS (SEQ ID NO: 6361), SIPKAXXAPTEL (SEQ ID NO: 6557):SATS (SEQ ID NO: 6361), HVTKPTXAPTKL (SEQ ID NO: 6511):SATS (SEQ ID NO: 6361), YVPKPXXAPTKL (SEQ ID NO: 6583):SATS (SEQ ID NO: 6361), TVPKPXXAPTQL (SEQ ID NO: 6575):SATS (SEQ ID NO: 6361), KVGKAXXAPTKL (SEQ ID NO: 6537):SATS (SEQ ID NO: 6361), KASKAXXAPTKL (SEQ ID NO: 6521):SATS (SEQ ID NO: 6361), GSAGPXXAPTKM (SEQ ID NO: 6495):SATS (SEQ ID NO: 6361), AAPASXXAPTRL (SEQ ID NO: 6455):SATS (SEQ ID NO: 6361), STPPTXXAPTRL (SEQ ID NO: 6567):SATS (SEQ ID NO: 6361), HVPKPXXAPTKL (SEQ ID NO: 6503):SATS (SEQ ID NO: 6361), RVPSTXXAPTKT (SEQ ID NO: 6549):SATS (SEQ ID NO: 6361), ASAAPXXAPTAL (SEQ ID NO: 6463):SATS (SEQ ID NO: 6361), ASASPXXAPTDL (SEQ ID NO: 6471):SATS (SEQ ID NO: 6361), KIPKAXXVPTEL (SEQ ID NO: 6535):SATS (SEQ ID NO: 6361), GIPEPXXVPEKM (SEQ ID NO: 6491):SATS (SEQ ID NO: 6361), SIPKAXXVPTEL (SEQ ID NO: 6563):SATS (SEQ ID NO: 6361), KVGKAXXVPTKL (SEQ ID NO: 6543):SATS (SEQ ID NO: 6361), KASKAXXVPTKL (SEQ ID NO: 6527):SATS (SEQ ID NO: 6361), GSAGPXXTPTKM (SEQ ID NO: 6497):SATS (SEQ ID NO: 6361), AAPASXXVPARL (SEQ ID NO: 6458):SATS (SEQ ID NO: 6361), STPPTXXVPTRL (SEQ ID NO: 6573):SATS (SEQ ID NO: 6361), RVPSTXXAPVKT (SEQ ID NO: 6550):SATS (SEQ ID NO: 6361), ASAAPXXVPQAL (SEQ ID NO: 6468):SATS (SEQ ID NO: 6361), ASASPXXVSQDL (SEQ ID NO: 6478):SATS (SEQ ID NO: 6361), ASASPXXVPQDL (SEQ ID NO: 6476):SATS (SEQ ID NO: 6361), NDEGLEXVPTEE (SEQ ID NO: 6545):SATS (SEQ ID NO: 6361), NDEGLEXVPTGQ (SEQ ID NO: 6546):SATS (SEQ ID NO: 6361), SSVKXQPSRVHH (SEQ ID NO: 6565):SATS (SEQ ID NO: 6361), RNVQXRPTQVQL (SEQ ID NO: 6548):SATS (SEQ ID NO: 6361), KIPKAXXVPTEL (SEQ ID NO: 6535):SPIS (SEQ ID NO: 6364), GIPEPXXVPTKM (SEQ ID NO: 6493):SPIS (SEQ ID NO: 6364), SIPKAXXVPTEL (SEQ ID NO: 6563):SPIS (SEQ ID NO: 6364), HVTKPTXVPTKL (SEQ ID NO: 6519):SPIS (SEQ ID NO: 6364), YVPKPXXVPTKL (SEQ ID NO: 6589):SPIS (SEQ ID NO: 6364), TVPKPXXVPTQL (SEQ ID NO: 6581):SPIS (SEQ ID NO: 6364), AVPKAXXVPTKL (SEQ ID NO: 6485):SPIS (SEQ ID NO: 6364), KASKAXXVPTKL (SEQ ID NO: 6527):SPIS (SEQ ID NO: 6364), GSAGPXXVPTKM (SEQ ID NO: 6501):SPIS (SEQ ID NO: 6364), AAPASXXVPTRL (SEQ ID NO: 6461):SPIS (SEQ ID NO: 6364), STPPTXXVPTRL (SEQ ID NO: 6573):SPIS (SEQ ID NO: 6364), HVPKPXXVPTKL (SEQ ID NO: 6509):SPIS (SEQ ID NO: 6364), RVPSTXXVPTKT (SEQ ID NO: 6555):SPIS (SEQ ID NO: 6364), ASAAPXXVPTAL (SEQ ID NO: 6469):SPIS (SEQ ID NO: 6364), ASASPXXVPTDL (SEQ ID NO: 6477):SPIS (SEQ ID NO: 6364), GIPEPXXVPEKM (SEQ ID NO: 6491):SPIS (SEQ ID NO: 6364), HVTKPTXAPTKL (SEQ ID NO: 6511):SPIS (SEQ ID NO: 6364), YVPKPXXAPTKL (SEQ ID NO: 6583):SPIS (SEQ ID NO: 6364), TVPKPXXAPTQL (SEQ ID NO: 6575):SPIS (SEQ ID NO: 6364), AVPKAXXAPTKL (SEQ ID NO: 6479):SPIS (SEQ ID NO: 6364), GSAGPXXTPTKM (SEQ ID NO: 6497):SPIS (SEQ ID NO: 6364), AAPASXXVPARL (SEQ ID NO: 6458):SPIS (SEQ ID NO: 6364), HVPKPXXAPTKL (SEQ ID NO: 6503):SPIS (SEQ ID NO: 6364), RVPSTXXAPVKT (SEQ ID NO: 6550):SPIS (SEQ ID NO: 6364), ASAAPXXVPQAL (SEQ ID NO: 6468):SPIS (SEQ ID NO: 6364), ASASPXXVSQDL (SEQ ID NO: 6478):SPIS (SEQ ID NO: 6364), ASASPXXVPQDL (SEQ ID NO: 6476):SPIS (SEQ ID NO: 6364), SSVKXQPSRVHH (SEQ ID NO: 6565):SPIS (SEQ ID NO: 6364), RNVQXRPTQVQL (SEQ ID NO: 6548):SPIS (SEQ ID NO: 6364), KIPKAXXVPTEL (SEQ ID NO: 6535):EPIS (SEQ ID NO: 6353), GIPEPXXVPTKM (SEQ ID NO: 6493):EPIS (SEQ ID NO: 6353), SIPKAXXVPTEL (SEQ ID NO: 6563):EPIS (SEQ ID NO: 6353), HVTKPTXVPTKL (SEQ ID NO: 6519):EPIS (SEQ ID NO: 6353), YVPKPXXVPTKL (SEQ ID NO: 6589):EPIS (SEQ ID NO: 6353), TVPKPXXVPTQL (SEQ ID NO: 6581):EPIS (SEQ ID NO: 6353), AVPKAXXVPTKL (SEQ ID NO: 6485):EPIS (SEQ ID NO: 6353), KVGKAXXVPTKL (SEQ ID NO: 6543):EPIS (SEQ ID NO: 6353), GSAGPXXVPTKM (SEQ ID NO: 6501):EPIS (SEQ ID NO: 6353), AAPASXXVPTRL (SEQ ID NO: 6461):EPIS (SEQ ID NO: 6353), STPPTXXVPTRL (SEQ ID NO: 6573):EPIS (SEQ ID NO: 6353), HVPKPXXVPTKL (SEQ ID NO: 6509):EPIS (SEQ ID NO: 6353), RVPSTXXVPTKT (SEQ ID NO: 6555):EPIS (SEQ ID NO: 6353), ASAAPXXVPTAL (SEQ ID NO: 6469):EPIS (SEQ ID NO: 6353), ASASPXXVPTDL (SEQ ID NO: 6477):EPIS (SEQ ID NO: 6353), GIPEPXXVPEKM (SEQ ID NO: 6491):EPIS (SEQ ID NO: 6353), HVTKPTXAPTKL (SEQ ID NO: 6511):EPIS (SEQ ID NO: 6353), YVPKPXXAPTKL (SEQ ID NO: 6583):EPIS (SEQ ID NO: 6353), TVPKPXXAPTQL (SEQ ID NO: 6575):EPIS (SEQ ID NO: 6353), AVPKAXXAPTKL (SEQ ID NO: 6479):EPIS (SEQ ID NO: 6353), GSAGPXXTPTKM (SEQ ID NO: 6497):EPIS (SEQ ID NO: 6353), AAPASXXVPARL (SEQ ID NO: 6458):EPIS (SEQ ID NO: 6353), HVPKPXXAPTKL (SEQ ID NO: 6503):EPIS (SEQ ID NO: 6353), RVPSTXXAPVKT (SEQ ID NO: 6550):EPIS (SEQ ID NO: 6353), ASAAPXXVPQAL (SEQ ID NO: 6468):EPIS (SEQ ID NO: 6353), ASASPXXVSQDL (SEQ ID NO: 6478):EPIS (SEQ ID NO: 6353), ASASPXXVPQDL (SEQ ID NO: 6476):EPIS (SEQ ID NO: 6353), SSVKXQPSRVHH (SEQ ID NO: 6565):EPIS (SEQ ID NO: 6353), RNVQXRPTQVQL (SEQ ID NO: 6548):EPIS (SEQ ID NO: 6353), KIPKAXXTPTEL (SEQ ID NO: 6531):SPIN (SEQ ID NO: 6363), GIPEPXXTPTKM (SEQ ID NO: 6489):SPIN (SEQ ID NO: 6363), SIPKAXXTPTEL (SEQ ID NO: 6559):SPIN (SEQ ID NO: 6363), HVTKPTXTPTKL (SEQ ID NO: 6514):SPIN (SEQ ID NO: 6363), YVPKPXXTPTKL (SEQ ID NO: 6585):SPIN (SEQ ID NO: 6363), TVPKPXXTPTQL (SEQ ID NO: 6577):SPIN (SEQ ID NO: 6363), AVPKAXXTPTKL (SEQ ID NO: 6481):SPIN (SEQ ID NO: 6363), KVGKAXXTPTKL (SEQ ID NO: 6539):SPIN (SEQ ID NO: 6363), KASKAXXTPTKL (SEQ ID NO: 6523):SPIN (SEQ ID NO: 6363), AAPASXXTPTRL (SEQ ID NO: 6457):SPIN (SEQ ID NO: 6363), STPPTXXTPTRL (SEQ ID NO: 6569):SPIN (SEQ ID NO: 6363), HVPKPXXTPTKL (SEQ ID NO: 6505):SPIN (SEQ ID NO: 6363), RVPSTXXTPTKT (SEQ ID NO: 6551):SPIN (SEQ ID NO: 6363), ASAAPXXTPTAL (SEQ ID NO: 6465):SPIN (SEQ ID NO: 6363), ASASPXXTPTDL (SEQ ID NO: 6473):SPIN (SEQ ID NO: 6363), KIPKAXXVPTEL (SEQ ID NO: 6535):SPIN (SEQ ID NO: 6363), GIPEPXXVPEKM (SEQ ID NO: 6491):SPIN (SEQ ID NO: 6363), SIPKAXXVPTEL (SEQ ID NO: 6563):SPIN (SEQ ID NO: 6363), HVTKPTXAPTKL (SEQ ID NO: 6511):SPIN (SEQ ID NO: 6363), YVPKPXXAPTKL (SEQ ID NO: 6583):SPIN (SEQ ID NO: 6363), TVPKPXXAPTQL (SEQ ID NO: 6575):SPIN (SEQ ID NO: 6363), AVPKAXXAPTKL (SEQ ID NO: 6479):SPIN (SEQ ID NO: 6363), KVGKAXXVPTKL (SEQ ID NO: 6543):SPIN (SEQ ID NO: 6363), KASKAXXVPTKL (SEQ ID NO: 6527):SPIN (SEQ ID NO: 6363), AAPASXXVPARL (SEQ ID NO: 6458):SPIN (SEQ ID NO: 6363), STPPTXXVPTRL (SEQ ID NO: 6573):SPIN (SEQ ID NO: 6363), HVPKPXXAPTKL (SEQ ID NO: 6503):SPIN (SEQ ID NO: 6363), RVPSTXXAPVKT (SEQ ID NO: 6550):SPIN (SEQ ID NO: 6363), ASAAPXXVPQAL (SEQ ID NO: 6468):SPIN (SEQ ID NO: 6363), ASASPXXVSQDL (SEQ ID NO: 6478):SPIN (SEQ ID NO: 6363), ASASPXXVPQDL (SEQ ID NO: 6476):SPIN (SEQ ID NO: 6363), NDEGLEXVPTEE (SEQ ID NO: 6545):SPIN (SEQ ID NO: 6363), NDEGLEXVPTGQ (SEQ ID NO: 6546):SPIN (SEQ ID NO: 6363), SSVKXQPSRVHH (SEQ ID NO: 6565):SPIN (SEQ ID NO: 6363), RNVQXRPTQVQL (SEQ ID NO: 6548):SPIN (SEQ ID NO: 6363), KIPKAXXVPAEL (SEQ ID NO: 6532):SPIS (SEQ ID NO: 6364), GIPEPXXVPAKM (SEQ ID NO: 6490):SPIS (SEQ ID NO: 6364), SIPKAXXVPAEL (SEQ ID NO: 6560):SPIS (SEQ ID NO: 6364), HVTKPTXVPAKL (SEQ ID NO: 6516):SPIS (SEQ ID NO: 6364), YVPKPXXVPAKL (SEQ ID NO: 6586):SPIS (SEQ ID NO: 6364), TVPKPXXVPAQL (SEQ ID NO: 6578):SPIS (SEQ ID NO: 6364), AVPKAXXVPAKL (SEQ ID NO: 6482):SPIS (SEQ ID NO: 6364), KVGKAXXVPAKL (SEQ ID NO: 6540):SPIS (SEQ ID NO: 6364), KASKAXXVPAKL (SEQ ID NO: 6524):SPIS (SEQ ID NO: 6364), GSAGPXXVPAKM (SEQ ID NO: 6498):SPIS (SEQ ID NO: 6364), STPPTXXVPARL (SEQ ID NO: 6570):SPIS (SEQ ID NO: 6364), HVPKPXXVPAKL (SEQ ID NO: 6506):SPIS (SEQ ID NO: 6364), RVPSTXXVPAKT (SEQ ID NO: 6552):SPIS (SEQ ID NO: 6364), ASAAPXXVPAAL (SEQ ID NO: 6466):SPIS (SEQ ID NO: 6364), ASASPXXVPADL (SEQ ID NO: 6474):SPIS (SEQ ID NO: 6364), KVGKAXXVPTKL (SEQ ID NO: 6543):SPIS (SEQ ID NO: 6364), NDEGLEXVPTEE (SEQ ID NO: 6545):SPIS (SEQ ID NO: 6364), NDEGLEXVPTGQ (SEQ ID NO: 6546):SPIS (SEQ ID NO: 6364), KIPKAXXAPVEL (SEQ ID NO: 6530):KPLS (SEQ ID NO: 6356), GIPEPXXAPVKM (SEQ ID NO: 6488):KPLS (SEQ ID NO: 6356), SIPKAXXAPVEL (SEQ ID NO: 6558):KPLS (SEQ ID NO: 6356), HVTKPTXAPVKL (SEQ ID NO: 6512):KPLS (SEQ ID NO: 6356), YVPKPXXAPVKL (SEQ ID NO: 6584):KPLS (SEQ ID NO: 6356), TVPKPXXAPVQL (SEQ ID NO: 6576):KPLS (SEQ ID NO: 6356), AVPKAXXAPVKL (SEQ ID NO: 6480):KPLS (SEQ ID NO: 6356), KVGKAXXAPVKL (SEQ ID NO: 6538):KPLS (SEQ ID NO: 6356), KASKAXXAPVKL (SEQ ID NO: 6522):KPLS (SEQ ID NO: 6356), GSAGPXXAPVKM (SEQ ID NO: 6496):KPLS (SEQ ID NO: 6356), AAPASXXAPVRL (SEQ ID NO: 6456):KPLS (SEQ ID NO: 6356), STPPTXXAPVRL (SEQ ID NO: 6568):KPLS (SEQ ID NO: 6356), HVPKPXXAPVKL (SEQ ID NO: 6504):KPLS (SEQ ID NO: 6356), ASAAPXXAPVAL (SEQ ID NO: 6464):KPLS (SEQ ID NO: 6356), ASASPXXAPVDL (SEQ ID NO: 6472):KPLS (SEQ ID NO: 6356), KIPKAXXVPTEL (SEQ ID NO: 6535):KPLS (SEQ ID NO: 6356), GIPEPXXVPEKM (SEQ ID NO: 6491):KPLS (SEQ ID NO: 6356), SIPKAXXVPTEL (SEQ ID NO: 6563):KPLS (SEQ ID NO: 6356), HVTKPTXAPTKL (SEQ ID NO: 6511):KPLS (SEQ ID NO: 6356), YVPKPXXAPTKL (SEQ ID NO: 6583):KPLS (SEQ ID NO: 6356), TVPKPXXAPTQL (SEQ ID NO: 6575):KPLS (SEQ ID NO: 6356), AVPKAXXAPTKL (SEQ ID NO: 6479):KPLS (SEQ ID NO: 6356), KVGKAXXVPTKL (SEQ ID NO: 6543):KPLS (SEQ ID NO: 6356), KASKAXXVPTKL (SEQ ID NO: 6527):KPLS (SEQ ID NO: 6356), GSAGPXXTPTKM (SEQ ID NO: 6497):KPLS (SEQ ID NO: 6356), AAPASXXVPARL (SEQ ID NO: 6458):KPLS (SEQ ID NO: 6356), STPPTXXVPTRL (SEQ ID NO: 6573):KPLS (SEQ ID NO: 6356), HVPKPXXAPTKL (SEQ ID NO: 6503):KPLS (SEQ ID NO: 6356), ASAAPXXVPQAL (SEQ ID NO: 6468):KPLS (SEQ ID NO: 6356), ASASPXXVSQDL (SEQ ID NO: 6478):KPLS (SEQ ID NO: 6356), ASASPXXVPQDL (SEQ ID NO: 6476):KPLS (SEQ ID NO: 6356), NDEGLEXVPTEE (SEQ ID NO: 6545):KPLS (SEQ ID NO: 6356), NDEGLEXVPTGQ (SEQ ID NO: 6546):KPLS (SEQ ID NO: 6356), SSVKXQPSRVHH (SEQ ID NO: 6565):KPLS (SEQ ID NO: 6356), RNVQXRPTQVQL (SEQ ID NO: 6548):KPLS (SEQ ID NO: 6356), KIPKAXXVPQEL (SEQ ID NO: 6534):EPLP (SEQ ID NO: 6354), GIPEPXXVPQKM (SEQ ID NO: 6492):EPLP (SEQ ID NO: 6354), SIPKAXXVPQEL (SEQ ID NO: 6562):EPLP (SEQ ID NO: 6354), HVTKPTXVPQKL (SEQ ID NO: 6518):EPLP (SEQ ID NO: 6354), YVPKPXXVPQKL (SEQ ID NO: 6588):EPLP (SEQ ID NO: 6354), TVPKPXXVPQQL (SEQ ID NO: 6580):EPLP (SEQ ID NO: 6354), AVPKAXXVPQKL (SEQ ID NO: 6484):EPLP (SEQ ID NO: 6354), KVGKAXXVPQKL (SEQ ID NO: 6542):EPLP (SEQ ID NO: 6354), KASKAXXVPQKL (SEQ ID NO: 6526):EPLP (SEQ ID NO: 6354), GSAGPXXVPQKM (SEQ ID NO: 6500):EPLP (SEQ ID NO: 6354), AAPASXXVPQRL (SEQ ID NO: 6460):EPLP (SEQ ID NO: 6354), STPPTXXVPQRL (SEQ ID NO: 6572):EPLP (SEQ ID NO: 6354), HVPKPXXVPQKL (SEQ ID NO: 6508):EPLP (SEQ ID NO: 6354), RVPSTXXVPQKT (SEQ ID NO: 6554):EPLP (SEQ ID NO: 6354), ASASPXXVPQDL (SEQ ID NO: 6476):EPLP (SEQ ID NO: 6354), KIPKAXXVPTEL (SEQ ID NO: 6535):EPLP (SEQ ID NO: 6354), GIPEPXXVPEKM (SEQ ID NO: 6491):EPLP (SEQ ID NO: 6354), SIPKAXXVPTEL (SEQ ID NO: 6563):EPLP (SEQ ID NO: 6354), HVTKPTXAPTKL (SEQ ID NO: 6511):EPLP (SEQ ID NO: 6354), YVPKPXXAPTKL (SEQ ID NO: 6583):EPLP (SEQ ID NO: 6354), TVPKPXXAPTQL (SEQ ID NO: 6575):EPLP (SEQ ID NO: 6354), AVPKAXXAPTKL (SEQ ID NO: 6479):EPLP (SEQ ID NO: 6354), KVGKAXXVPTKL (SEQ ID NO: 6543):EPLP (SEQ ID NO: 6354), KASKAXXVPTKL (SEQ ID NO: 6527):EPLP (SEQ ID NO: 6354), GSAGPXXTPTKM (SEQ ID NO: 6497):EPLP (SEQ ID NO: 6354), AAPASXXVPARL (SEQ ID NO: 6458):EPLP (SEQ ID NO: 6354), STPPTXXVPTRL (SEQ ID NO: 6573):EPLP (SEQ ID NO: 6354), HVPKPXXAPTKL (SEQ ID NO: 6503):EPLP (SEQ ID NO: 6354), RVPSTXXAPVKT (SEQ ID NO: 6550):EPLP (SEQ ID NO: 6354), ASASPXXVSQDL (SEQ ID NO: 6478):EPLP (SEQ ID NO: 6354), NDEGLEXVPTEE (SEQ ID NO: 6545):EPLP (SEQ ID NO: 6354), NDEGLEXVPTGQ (SEQ ID NO: 6546):EPLP (SEQ ID NO: 6354), SSVKXQPSRVHH (SEQ ID NO: 6565):EPLP (SEQ ID NO: 6354), RNVQXRPTQVQL (SEQ ID NO: 6548):EPLP (SEQ ID NO: 6354), KIPKAXXVSQEL (SEQ ID NO: 6536):EPLT (SEQ ID NO: 6355), GIPEPXXVSQKM (SEQ ID NO: 6494):EPLT (SEQ ID NO: 6355), SIPKAXXVSQEL (SEQ ID NO: 6564):EPLT (SEQ ID NO: 6355), HVTKPTXVSQKL (SEQ ID NO: 6520):EPLT (SEQ ID NO: 6355), YVPKPXXVSQKL (SEQ ID NO: 6590):EPLT (SEQ ID NO: 6355), TVPKPXXVSQQL (SEQ ID NO: 6582):EPLT (SEQ ID NO: 6355), AVPKAXXVSQKL (SEQ ID NO: 6486):EPLT (SEQ ID NO: 6355), KVGKAXXVSQKL (SEQ ID NO: 6544):EPLT (SEQ ID NO: 6355), KASKAXXVSQKL (SEQ ID NO: 6528):EPLT (SEQ ID NO: 6355), GSAGPXXVSQKM (SEQ ID NO: 6502):EPLT (SEQ ID NO: 6355), AAPASXXVSQRL (SEQ ID NO: 6462):EPLT (SEQ ID NO: 6355), STPPTXXVSQRL (SEQ ID NO: 6574):EPLT (SEQ ID NO: 6355), HVPKPXXVSQKL (SEQ ID NO: 6510):EPLT (SEQ ID NO: 6355), RVPSTXXVSQKT (SEQ ID NO: 6556):EPLT (SEQ ID NO: 6355), ASAAPXXVSQAL (SEQ ID NO: 6470):EPLT (SEQ ID NO: 6355), ASASPXXVSQDL (SEQ ID NO: 6478):EPLT (SEQ ID NO: 6355), KIPKAXXVPTEL (SEQ ID NO: 6535):EPLT (SEQ ID NO: 6355), GIPEPXXVPEKM (SEQ ID NO: 6491):EPLT (SEQ ID NO: 6355), SIPKAXXVPTEL (SEQ ID NO: 6563):EPLT (SEQ ID NO: 6355), HVTKPTXAPTKL (SEQ ID NO: 6511):EPLT (SEQ ID NO: 6355), YVPKPXXAPTKL (SEQ ID NO: 6583):EPLT (SEQ ID NO: 6355), TVPKPXXAPTQL (SEQ ID NO: 6575):EPLT (SEQ ID NO: 6355), AVPKAXXAPTKL (SEQ ID NO: 6479):EPLT (SEQ ID NO: 6355), KVGKAXXVPTKL (SEQ ID NO: 6543):EPLT (SEQ ID NO: 6355), KASKAXXVPTKL (SEQ ID NO: 6527):EPLT (SEQ ID NO: 6355), GSAGPXXTPTKM (SEQ ID NO: 6497):EPLT (SEQ ID NO: 6355), AAPASXXVPARL (SEQ ID NO: 6458):EPLT (SEQ ID NO: 6355), STPPTXXVPTRL (SEQ ID NO: 6573):EPLT (SEQ ID NO: 6355), HVPKPXXAPTKL (SEQ ID NO: 6503):EPLT (SEQ ID NO: 6355), RVPSTXXAPVKT (SEQ ID NO: 6550):EPLT (SEQ ID NO: 6355), ASAAPXXVPQAL (SEQ ID NO: 6468):EPLT (SEQ ID NO: 6355), NDEGLEXVPTEE (SEQ ID NO: 6545):EPLT (SEQ ID NO: 6355), NDEGLEXVPTGQ (SEQ ID NO: 6546):EPLT (SEQ ID NO: 6355), SSVKXQPSRVHH (SEQ ID NO: 6565):EPLT (SEQ ID NO: 6355), RNVQXRPTQVQL (SEQ ID NO: 6548):EPLT (SEQ ID NO: 6355), KIPKAXXVPQEL (SEQ ID NO: 6534):EPLT (SEQ ID NO: 6355), GIPEPXXVPQKM (SEQ ID NO: 6492):EPLT (SEQ ID NO: 6355), SIPKAXXVPQEL (SEQ ID NO: 6562):EPLT (SEQ ID NO: 6355), HVTKPTXVPQKL (SEQ ID NO: 6518):EPLT (SEQ ID NO: 6355), YVPKPXXVPQKL (SEQ ID NO: 6588):EPLT (SEQ ID NO: 6355), TVPKPXXVPQQL (SEQ ID NO: 6580):EPLT (SEQ ID NO: 6355), AVPKAXXVPQKL (SEQ ID NO: 6484):EPLT (SEQ ID NO: 6355), KVGKAXXVPQKL (SEQ ID NO: 6542):EPLT (SEQ ID NO: 6355), KASKAXXVPQKL (SEQ ID NO: 6526):EPLT (SEQ ID NO: 6355), GSAGPXXVPQKM (SEQ ID NO: 6500):EPLT (SEQ ID NO: 6355), AAPASXXVPQRL (SEQ ID NO: 6460):EPLT (SEQ ID NO: 6355), STPPTXXVPQRL (SEQ ID NO: 6572):EPLT (SEQ ID NO: 6355), HVPKPXXVPQKL (SEQ ID NO: 6508):EPLT (SEQ ID NO: 6355), RVPSTXXVPQKT (SEQ ID NO: 6554):EPLT (SEQ ID NO: 6355), ASASPXXVPQDL (SEQ ID NO: 6476):EPLT (SEQ ID NO: 6355), NDEGLEXVPTGQ (SEQ ID NO: 6546):SNIT (SEQ ID NO: 6362), GIPEPXXVPEKM (SEQ ID NO: 6491):SNIT (SEQ ID NO: 6362), HVTKPTXAPTKL (SEQ ID NO: 6511):SNIT (SEQ ID NO: 6362), YVPKPXXAPTKL (SEQ ID NO: 6583):SNIT (SEQ ID NO: 6362), TVPKPXXAPTQL (SEQ ID NO: 6575):SNIT (SEQ ID NO: 6362), AVPKAXXAPTKL (SEQ ID NO: 6479):SNIT (SEQ ID NO: 6362), GSAGPXXTPTKM (SEQ ID NO: 6497):SNIT (SEQ ID NO: 6362), AAPASXXVPARL (SEQ ID NO: 6458):SNIT (SEQ ID NO: 6362), HVPKPXXAPTKL (SEQ ID NO: 6503):SNIT (SEQ ID NO: 6362), RVPSTXXAPVKT (SEQ ID NO: 6550):SNIT (SEQ ID NO: 6362), ASAAPXXVPQAL (SEQ ID NO: 6468):SNIT (SEQ ID NO: 6362), ASASPXXVSQDL (SEQ ID NO: 6478):SNIT (SEQ ID NO: 6362), ASASPXXVPQDL (SEQ ID NO: 6476):SNIT (SEQ ID NO: 6362), SSVKXQPSRVHH (SEQ ID NO: 6565):SNIT (SEQ ID NO: 6362), RNVQXRPTQVQL (SEQ ID NO: 6548):SNIT (SEQ ID NO: 6362), RNVQXRPSRVQL (SEQ ID NO: 6547):RSVK (SEQ ID NO: 6359), KIPKAXXVPTEL (SEQ ID NO: 6535):RSVK (SEQ ID NO: 6359), GIPEPXXVPEKM (SEQ ID NO: 6491):RSVK (SEQ ID NO: 6359), SIPKAXXVPTEL (SEQ ID NO: 6563):RSVK (SEQ ID NO: 6359), HVTKPTXAPTKL (SEQ ID NO: 6511):RSVK (SEQ ID NO: 6359), YVPKPXXAPTKL (SEQ ID NO: 6583):RSVK (SEQ ID NO: 6359), TVPKPXXAPTQL (SEQ ID NO: 6575):RSVK (SEQ ID NO: 6359), AVPKAXXAPTKL (SEQ ID NO: 6479):RSVK (SEQ ID NO: 6359), KVGKAXXVPTKL (SEQ ID NO: 6543):RSVK (SEQ ID NO: 6359), KASKAXXVPTKL (SEQ ID NO: 6527):RSVK (SEQ ID NO: 6359), GSAGPXXTPTKM (SEQ ID NO: 6497):RSVK (SEQ ID NO: 6359), AAPASXXVPARL (SEQ ID NO: 6458):RSVK (SEQ ID NO: 6359), STPPTXXVPTRL (SEQ ID NO: 6573):RSVK (SEQ ID NO: 6359), HVPKPXXAPTKL (SEQ ID NO: 6503):RSVK (SEQ ID NO: 6359), RVPSTXXAPVKT (SEQ ID NO: 6550):RSVK (SEQ ID NO: 6359), ASAAPXXVPQAL (SEQ ID NO: 6468):RSVK (SEQ ID NO: 6359), ASASPXXVSQDL (SEQ ID NO: 6478):RSVK (SEQ ID NO: 6359), ASASPXXVPQDL (SEQ ID NO: 6476):RSVK (SEQ ID NO: 6359), NDEGLEXVPTEE (SEQ ID NO: 6545):RSVK (SEQ ID NO: 6359), NDEGLEXVPTGQ (SEQ ID NO: 6546):RSVK (SEQ ID NO: 6359), RNVQXRPTQVQL (SEQ ID NO: 6548):RSVK (SEQ ID NO: 6359), SSVKXQPTQVHH (SEQ ID NO: 6566):RPVQ (SEQ ID NO: 6358), KIPKAXXVPTEL (SEQ ID NO: 6535):RPVQ (SEQ ID NO: 6358), GIPEPXXVPEKM (SEQ ID NO: 6491):RPVQ (SEQ ID NO: 6358), SIPKAXXVPTEL (SEQ ID NO: 6563):RPVQ (SEQ ID NO: 6358), HVTKPTXAPTKL (SEQ ID NO: 6511):RPVQ (SEQ ID NO: 6358), YVPKPXXAPTKL (SEQ ID NO: 6583):RPVQ (SEQ ID NO: 6358), TVPKPXXAPTQL (SEQ ID NO: 6575):RPVQ (SEQ ID NO: 6358), AVPKAXXAPTKL (SEQ ID NO: 6479):RPVQ (SEQ ID NO: 6358), KVGKAXXVPTKL (SEQ ID NO: 6543):RPVQ (SEQ ID NO: 6358), KASKAXXVPTKL (SEQ ID NO: 6527):RPVQ (SEQ ID NO: 6358), GSAGPXXTPTKM (SEQ ID NO: 6497):RPVQ (SEQ ID NO: 6358), AAPASXXVPARL (SEQ ID NO: 6458):RPVQ (SEQ ID NO: 6358), STPPTXXVPTRL (SEQ ID NO: 6573):RPVQ (SEQ ID NO: 6358), HVPKPXXAPTKL (SEQ ID NO: 6503):RPVQ (SEQ ID NO: 6358), RVPSTXXAPVKT (SEQ ID NO: 6550):RPVQ (SEQ ID NO: 6358), ASAAPXXVPQAL (SEQ ID NO: 6468):RPVQ (SEQ ID NO: 6358), ASASPXXVSQDL (SEQ ID NO: 6478):RPVQ (SEQ ID NO: 6358), ASASPXXVPQDL (SEQ ID NO: 6476):RPVQ (SEQ ID NO: 6358), NDEGLEXVPTEE (SEQ ID NO: 6545):RPVQ (SEQ ID NO: 6358), NDEGLEXVPTGQ (SEQ ID NO: 6546):RPVQ (SEQ ID NO: 6358) and SSVKXQPSRVHH (SEQ ID NO: 6565):RPVQ (SEQ ID NO: 6358).
In particular, in certain embodiments, the pair PEP3:PEP12 is selected from the group consisting of VPT:SAIS-AA17-LYL (SEQ ID NO: 6598), VPE:SAIS-AA17-LYL (SEQ ID NO: 6598), APT:SAIS-AA17-LYL (SEQ ID NO: 6598), TPT:SAIS-AA17-LYL (SEQ ID NO: 6598), VPA:SAIS-AA17-LYL (SEQ ID NO: 6598), APV:SAIS-AA17-LYL (SEQ ID NO: 6598), VPQ:SAIS-AA17-LYL (SEQ ID NO: 6598), VSQ:SAIS-AA17-LYL (SEQ ID NO: 6598), SRV:SAIS-AA17-LYL (SEQ ID NO: 6598), TQV:SAIS-AA17-LYL (SEQ ID NO: 6598), VPE:SSLS-AA17-LFF (SEQ ID NO: 6605), VPT:SSLS-AA17-LFF (SEQ ID NO: 6605), APT:SSLS-AA17-LFF (SEQ ID NO: 6605), TPT:SSLS-AA17-LFF (SEQ ID NO: 6605), VPA:SSLS-AA17-LFF (SEQ ID NO: 6605), APV:SSLS-AA17-LFF (SEQ ID NO: 6605), VPQ:SSLS-AA17-LFF (SEQ ID NO: 6605), VSQ:SSLS-AA17-LFF (SEQ ID NO: 6605), SRV:SSLS-AA17-LFF (SEQ ID NO: 6605), TQV:SSLS-AA17-LFF (SEQ ID NO: 6605), APT:NAIS-AA17-LYF (SEQ ID NO: 6595), VPT:NAIS-AA17-LYF (SEQ ID NO: 6595), VPE:NAIS-AA17-LYF (SEQ ID NO: 6595), TPT:NAIS-AA17-LYF (SEQ ID NO: 6595), VPA:NAIS-AA17-LYF (SEQ ID NO: 6595), APV:NAIS-AA17-LYF (SEQ ID NO: 6595), VPQ:NAIS-AA17-LYF (SEQ ID NO: 6595), VSQ:NAIS-AA17-LYF (SEQ ID NO: 6595), SRV:NAIS-AA17-LYF (SEQ ID NO: 6595), TQV:NAIS-AA17-LYF (SEQ ID NO: 6595), APT:SATS-AA17-LYY (SEQ ID NO: 6599), VPT:SATS-AA17-LYY (SEQ ID NO: 6599), VPE:SATS-AA17-LYY (SEQ ID NO: 6599), TPT:SATS-AA17-LYY (SEQ ID NO: 6599), VPA:SATS-AA17-LYY (SEQ ID NO: 6599), APV:SATS-AA17-LYY (SEQ ID NO: 6599), VPQ:SATS-AA17-LYY (SEQ ID NO: 6599), VSQ:SATS-AA17-LYY (SEQ ID NO: 6599), SRV:SATS-AA17-LYY (SEQ ID NO: 6599), TQV:SATS-AA17-LYY (SEQ ID NO: 6599), VPT:SPIS-AA17-LYK (SEQ ID NO: 6604), VPE:SPIS-AA17-LYK (SEQ ID NO: 6604), APT:SPIS-AA17-LYK (SEQ ID NO: 6604), TPT:SPIS-AA17-LYK (SEQ ID NO: 6604), VPA:SPIS-AA17-LYK (SEQ ID NO: 6604), APV:SPIS-AA17-LYK (SEQ ID NO: 6604), VPQ:SPIS-AA17-LYK (SEQ ID NO: 6604), VSQ:SPIS-AA17-LYK (SEQ ID NO: 6604), SRV:SPIS-AA17-LYK (SEQ ID NO: 6604), TQV:SPIS-AA17-LYK (SEQ ID NO: 6604), VPT:EPIS-AA17-LYL (SEQ ID NO: 6591), VPE:EPIS-AA17-LYL (SEQ ID NO: 6591), APT:EPIS-AA17-LYL (SEQ ID NO: 6591), TPT:EPIS-AA17-LYL (SEQ ID NO: 6591), VPA:EPIS-AA17-LYL (SEQ ID NO: 6591), APV:EPIS-AA17-LYL (SEQ ID NO: 6591), VPQ:EPIS-AA17-LYL (SEQ ID NO: 6591), VSQ:EPIS-AA17-LYL (SEQ ID NO: 6591), SRV:EPIS-AA17-LYL (SEQ ID NO: 6591), TQV:EPIS-AA17-LYL (SEQ ID NO: 6591), TPT:SPIN-AA17-LYF (SEQ ID NO: 6601), VPT:SPIN-AA17-LYF (SEQ ID NO: 6601), VPE:SPIN-AA17-LYF (SEQ ID NO: 6601), APT:SPIN-AA17-LYF (SEQ ID NO: 6601), VPA:SPIN-AA17-LYF (SEQ ID NO: 6601), APV:SPIN-AA17-LYF (SEQ ID NO: 6601), VPQ:SPIN-AA17-LYF (SEQ ID NO: 6601), VSQ:SPIN-AA17-LYF (SEQ ID NO: 6601), SRV:SPIN-AA17-LYF (SEQ ID NO: 6601), TQV:SPIN-AA17-LYF (SEQ ID NO: 6601), VPA:SPIS-AA17-LYI (SEQ ID NO: 6603), VPT:SPIS-AA17-LYI (SEQ ID NO: 6603), VPE:SPIS-AA17-LYI (SEQ ID NO: 6603), APT:SPIS-AA17-LYI (SEQ ID NO: 6603), TPT:SPIS-AA17-LYI (SEQ ID NO: 6603), APV:SPIS-AA17-LYI (SEQ ID NO: 6603), VPQ:SPIS-AA17-LYI (SEQ ID NO: 6603), VSQ:SPIS-AA17-LYI (SEQ ID NO: 6603), SRV:SPIS-AA17-LYI (SEQ ID NO: 6603), TQV:SPIS-AA17-LYI (SEQ ID NO: 6603), VPT:SPIS-AA17-LFI (SEQ ID NO: 6602), VPE:SPIS-AA17-LFI (SEQ ID NO: 6602), APT:SPIS-AA17-LFI (SEQ ID NO: 6602), TPT:SPIS-AA17-LFI (SEQ ID NO: 6602), VPA:SPIS-AA17-LFI (SEQ ID NO: 6602), APV:SPIS-AA17-LFI (SEQ ID NO: 6602), VPQ:SPIS-AA17-LFI (SEQ ID NO: 6602), VSQ:SPIS-AA17-LFI (SEQ ID NO: 6602), SRV:SPIS-AA17-LFI (SEQ ID NO: 6602), TQV:SPIS-AA17-LFI (SEQ ID NO: 6602), APV:KPLS-AA17-LYV (SEQ ID NO: 6594), VPT:KPLS-AA17-LYV (SEQ ID NO: 6594), VPE:KPLS-AA17-LYV (SEQ ID NO: 6594), APT:KPLS-AA17-LYV (SEQ ID NO: 6594), TPT:KPLS-AA17-LYV (SEQ ID NO: 6594), VPA:KPLS-AA17-LYV (SEQ ID NO: 6594), VPQ:KPLS-AA17-LYV (SEQ ID NO: 6594), VSQ:KPLS-AA17-LYV (SEQ ID NO: 6594), SRV:KPLS-AA17-LYV (SEQ ID NO: 6594), TQV:KPLS-AA17-LYV (SEQ ID NO: 6594), VPQ:EPLP-AA17-VYY (SEQ ID NO: 6592), VPT:EPLP-AA17-VYY (SEQ ID NO: 6592), VPE:EPLP-AA17-VYY (SEQ ID NO: 6592), APT:EPLP-AA17-VYY (SEQ ID NO: 6592), TPT:EPLP-AA17-VYY (SEQ ID NO: 6592), VPA:EPLP-AA17-VYY (SEQ ID NO: 6592), APV:EPLP-AA17-VYY (SEQ ID NO: 6592), VSQ:EPLP-AA17-VYY (SEQ ID NO: 6592), SRV:EPLP-AA17-VYY (SEQ ID NO: 6592), TQV:EPLP-AA17-VYY (SEQ ID NO: 6592), VSQ:EPLT-AA17-LYY (SEQ ID NO: 6593), VPT:EPLT-AA17-LYY (SEQ ID NO: 6593), VPE:EPLT-AA17-LYY (SEQ ID NO: 6593), APT:EPLT-AA17-LYY (SEQ ID NO: 6593), TPT:EPLT-AA17-LYY (SEQ ID NO: 6593), VPA:EPLT-AA17-LYY (SEQ ID NO: 6593), APV:EPLT-AA17-LYY (SEQ ID NO: 6593), VPQ:EPLT-AA17-LYY (SEQ ID NO: 6593), SRV:EPLT-AA17-LYY (SEQ ID NO: 6593), TQV:EPLT-AA17-LYY (SEQ ID NO: 6593), VPT:SNIT-AA17-QIM (SEQ ID NO: 6600), VPE:SNIT-AA17-QIM (SEQ ID NO: 6600), APT:SNIT-AA17-QIM (SEQ ID NO: 6600), TPT:SNIT-AA17-QIM (SEQ ID NO: 6600), VPA:SNIT-AA17-QIM (SEQ ID NO: 6600), APV:SNIT-AA17-QIM (SEQ ID NO: 6600), VPQ:SNIT-AA17-QIM (SEQ ID NO: 6600), VSQ:SNIT-AA17-QIM (SEQ ID NO: 6600), SRV:SNIT-AA17-QIM (SEQ ID NO: 6600), TQV:SNIT-AA17-QIM (SEQ ID NO: 6600), SRV:RSVK-AA17-AKV (SEQ ID NO: 6597), VPT:RSVK-AA17-AKV (SEQ ID NO: 6597), VPE:RSVK-AA17-AKV (SEQ ID NO: 6597), APT:RSVK-AA17-AKV (SEQ ID NO: 6597), TPT:RSVK-AA17-AKV (SEQ ID NO: 6597), VPA:RSVK-AA17-AKV (SEQ ID NO: 6597), APV:RSVK-AA17-AKV (SEQ ID NO: 6597), VPQ:RSVK-AA17-AKV (SEQ ID NO: 6597), VSQ:RSVK-AA17-AKV (SEQ ID NO: 6597), TQV:RSVK-AA17-AKV (SEQ ID NO: 6597), TQV:RPVQ-AA17-RKI (SEQ ID NO: 6596), VPT:RPVQ-AA17-RKI (SEQ ID NO: 6596), VPE:RPVQ-AA17-RKI (SEQ ID NO: 6596), APT:RPVQ-AA17-RKI (SEQ ID NO: 6596), TPT:RPVQ-AA17-RKI (SEQ ID NO: 6596), VPA:RPVQ-AA17-RKI (SEQ ID NO: 6596), APV:RPVQ-AA17-RKI (SEQ ID NO: 6596), VPQ:RPVQ-AA17-RKI (SEQ ID NO: 6596), VSQ:RPVQ-AA17-RKI (SEQ ID NO: 6596) and SRV:RPVQ-AA17-RKI (SEQ ID NO: 6596); and wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T).
In particular, in certain embodiments, the pair PEP12:PEP5 is selected from the group consisting of VPTKM (SEQ ID NO: 6424):SAIS-AA17-LYL (SEQ ID NO: 6598), VPTKL (SEQ ID NO: 6423):SAIS-AA17-LYL (SEQ ID NO: 6598), VPTQL (SEQ ID NO: 6426):SAIS-AA17-LYL (SEQ ID NO: 6598), VPTRL (SEQ ID NO: 6427):SAIS-AA17-LYL (SEQ ID NO: 6598), VPTKT (SEQ ID NO: 6425):SAIS-AA17-LYL (SEQ ID NO: 6598), VPTAL (SEQ ID NO: 6418):SAIS-AA17-LYL (SEQ ID NO: 6598), VPTDL (SEQ ID NO: 6419):SAIS-AA17-LYL (SEQ ID NO: 6598), VPEKM (SEQ ID NO: 6406):SAIS-AA17-LYL (SEQ ID NO: 6598), APTKL (SEQ ID NO: 6369):SAIS-AA17-LYL (SEQ ID NO: 6598), APTQL (SEQ ID NO: 6372):SAIS-AA17-LYL (SEQ ID NO: 6598), TPTKM (SEQ ID NO: 6388):SAIS-AA17-LYL (SEQ ID NO: 6598), VPARL (SEQ ID NO: 6401):SAIS-AA17-LYL (SEQ ID NO: 6598), APVKT (SEQ ID NO: 6379):SAIS-AA17-LYL (SEQ ID NO: 6598), VPQAL (SEQ ID NO: 6410):SAIS-AA17-LYL (SEQ ID NO: 6598), VSODL (SEQ ID NO: 6429):SAIS-AA17-LYL (SEQ ID NO: 6598), VPQDL (SEQ ID NO: 6411):SAIS-AA17-LYL (SEQ ID NO: 6598), SRVHH (SEQ ID NO: 6382):SAIS-AA17-LYL (SEQ ID NO: 6598), TQVQL (SEQ ID NO: 6393):SAIS-AA17-LYL (SEQ ID NO: 6598), VPEEL (SEQ ID NO: 6404):SSLS-AA17-LFF (SEQ ID NO: 6605), VPEKL (SEQ ID NO: 6405):SSLS-AA17-LFF (SEQ ID NO: 6605), VPEQL (SEQ ID NO: 6408):SSLS-AA17-LFF (SEQ ID NO: 6605), VPEKM (SEQ ID NO: 6406):SSLS-AA17-LFF (SEQ ID NO: 6605), VPERL (SEQ ID NO: 6409):SSLS-AA17-LFF (SEQ ID NO: 6605), VPEKT (SEQ ID NO: 6407):SSLS-AA17-LFF (SEQ ID NO: 6605), VPEAL (SEQ ID NO: 6402):SSLS-AA17-LFF (SEQ ID NO: 6605), VPEDL (SEQ ID NO: 6403):SSLS-AA17-LFF (SEQ ID NO: 6605), VPTEL (SEQ ID NO: 6421):SSLS-AA17-LFF (SEQ ID NO: 6605), APTKL (SEQ ID NO: 6369):SSLS-AA17-LFF (SEQ ID NO: 6605), APTOL (SEQ ID NO: 6372):SSLS-AA17-LFF (SEQ ID NO: 6605), VPTKL (SEQ ID NO: 6423):SSLS-AA17-LFF (SEQ ID NO: 6605), TPTKM (SEQ ID NO: 6388):SSLS-AA17-LFF (SEQ ID NO: 6605), VPARL (SEQ ID NO: 6401):SSLS-AA17-LFF (SEQ ID NO: 6605), VPTRL (SEQ ID NO: 6427):SSLS-AA17-LFF (SEQ ID NO: 6605), APVKT (SEQ ID NO: 6379):SSLS-AA17-LFF (SEQ ID NO: 6605), VPQAL (SEQ ID NO: 6410):SSLS-AA17-LFF (SEQ ID NO: 6605), VSODL (SEQ ID NO: 6429):SSLS-AA17-LFF (SEQ ID NO: 6605), VPQDL (SEQ ID NO: 6411):SSLS-AA17-LFF (SEQ ID NO: 6605), VPTEE (SEQ ID NO: 6420):SSLS-AA17-LFF (SEQ ID NO: 6605), VPTGQ (SEQ ID NO: 6422):SSLS-AA17-LFF (SEQ ID NO: 6605), SRVHH (SEQ ID NO: 6382):SSLS-AA17-LFF (SEQ ID NO: 6605), TQVQL (SEQ ID NO: 6393):SSLS-AA17-LFF (SEQ ID NO: 6605), APTEL (SEQ ID NO: 6368):NAIS-AA17-LYF (SEQ ID NO: 6595), APTKM (SEQ ID NO: 6370):NAIS-AA17-LYF (SEQ ID NO: 6595), APTKL (SEQ ID NO: 6369):NAIS-AA17-LYF (SEQ ID NO: 6595), APTRL (SEQ ID NO: 6373):NAIS-AA17-LYF (SEQ ID NO: 6595), APTKT (SEQ ID NO: 6371):NAIS-AA17-LYF (SEQ ID NO: 6595), APTAL (SEQ ID NO: 6366):NAIS-AA17-LYF (SEQ ID NO: 6595), APTDL (SEQ ID NO: 6367):NAIS-AA17-LYF (SEQ ID NO: 6595), VPTEL (SEQ ID NO: 6421):NAIS-AA17-LYF (SEQ ID NO: 6595), VPEKM (SEQ ID NO: 6406):NAIS-AA17-LYF (SEQ ID NO: 6595), VPTKL (SEQ ID NO: 6423):NAIS-AA17-LYF (SEQ ID NO: 6595), TPTKM (SEQ ID NO: 6388):NAIS-AA17-LYF (SEQ ID NO: 6595), VPARL (SEQ ID NO: 6401):NAIS-AA17-LYF (SEQ ID NO: 6595), VPTRL (SEQ ID NO: 6427):NAIS-AA17-LYF (SEQ ID NO: 6595), APVKT (SEQ ID NO: 6379):NAIS-AA17-LYF (SEQ ID NO: 6595), VPQAL (SEQ ID NO: 6410):NAIS-AA17-LYF (SEQ ID NO: 6595), VSODL (SEQ ID NO: 6429):NAIS-AA17-LYF (SEQ ID NO: 6595), VPQDL (SEQ ID NO: 6411):NAIS-AA17-LYF (SEQ ID NO: 6595), VPTEE (SEQ ID NO: 6420):NAIS-AA17-LYF (SEQ ID NO: 6595), VPTGQ (SEQ ID NO: 6422):NAIS-AA17-LYF (SEQ ID NO: 6595), SRVHH (SEQ ID NO: 6382):NAIS-AA17-LYF (SEQ ID NO: 6595), TQVQL (SEQ ID NO: 6393):NAIS-AA17-LYF (SEQ ID NO: 6595), APTEL (SEQ ID NO: 6368):SATS-AA17-LYY (SEQ ID NO: 6599), APTKM (SEQ ID NO: 6370):SATS-AA17-LYY (SEQ ID NO: 6599), APTKL (SEQ ID NO: 6369):SATS-AA17-LYY (SEQ ID NO: 6599), APTOL (SEQ ID NO: 6372):SATS-AA17-LYY (SEQ ID NO: 6599), APTRL (SEQ ID NO: 6373):SATS-AA17-LYY (SEQ ID NO: 6599), APTKT (SEQ ID NO: 6371):SATS-AA17-LYY (SEQ ID NO: 6599), APTAL (SEQ ID NO: 6366):SATS-AA17-LYY (SEQ ID NO: 6599), APTDL (SEQ ID NO: 6367):SATS-AA17-LYY (SEQ ID NO: 6599), VPTEL (SEQ ID NO: 6421):SATS-AA17-LYY (SEQ ID NO: 6599), VPEKM (SEQ ID NO: 6406):SATS-AA17-LYY (SEQ ID NO: 6599), VPTKL (SEQ ID NO: 6423):SATS-AA17-LYY (SEQ ID NO: 6599), TPTKM (SEQ ID NO: 6388):SATS-AA17-LYY (SEQ ID NO: 6599), VPARL (SEQ ID NO: 6401):SATS-AA17-LYY (SEQ ID NO: 6599), VPTRL (SEQ ID NO: 6427):SATS-AA17-LYY (SEQ ID NO: 6599), APVKT (SEQ ID NO: 6379):SATS-AA17-LYY (SEQ ID NO: 6599), VPQAL (SEQ ID NO: 6410):SATS-AA17-LYY (SEQ ID NO: 6599), VSODL (SEQ ID NO: 6429):SATS-AA17-LYY (SEQ ID NO: 6599), VPQDL (SEQ ID NO: 6411):SATS-AA17-LYY (SEQ ID NO: 6599), VPTEE (SEQ ID NO: 6420):SATS-AA17-LYY (SEQ ID NO: 6599), VPTGQ (SEQ ID NO: 6422):SATS-AA17-LYY (SEQ ID NO: 6599), SRVHH (SEQ ID NO: 6382):SATS-AA17-LYY (SEQ ID NO: 6599), TQVQL (SEQ ID NO: 6393):SATS-AA17-LYY (SEQ ID NO: 6599), VPTEL (SEQ ID NO: 6421):SPIS-AA17-LYK (SEQ ID NO: 6604), VPTKM (SEQ ID NO: 6424):SPIS-AA17-LYK (SEQ ID NO: 6604), VPTKL (SEQ ID NO: 6423):SPIS-AA17-LYK (SEQ ID NO: 6604), VPTQL (SEQ ID NO: 6426):SPIS-AA17-LYK (SEQ ID NO: 6604), VPTRL (SEQ ID NO: 6427):SPIS-AA17-LYK (SEQ ID NO: 6604), VPTKT (SEQ ID NO: 6425):SPIS-AA17-LYK (SEQ ID NO: 6604), VPTAL (SEQ ID NO: 6418):SPIS-AA17-LYK (SEQ ID NO: 6604), VPTDL (SEQ ID NO: 6419):SPIS-AA17-LYK (SEQ ID NO: 6604), VPEKM (SEQ ID NO: 6406):SPIS-AA17-LYK (SEQ ID NO: 6604), APTKL (SEQ ID NO: 6369):SPIS-AA17-LYK (SEQ ID NO: 6604), APTQL (SEQ ID NO: 6372):SPIS-AA17-LYK (SEQ ID NO: 6604), TPTKM (SEQ ID NO: 6388):SPIS-AA17-LYK (SEQ ID NO: 6604), VPARL (SEQ ID NO: 6401):SPIS-AA17-LYK (SEQ ID NO: 6604), APVKT (SEQ ID NO: 6379):SPIS-AA17-LYK (SEQ ID NO: 6604), VPQAL (SEQ ID NO: 6410):SPIS-AA17-LYK (SEQ ID NO: 6604), VSODL (SEQ ID NO: 6429):SPIS-AA17-LYK (SEQ ID NO: 6604), VPQDL (SEQ ID NO: 6411):SPIS-AA17-LYK (SEQ ID NO: 6604), SRVHH (SEQ ID NO: 6382):SPIS-AA17-LYK (SEQ ID NO: 6604), TQVQL (SEQ ID NO: 6393):SPIS-AA17-LYK (SEQ ID NO: 6604), VPTEL (SEQ ID NO: 6421):EPIS-AA17-LYL (SEQ ID NO: 6591), VPTKM (SEQ ID NO: 6424):EPIS-AA17-LYL (SEQ ID NO: 6591), VPTKL (SEQ ID NO: 6423):EPIS-AA17-LYL (SEQ ID NO: 6591), VPTQL (SEQ ID NO: 6426):EPIS-AA17-LYL (SEQ ID NO: 6591), VPTRL (SEQ ID NO: 6427):EPIS-AA17-LYL (SEQ ID NO: 6591), VPTKT (SEQ ID NO: 6425):EPIS-AA17-LYL (SEQ ID NO: 6591), VPTAL (SEQ ID NO: 6418):EPIS-AA17-LYL (SEQ ID NO: 6591), VPTDL (SEQ ID NO: 6419):EPIS-AA17-LYL (SEQ ID NO: 6591), VPEKM (SEQ ID NO: 6406):EPIS-AA17-LYL (SEQ ID NO: 6591), APTKL (SEQ ID NO: 6369):EPIS-AA17-LYL (SEQ ID NO: 6591), APTQL (SEQ ID NO: 6372):EPIS-AA17-LYL (SEQ ID NO: 6591), TPTKM (SEQ ID NO: 6388):EPIS-AA17-LYL (SEQ ID NO: 6591), VPARL (SEQ ID NO: 6401):EPIS-AA17-LYL (SEQ ID NO: 6591), APVKT (SEQ ID NO: 6379):EPIS-AA17-LYL (SEQ ID NO: 6591), VPQAL (SEQ ID NO: 6410):EPIS-AA17-LYL (SEQ ID NO: 6591), VSODL (SEQ ID NO: 6429):EPIS-AA17-LYL (SEQ ID NO: 6591), VPQDL (SEQ ID NO: 6411):EPIS-AA17-LYL (SEQ ID NO: 6591), SRVHH (SEQ ID NO: 6382):EPIS-AA17-LYL (SEQ ID NO: 6591), TQVQL (SEQ ID NO: 6393):EPIS-AA17-LYL (SEQ ID NO: 6591), TPTEL (SEQ ID NO: 6386):SPIN-AA17-LYF (SEQ ID NO: 6601), TPTKM (SEQ ID NO: 6388):SPIN-AA17-LYF (SEQ ID NO: 6601), TPTKL (SEQ ID NO: 6387):SPIN-AA17-LYF (SEQ ID NO: 6601), TPTQL (SEQ ID NO: 6390):SPIN-AA17-LYF (SEQ ID NO: 6601), TPTRL (SEQ ID NO: 6391):SPIN-AA17-LYF (SEQ ID NO: 6601), TPTKT (SEQ ID NO: 6389):SPIN-AA17-LYF (SEQ ID NO: 6601), TPTAL (SEQ ID NO: 6384):SPIN-AA17-LYF (SEQ ID NO: 6601), TPTDL (SEQ ID NO: 6385):SPIN-AA17-LYF (SEQ ID NO: 6601), VPTEL (SEQ ID NO: 6421):SPIN-AA17-LYF (SEQ ID NO: 6601), VPEKM (SEQ ID NO: 6406):SPIN-AA17-LYF (SEQ ID NO: 6601), APTKL (SEQ ID NO: 6369):SPIN-AA17-LYF (SEQ ID NO: 6601), APTOL (SEQ ID NO: 6372):SPIN-AA17-LYF (SEQ ID NO: 6601), VPTKL (SEQ ID NO: 6423):SPIN-AA17-LYF (SEQ ID NO: 6601), VPARL (SEQ ID NO: 6401):SPIN-AA17-LYF (SEQ ID NO: 6601), VPTRL (SEQ ID NO: 6427):SPIN-AA17-LYF (SEQ ID NO: 6601), APVKT (SEQ ID NO: 6379):SPIN-AA17-LYF (SEQ ID NO: 6601), VPQAL (SEQ ID NO: 6410):SPIN-AA17-LYF (SEQ ID NO: 6601), VSODL (SEQ ID NO: 6429):SPIN-AA17-LYF (SEQ ID NO: 6601), VPQDL (SEQ ID NO: 6411):SPIN-AA17-LYF (SEQ ID NO: 6601), VPTEE (SEQ ID NO: 6420):SPIN-AA17-LYF (SEQ ID NO: 6601), VPTGQ (SEQ ID NO: 6422):SPIN-AA17-LYF (SEQ ID NO: 6601), SRVHH (SEQ ID NO: 6382):SPIN-AA17-LYF (SEQ ID NO: 6601), TQVQL (SEQ ID NO: 6393):SPIN-AA17-LYF (SEQ ID NO: 6601), VPAEL (SEQ ID NO: 6396):SPIS-AA17-LYI (SEQ ID NO: 6603), VPAKM (SEQ ID NO: 6398):SPIS-AA17-LYI (SEQ ID NO: 6603), VPAKL (SEQ ID NO: 6397):SPIS-AA17-LYI (SEQ ID NO: 6603), VPAQL (SEQ ID NO: 6400):SPIS-AA17-LYI (SEQ ID NO: 6603), VPARL (SEQ ID NO: 6401):SPIS-AA17-LYI (SEQ ID NO: 6603), VPAKT (SEQ ID NO: 6399):SPIS-AA17-LYI (SEQ ID NO: 6603), VPAAL (SEQ ID NO: 6394):SPIS-AA17-LYI (SEQ ID NO: 6603), VPADL (SEQ ID NO: 6395):SPIS-AA17-LYI (SEQ ID NO: 6603), VPTEL (SEQ ID NO: 6421):SPIS-AA17-LYI (SEQ ID NO: 6603), VPEKM (SEQ ID NO: 6406):SPIS-AA17-LYI (SEQ ID NO: 6603), APTKL (SEQ ID NO: 6369):SPIS-AA17-LYI (SEQ ID NO: 6603), APTQL (SEQ ID NO: 6372):SPIS-AA17-LYI (SEQ ID NO: 6603), VPTKL (SEQ ID NO: 6423):SPIS-AA17-LYI (SEQ ID NO: 6603), TPTKM (SEQ ID NO: 6388):SPIS-AA17-LYI (SEQ ID NO: 6603), VPTRL (SEQ ID NO: 6427):SPIS-AA17-LYI (SEQ ID NO: 6603), APVKT (SEQ ID NO: 6379):SPIS-AA17-LYI (SEQ ID NO: 6603), VPQAL (SEQ ID NO: 6410):SPIS-AA17-LYI (SEQ ID NO: 6603), VSQDL (SEQ ID NO: 6429):SPIS-AA17-LYI (SEQ ID NO: 6603), VPQDL (SEQ ID NO: 6411):SPIS-AA17-LYI (SEQ ID NO: 6603), VPTEE (SEQ ID NO: 6420):SPIS-AA17-LYI (SEQ ID NO: 6603), VPTGQ (SEQ ID NO: 6422):SPIS-AA17-LYI (SEQ ID NO: 6603), SRVHH (SEQ ID NO: 6382):SPIS-AA17-LYI (SEQ ID NO: 6603), TQVQL (SEQ ID NO: 6393):SPIS-AA17-LYI (SEQ ID NO: 6603), VPTEL (SEQ ID NO: 6421):SPIS-AA17-LFI (SEQ ID NO: 6602), VPTKM (SEQ ID NO: 6424):SPIS-AA17-LFI (SEQ ID NO: 6602), VPTKL (SEQ ID NO: 6423):SPIS-AA17-LFI (SEQ ID NO: 6602), VPTQL (SEQ ID NO: 6426):SPIS-AA17-LFI (SEQ ID NO: 6602), VPTRL (SEQ ID NO: 6427):SPIS-AA17-LFI (SEQ ID NO: 6602), VPTKT (SEQ ID NO: 6425):SPIS-AA17-LFI (SEQ ID NO: 6602), VPTAL (SEQ ID NO: 6418):SPIS-AA17-LFI (SEQ ID NO: 6602), VPTDL (SEQ ID NO: 6419):SPIS-AA17-LFI (SEQ ID NO: 6602), VPEKM (SEQ ID NO: 6406):SPIS-AA17-LFI (SEQ ID NO: 6602), APTKL (SEQ ID NO: 6369):SPIS-AA17-LFI (SEQ ID NO: 6602), APTQL (SEQ ID NO: 6372):SPIS-AA17-LFI (SEQ ID NO: 6602), TPTKM (SEQ ID NO: 6388):SPIS-AA17-LFI (SEQ ID NO: 6602), VPARL (SEQ ID NO: 6401):SPIS-AA17-LFI (SEQ ID NO: 6602), APVKT (SEQ ID NO: 6379):SPIS-AA17-LFI (SEQ ID NO: 6602), VPQAL (SEQ ID NO: 6410):SPIS-AA17-LFI (SEQ ID NO: 6602), VSODL (SEQ ID NO: 6429):SPIS-AA17-LFI (SEQ ID NO: 6602), VPQDL (SEQ ID NO: 6411):SPIS-AA17-LFI (SEQ ID NO: 6602), SRVHH (SEQ ID NO: 6382):SPIS-AA17-LFI (SEQ ID NO: 6602), TQVQL (SEQ ID NO: 6393):SPIS-AA17-LFI (SEQ ID NO: 6602), APVEL (SEQ ID NO: 6376):KPLS-AA17-LYV (SEQ ID NO: 6594), APVKM (SEQ ID NO: 6378):KPLS-AA17-LYV (SEQ ID NO: 6594), APVKL (SEQ ID NO: 6377):KPLS-AA17-LYV (SEQ ID NO: 6594), APVQL (SEQ ID NO: 6380):KPLS-AA17-LYV (SEQ ID NO: 6594), APVRL (SEQ ID NO: 6381):KPLS-AA17-LYV (SEQ ID NO: 6594), APVAL (SEQ ID NO: 6374):KPLS-AA17-LYV (SEQ ID NO: 6594), APVDL (SEQ ID NO: 6375):KPLS-AA17-LYV (SEQ ID NO: 6594), VPTEL (SEQ ID NO: 6421):KPLS-AA17-LYV (SEQ ID NO: 6594), VPEKM (SEQ ID NO: 6406):KPLS-AA17-LYV (SEQ ID NO: 6594), APTKL (SEQ ID NO: 6369):KPLS-AA17-LYV (SEQ ID NO: 6594), APTOL (SEQ ID NO: 6372):KPLS-AA17-LYV (SEQ ID NO: 6594), VPTKL (SEQ ID NO: 6423):KPLS-AA17-LYV (SEQ ID NO: 6594), TPTKM (SEQ ID NO: 6388):KPLS-AA17-LYV (SEQ ID NO: 6594), VPARL (SEQ ID NO: 6401):KPLS-AA17-LYV (SEQ ID NO: 6594), VPTRL (SEQ ID NO: 6427):KPLS-AA17-LYV (SEQ ID NO: 6594), VPQAL (SEQ ID NO: 6410):KPLS-AA17-LYV (SEQ ID NO: 6594), VSODL (SEQ ID NO: 6429):KPLS-AA17-LYV (SEQ ID NO: 6594), VPQDL (SEQ ID NO: 6411):KPLS-AA17-LYV (SEQ ID NO: 6594), VPTEE (SEQ ID NO: 6420):KPLS-AA17-LYV (SEQ ID NO: 6594), VPTGQ (SEQ ID NO: 6422):KPLS-AA17-LYV (SEQ ID NO: 6594), SRVHH (SEQ ID NO: 6382):KPLS-AA17-LYV (SEQ ID NO: 6594), TQVQL (SEQ ID NO: 6393):KPLS-AA17-LYV (SEQ ID NO: 6594), VPQEL (SEQ ID NO: 6412):EPLP-AA17-VYY (SEQ ID NO: 6592), VPQKM (SEQ ID NO: 6414):EPLP-AA17-VYY (SEQ ID NO: 6592), VPQKL (SEQ ID NO: 6413):EPLP-AA17-VYY (SEQ ID NO: 6592), VPQQL (SEQ ID NO: 6416):EPLP-AA17-VYY (SEQ ID NO: 6592), VPQRL (SEQ ID NO: 6417):EPLP-AA17-VYY (SEQ ID NO: 6592), VPQKT (SEQ ID NO: 6415):EPLP-AA17-VYY (SEQ ID NO: 6592), VPQDL (SEQ ID NO: 6416):EPLP-AA17-VYY (SEQ ID NO: 6592), VPTEL (SEQ ID NO: 6421):EPLP-AA17-VYY (SEQ ID NO: 6592), VPEKM (SEQ ID NO: 6406):EPLP-AA17-VYY (SEQ ID NO: 6592), APTKL (SEQ ID NO: 6369):EPLP-AA17-VYY (SEQ ID NO: 6592), APTQL (SEQ ID NO: 6372):EPLP-AA17-VYY (SEQ ID NO: 6592), VPTKL (SEQ ID NO: 6423):EPLP-AA17-VYY (SEQ ID NO: 6592), TPTKM (SEQ ID NO: 6388):EPLP-AA17-VYY (SEQ ID NO: 6592), VPARL (SEQ ID NO: 6401):EPLP-AA17-VYY (SEQ ID NO: 6592), VPTRL (SEQ ID NO: 6427):EPLP-AA17-VYY (SEQ ID NO: 6592), APVKT (SEQ ID NO: 6379):EPLP-AA17-VYY (SEQ ID NO: 6592), VSODL (SEQ ID NO: 6429):EPLP-AA17-VYY (SEQ ID NO: 6592), VPTEE (SEQ ID NO: 6420):EPLP-AA17-VYY (SEQ ID NO: 6592), VPTGQ (SEQ ID NO: 6422):EPLP-AA17-VYY (SEQ ID NO: 6592), SRVHH (SEQ ID NO: 6382):EPLP-AA17-VYY (SEQ ID NO: 6592), TQVQL (SEQ ID NO: 6393):EPLP-AA17-VYY (SEQ ID NO: 6592), VSQEL (SEQ ID NO: 6430):EPLT-AA17-LYY (SEQ ID NO: 6593), VSQKM (SEQ ID NO: 6432):EPLT-AA17-LYY (SEQ ID NO: 6593), VSQKL (SEQ ID NO: 6431):EPLT-AA17-LYY (SEQ ID NO: 6593), VSQQL (SEQ ID NO: 6434):EPLT-AA17-LYY (SEQ ID NO: 6593), VSQRL (SEQ ID NO: 6435):EPLT-AA17-LYY (SEQ ID NO: 6593), VSQKT (SEQ ID NO: 6433):EPLT-AA17-LYY (SEQ ID NO: 6593), VSQAL (SEQ ID NO: 6428):EPLT-AA17-LYY (SEQ ID NO: 6593), VSODL (SEQ ID NO: 6429):EPLT-AA17-LYY (SEQ ID NO: 6593), VPTEL (SEQ ID NO: 6421):EPLT-AA17-LYY (SEQ ID NO: 6593), VPEKM (SEQ ID NO: 6406):EPLT-AA17-LYY (SEQ ID NO: 6593), APTKL (SEQ ID NO: 6369):EPLT-AA17-LYY (SEQ ID NO: 6593), APTQL (SEQ ID NO: 6372):EPLT-AA17-LYY (SEQ ID NO: 6593), VPTKL (SEQ ID NO: 6423):EPLT-AA17-LYY (SEQ ID NO: 6593), TPTKM (SEQ ID NO: 6388):EPLT-AA17-LYY (SEQ ID NO: 6593), VPARL (SEQ ID NO: 6401):EPLT-AA17-LYY (SEQ ID NO: 6593), VPTRL (SEQ ID NO: 6427):EPLT-AA17-LYY (SEQ ID NO: 6593), APVKT (SEQ ID NO: 6379):EPLT-AA17-LYY (SEQ ID NO: 6593), VPQAL (SEQ ID NO: 6410):EPLT-AA17-LYY (SEQ ID NO: 6593), VPTEE (SEQ ID NO: 6420):EPLT-AA17-LYY (SEQ ID NO: 6593), VPTGQ (SEQ ID NO: 6422):EPLT-AA17-LYY (SEQ ID NO: 6593), SRVHH (SEQ ID NO: 6382):EPLT-AA17-LYY (SEQ ID NO: 6593), TQVQL (SEQ ID NO: 6393):EPLT-AA17-LYY (SEQ ID NO: 6593), VPQEL (SEQ ID NO: 6412):EPLT-AA17-LYY (SEQ ID NO: 6593), VPQKM (SEQ ID NO: 6414):EPLT-AA17-LYY (SEQ ID NO: 6593), VPQKL (SEQ ID NO: 6413):EPLT-AA17-LYY (SEQ ID NO: 6593), VPQQL (SEQ ID NO: 6416):EPLT-AA17-LYY (SEQ ID NO: 6593), VPQRL (SEQ ID NO: 6417):EPLT-AA17-LYY (SEQ ID NO: 6593), VPQKT (SEQ ID NO: 6415):EPLT-AA17-LYY (SEQ ID NO: 6593), VPQDL (SEQ ID NO: 6411):EPLT-AA17-LYY (SEQ ID NO: 6593), VPTGQ (SEQ ID NO: 6422):SNIT-AA17-QIM (SEQ ID NO: 6600), VPEKM (SEQ ID NO: 6406):SNIT-AA17-QIM (SEQ ID NO: 6600), APTKL (SEQ ID NO: 6369):SNIT-AA17-QIM (SEQ ID NO: 6600), APTQL (SEQ ID NO: 6372):SNIT-AA17-QIM (SEQ ID NO: 6600), TPTKM (SEQ ID NO: 6388):SNIT-AA17-QIM (SEQ ID NO: 6600), VPARL (SEQ ID NO: 6401):SNIT-AA17-QIM (SEQ ID NO: 6600), APVKT (SEQ ID NO: 6379):SNIT-AA17-QIM (SEQ ID NO: 6600), VPQAL (SEQ ID NO: 6410):SNIT-AA17-QIM (SEQ ID NO: 6600), VSODL (SEQ ID NO: 6429):SNIT-AA17-QIM (SEQ ID NO: 6600), VPQDL (SEQ ID NO: 6411):SNIT-AA17-QIM (SEQ ID NO: 6600), SRVHH (SEQ ID NO: 6382):SNIT-AA17-QIM (SEQ ID NO: 6600), TQVQL (SEQ ID NO: 6393):SNIT-AA17-QIM (SEQ ID NO: 6600), SRVQL (SEQ ID NO: 6383):RSVK-AA17-AKV (SEQ ID NO: 6597), VPTEL (SEQ ID NO: 6421):RSVK-AA17-AKV (SEQ ID NO: 6597), VPEKM (SEQ ID NO: 6406):RSVK-AA17-AKV (SEQ ID NO: 6597), APTKL (SEQ ID NO: 6369):RSVK-AA17-AKV (SEQ ID NO: 6597), APTQL (SEQ ID NO: 6372):RSVK-AA17-AKV (SEQ ID NO: 6597), VPTKL (SEQ ID NO: 6423):RSVK-AA17-AKV (SEQ ID NO: 6597), TPTKM (SEQ ID NO: 6388):RSVK-AA17-AKV (SEQ ID NO: 6597), VPARL (SEQ ID NO: 6401):RSVK-AA17-AKV (SEQ ID NO: 6597), VPTRL (SEQ ID NO: 6427):RSVK-AA17-AKV (SEQ ID NO: 6597), APVKT (SEQ ID NO: 6379):RSVK-AA17-AKV (SEQ ID NO: 6597), VPQAL (SEQ ID NO: 6410):RSVK-AA17-AKV (SEQ ID NO: 6597), VSODL (SEQ ID NO: 6429):RSVK-AA17-AKV (SEQ ID NO: 6597), VPQDL (SEQ ID NO: 6411):RSVK-AA17-AKV (SEQ ID NO: 6597), VPTEE (SEQ ID NO: 6420):RSVK-AA17-AKV (SEQ ID NO: 6597), VPTGQ (SEQ ID NO: 6422):RSVK-AA17-AKV (SEQ ID NO: 6597), TQVQL (SEQ ID NO: 6393):RSVK-AA17-AKV (SEQ ID NO: 6597), TQVHH (SEQ ID NO: 6392):RPVQ-AA17-RKI (SEQ ID NO: 6596), VPTEL (SEQ ID NO: 6421):RPVQ-AA17-RKI (SEQ ID NO: 6596), VPEKM (SEQ ID NO: 6406):RPVQ-AA17-RKI (SEQ ID NO: 6596), APTKL (SEQ ID NO: 6369):RPVQ-AA17-RKI (SEQ ID NO: 6596), APTQL (SEQ ID NO: 6372):RPVQ-AA17-RKI (SEQ ID NO: 6596), VPTKL (SEQ ID NO: 6423):RPVQ-AA17-RKI (SEQ ID NO: 6596), TPTKM (SEQ ID NO: 6388):RPVQ-AA17-RKI (SEQ ID NO: 6596), VPARL (SEQ ID NO: 6401):RPVQ-AA17-RKI (SEQ ID NO: 6596), VPTRL (SEQ ID NO: 6427):RPVQ-AA17-RKI (SEQ ID NO: 6596), APVKT (SEQ ID NO: 6379):RPVQ-AA17-RKI (SEQ ID NO: 6596), VPQAL (SEQ ID NO: 6410):RPVQ-AA17-RKI (SEQ ID NO: 6596), VSODL (SEQ ID NO: 6429):RPVQ-AA17-RKI (SEQ ID NO: 6596), VPQDL (SEQ ID NO: 6411):RPVQ-AA17-RKI (SEQ ID NO: 6596), VPTEE (SEQ ID NO: 6420):RPVQ-AA17-RKI (SEQ ID NO: 6596), VPTGQ (SEQ ID NO: 6422):RPVQ-AA17-RKI (SEQ ID NO: 6596) and SRVHH (SEQ ID NO: 6382):RPVQ-AA17-RKI (SEQ ID NO: 6596); and wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T).
In particular, in certain embodiments, the pair PEP12:PEP7 is selected from the group consisting of GIPEPXX (SEQ ID NO: 6440):SAIS-AA17-LYL (SEQ ID NO: 6598), HVTKPTX (SEQ ID NO: 6443):SAIS-AA17-LYL (SEQ ID NO: 6598), YVPKPXX (SEQ ID NO: 6454):SAIS-AA17-LYL (SEQ ID NO: 6598), TVPKPXX (SEQ ID NO: 6453):SAIS-AA17-LYL (SEQ ID NO: 6598), AVPKAXX (SEQ ID NO: 6439):SAIS-AA17-LYL (SEQ ID NO: 6598), KVGKAXX (SEQ ID NO: 6446):SAIS-AA17-LYL (SEQ ID NO: 6598), KASKAXX (SEQ ID NO: 6444):SAIS-AA17-LYL (SEQ ID NO: 6598), GSAGPXX (SEQ ID NO: 6441):SAIS-AA17-LYL (SEQ ID NO: 6598), AAPASXX (SEQ ID NO: 6436):SAIS-AA17-LYL (SEQ ID NO: 6598), STPPTXX (SEQ ID NO: 6452):SAIS-AA17-LYL (SEQ ID NO: 6598), HVPKPXX (SEQ ID NO: 6442):SAIS-AA17-LYL (SEQ ID NO: 6598), RVPSTXX (SEQ ID NO: 6449):SAIS-AA17-LYL (SEQ ID NO: 6598), ASAAPXX (SEQ ID NO: 6437):SAIS-AA17-LYL (SEQ ID NO: 6598), ASASPXX (SEQ ID NO: 6438):SAIS-AA17-LYL (SEQ ID NO: 6598), SSVKXQP (SEQ ID NO: 6451):SAIS-AA17-LYL (SEQ ID NO: 6598), RNVQXRP (SEQ ID NO: 6448):SAIS-AA17-LYL (SEQ ID NO: 6598), KIPKAXX (SEQ ID NO: 6445):SSLS-AA17-LFF (SEQ ID NO: 6605), SIPKAXX (SEQ ID NO: 6450):SSLS-AA17-LFF (SEQ ID NO: 6605), HVTKPTX (SEQ ID NO: 6443):SSLS-AA17-LFF (SEQ ID NO: 6605), YVPKPXX (SEQ ID NO: 6454):SSLS-AA17-LFF (SEQ ID NO: 6605), TVPKPXX (SEQ ID NO: 6453):SSLS-AA17-LFF (SEQ ID NO: 6605), AVPKAXX (SEQ ID NO: 6439):SSLS-AA17-LFF (SEQ ID NO: 6605), KVGKAXX (SEQ ID NO: 6446):SSLS-AA17-LFF (SEQ ID NO: 6605), KASKAXX (SEQ ID NO: 6444):SSLS-AA17-LFF (SEQ ID NO: 6605), GSAGPXX (SEQ ID NO: 6441):SSLS-AA17-LFF (SEQ ID NO: 6605), AAPASXX (SEQ ID NO: 6436):SSLS-AA17-LFF (SEQ ID NO: 6605), STPPTXX (SEQ ID NO: 6452):SSLS-AA17-LFF (SEQ ID NO: 6605), HVPKPXX (SEQ ID NO: 6442):SSLS-AA17-LFF (SEQ ID NO: 6605), RVPSTXX (SEQ ID NO: 6449):SSLS-AA17-LFF (SEQ ID NO: 6605), ASAAPXX (SEQ ID NO: 6437):SSLS-AA17-LFF (SEQ ID NO: 6605), ASASPXX (SEQ ID NO: 6438):SSLS-AA17-LFF (SEQ ID NO: 6605), NDEGLEX (SEQ ID NO: 6447):SSLS-AA17-LFF (SEQ ID NO: 6605), SSVKXQP (SEQ ID NO: 6451):SSLS-AA17-LFF (SEQ ID NO: 6605), RNVQXRP (SEQ ID NO: 6448):SSLS-AA17-LFF (SEQ ID NO: 6605), KIPKAXX (SEQ ID NO: 6445):NAIS-AA17-LYF (SEQ ID NO: 6595), GIPEPXX (SEQ ID NO: 6440):NAIS-AA17-LYF (SEQ ID NO: 6595), SIPKAXX (SEQ ID NO: 6450):NAIS-AA17-LYF (SEQ ID NO: 6595), AVPKAXX (SEQ ID NO: 6439):NAIS-AA17-LYF (SEQ ID NO: 6595), KVGKAXX (SEQ ID NO: 6446):NAIS-AA17-LYF (SEQ ID NO: 6595), KASKAXX (SEQ ID NO: 6444):NAIS-AA17-LYF (SEQ ID NO: 6595), GSAGPXX (SEQ ID NO: 6441):NAIS-AA17-LYF (SEQ ID NO: 6595), AAPASXX (SEQ ID NO: 6436):NAIS-AA17-LYF (SEQ ID NO: 6595), STPPTXX (SEQ ID NO: 6452):NAIS-AA17-LYF (SEQ ID NO: 6595), RVPSTXX (SEQ ID NO: 6449):NAIS-AA17-LYF (SEQ ID NO: 6595), ASAAPXX (SEQ ID NO: 6437):NAIS-AA17-LYF (SEQ ID NO: 6595), ASASPXX (SEQ ID NO: 6438):NAIS-AA17-LYF (SEQ ID NO: 6595), NDEGLEX (SEQ ID NO: 6447):NAIS-AA17-LYF (SEQ ID NO: 6595), SSVKXQP (SEQ ID NO: 6451):NAIS-AA17-LYF (SEQ ID NO: 6595), RNVQXRP (SEQ ID NO: 6448):NAIS-AA17-LYF (SEQ ID NO: 6595), KIPKAXX (SEQ ID NO: 6445):SATS-AA17-LYY (SEQ ID NO: 6599), GIPEPXX (SEQ ID NO: 6440):SATS-AA17-LYY (SEQ ID NO: 6599), SIPKAXX (SEQ ID NO: 6450):SATS-AA17-LYY (SEQ ID NO: 6599), HVTKPTX (SEQ ID NO: 6443):SATS-AA17-LYY (SEQ ID NO: 6599), YVPKPXX (SEQ ID NO: 6454):SATS-AA17-LYY (SEQ ID NO: 6599), TVPKPXX (SEQ ID NO: 6453):SATS-AA17-LYY (SEQ ID NO: 6599), KVGKAXX (SEQ ID NO: 6446):SATS-AA17-LYY (SEQ ID NO: 6599), KASKAXX (SEQ ID NO: 6444):SATS-AA17-LYY (SEQ ID NO: 6599), GSAGPXX (SEQ ID NO: 6441):SATS-AA17-LYY (SEQ ID NO: 6599), AAPASXX (SEQ ID NO: 6436):SATS-AA17-LYY (SEQ ID NO: 6599), STPPTXX (SEQ ID NO: 6452):SATS-AA17-LYY (SEQ ID NO: 6599), HVPKPXX (SEQ ID NO: 6442):SATS-AA17-LYY (SEQ ID NO: 6599), RVPSTXX (SEQ ID NO: 6449):SATS-AA17-LYY (SEQ ID NO: 6599), ASAAPXX (SEQ ID NO: 6437):SATS-AA17-LYY (SEQ ID NO: 6599), ASASPXX (SEQ ID NO: 6438):SATS-AA17-LYY (SEQ ID NO: 6599), NDEGLEX (SEQ ID NO: 6447):SATS-AA17-LYY (SEQ ID NO: 6599), SSVKXQP (SEQ ID NO: 6451):SATS-AA17-LYY (SEQ ID NO: 6599), RNVQXRP (SEQ ID NO: 6448):SATS-AA17-LYY (SEQ ID NO: 6599), KIPKAXX (SEQ ID NO: 6445):SPIS-AA17-LYK (SEQ ID NO: 6604), GIPEPXX (SEQ ID NO: 6440):SPIS-AA17-LYK (SEQ ID NO: 6604), SIPKAXX (SEQ ID NO: 6450):SPIS-AA17-LYK (SEQ ID NO: 6604), HVTKPTX (SEQ ID NO: 6443):SPIS-AA17-LYK (SEQ ID NO: 6604), YVPKPXX (SEQ ID NO: 6454):SPIS-AA17-LYK (SEQ ID NO: 6604), TVPKPXX (SEQ ID NO: 6453):SPIS-AA17-LYK (SEQ ID NO: 6604), AVPKAXX (SEQ ID NO: 6439):SPIS-AA17-LYK (SEQ ID NO: 6604), KASKAXX (SEQ ID NO: 6444):SPIS-AA17-LYK (SEQ ID NO: 6604), GSAGPXX (SEQ ID NO: 6441):SPIS-AA17-LYK (SEQ ID NO: 6604), AAPASXX (SEQ ID NO: 6436):SPIS-AA17-LYK (SEQ ID NO: 6604), STPPTXX (SEQ ID NO: 6452):SPIS-AA17-LYK (SEQ ID NO: 6604), HVPKPXX (SEQ ID NO: 6442):SPIS-AA17-LYK (SEQ ID NO: 6604), RVPSTXX (SEQ ID NO: 6449):SPIS-AA17-LYK (SEQ ID NO: 6604), ASAAPXX (SEQ ID NO: 6437):SPIS-AA17-LYK (SEQ ID NO: 6604), ASASPXX (SEQ ID NO: 6438):SPIS-AA17-LYK (SEQ ID NO: 6604), SSVKXQP (SEQ ID NO: 6451):SPIS-AA17-LYK (SEQ ID NO: 6604), RNVQXRP (SEQ ID NO: 6448):SPIS-AA17-LYK (SEQ ID NO: 6604), KIPKAXX (SEQ ID NO: 6445):EPIS-AA17-LYL (SEQ ID NO: 6591), GIPEPXX (SEQ ID NO: 6440):EPIS-AA17-LYL (SEQ ID NO: 6591), SIPKAXX (SEQ ID NO: 6450):EPIS-AA17-LYL (SEQ ID NO: 6591), HVTKPTX (SEQ ID NO: 6443):EPIS-AA17-LYL (SEQ ID NO: 6591), YVPKPXX (SEQ ID NO: 6454):EPIS-AA17-LYL (SEQ ID NO: 6591), TVPKPXX (SEQ ID NO: 6453):EPIS-AA17-LYL (SEQ ID NO: 6591), AVPKAXX (SEQ ID NO: 6439):EPIS-AA17-LYL (SEQ ID NO: 6591), KVGKAXX (SEQ ID NO: 6446):EPIS-AA17-LYL (SEQ ID NO: 6591), GSAGPXX (SEQ ID NO: 6441):EPIS-AA17-LYL (SEQ ID NO: 6591), AAPASXX (SEQ ID NO: 6436):EPIS-AA17-LYL (SEQ ID NO: 6591), STPPTXX (SEQ ID NO: 6452):EPIS-AA17-LYL (SEQ ID NO: 6591), HVPKPXX (SEQ ID NO: 6442):EPIS-AA17-LYL (SEQ ID NO: 6591), RVPSTXX (SEQ ID NO: 6449):EPIS-AA17-LYL (SEQ ID NO: 6591), ASAAPXX (SEQ ID NO: 6437):EPIS-AA17-LYL (SEQ ID NO: 6591), ASASPXX (SEQ ID NO: 6438):EPIS-AA17-LYL (SEQ ID NO: 6591), SSVKXQP (SEQ ID NO: 6451):EPIS-AA17-LYL (SEQ ID NO: 6591), RNVQXRP (SEQ ID NO: 6448):EPIS-AA17-LYL (SEQ ID NO: 6591), KIPKAXX (SEQ ID NO: 6445):SPIN-AA17-LYF (SEQ ID NO: 6601), GIPEPXX (SEQ ID NO: 6440):SPIN-AA17-LYF (SEQ ID NO: 6601), SIPKAXX (SEQ ID NO: 6450):SPIN-AA17-LYF (SEQ ID NO: 6601), HVTKPTX (SEQ ID NO: 6443):SPIN-AA17-LYF (SEQ ID NO: 6601), YVPKPXX (SEQ ID NO: 6454):SPIN-AA17-LYF (SEQ ID NO: 6601), TVPKPXX (SEQ ID NO: 6453):SPIN-AA17-LYF (SEQ ID NO: 6601), AVPKAXX (SEQ ID NO: 6439):SPIN-AA17-LYF (SEQ ID NO: 6601), KVGKAXX (SEQ ID NO: 6446):SPIN-AA17-LYF (SEQ ID NO: 6601), KASKAXX (SEQ ID NO: 6444):SPIN-AA17-LYF (SEQ ID NO: 6601), AAPASXX (SEQ ID NO: 6436):SPIN-AA17-LYF (SEQ ID NO: 6601), STPPTXX (SEQ ID NO: 6452):SPIN-AA17-LYF (SEQ ID NO: 6601), HVPKPXX (SEQ ID NO: 6442):SPIN-AA17-LYF (SEQ ID NO: 6601), RVPSTXX (SEQ ID NO: 6449):SPIN-AA17-LYF (SEQ ID NO: 6601), ASAAPXX (SEQ ID NO: 6437):SPIN-AA17-LYF (SEQ ID NO: 6601), ASASPXX (SEQ ID NO: 6438):SPIN-AA17-LYF (SEQ ID NO: 6601), NDEGLEX (SEQ ID NO: 6447):SPIN-AA17-LYF (SEQ ID NO: 6601), SSVKXQP (SEQ ID NO: 6451):SPIN-AA17-LYF (SEQ ID NO: 6601), RNVQXRP (SEQ ID NO: 6448):SPIN-AA17-LYF (SEQ ID NO: 6601), KIPKAXX (SEQ ID NO: 6445):SPIS-AA17-LYI (SEQ ID NO: 6603), GIPEPXX (SEQ ID NO: 6440):SPIS-AA17-LYI (SEQ ID NO: 6603), SIPKAXX (SEQ ID NO: 6450):SPIS-AA17-LYI (SEQ ID NO: 6603), HVTKPTX (SEQ ID NO: 6443):SPIS-AA17-LYI (SEQ ID NO: 6603), YVPKPXX (SEQ ID NO: 6454):SPIS-AA17-LYI (SEQ ID NO: 6603), TVPKPXX (SEQ ID NO: 6453):SPIS-AA17-LYI (SEQ ID NO: 6603), AVPKAXX (SEQ ID NO: 6439):SPIS-AA17-LYI (SEQ ID NO: 6603), KVGKAXX (SEQ ID NO: 6446):SPIS-AA17-LYI (SEQ ID NO: 6603), KASKAXX (SEQ ID NO: 6444):SPIS-AA17-LYI (SEQ ID NO: 6603), GSAGPXX (SEQ ID NO: 6441):SPIS-AA17-LYI (SEQ ID NO: 6603), STPPTXX (SEQ ID NO: 6452):SPIS-AA17-LYI (SEQ ID NO: 6603), HVPKPXX (SEQ ID NO: 6442):SPIS-AA17-LYI (SEQ ID NO: 6603), RVPSTXX (SEQ ID NO: 6449):SPIS-AA17-LYI (SEQ ID NO: 6603), ASAAPXX (SEQ ID NO: 6437):SPIS-AA17-LYI (SEQ ID NO: 6603), ASASPXX (SEQ ID NO: 6438):SPIS-AA17-LYI (SEQ ID NO: 6603), NDEGLEX (SEQ ID NO: 6447):SPIS-AA17-LYI (SEQ ID NO: 6603), SSVKXQP (SEQ ID NO: 6451):SPIS-AA17-LYI (SEQ ID NO: 6603), RNVQXRP (SEQ ID NO: 6448):SPIS-AA17-LYI (SEQ ID NO: 6603), KIPKAXX (SEQ ID NO: 6445):SPIS-AA17-LFI (SEQ ID NO: 6602), GIPEPXX (SEQ ID NO: 6440):SPIS-AA17-LFI (SEQ ID NO: 6602), SIPKAXX (SEQ ID NO: 6450):SPIS-AA17-LFI (SEQ ID NO: 6602), HVTKPTX (SEQ ID NO: 6443):SPIS-AA17-LFI (SEQ ID NO: 6602), YVPKPXX (SEQ ID NO: 6454):SPIS-AA17-LFI (SEQ ID NO: 6602), TVPKPXX (SEQ ID NO: 6453):SPIS-AA17-LFI (SEQ ID NO: 6602), AVPKAXX (SEQ ID NO: 6439):SPIS-AA17-LFI (SEQ ID NO: 6602), KVGKAXX (SEQ ID NO: 6446):SPIS-AA17-LFI (SEQ ID NO: 6602), KASKAXX (SEQ ID NO: 6444):SPIS-AA17-LFI (SEQ ID NO: 6602), GSAGPXX (SEQ ID NO: 6441):SPIS-AA17-LFI (SEQ ID NO: 6602), AAPASXX (SEQ ID NO: 6436):SPIS-AA17-LFI (SEQ ID NO: 6602), HVPKPXX (SEQ ID NO: 6442):SPIS-AA17-LFI (SEQ ID NO: 6602), RVPSTXX (SEQ ID NO: 6449):SPIS-AA17-LFI (SEQ ID NO: 6602), ASAAPXX (SEQ ID NO: 6437):SPIS-AA17-LFI (SEQ ID NO: 6602), ASASPXX (SEQ ID NO: 6438):SPIS-AA17-LFI (SEQ ID NO: 6602), SSVKXQP (SEQ ID NO: 6451):SPIS-AA17-LFI (SEQ ID NO: 6602), RNVQXRP (SEQ ID NO: 6448):SPIS-AA17-LFI (SEQ ID NO: 6602), KIPKAXX (SEQ ID NO: 6445):KPLS-AA17-LYV (SEQ ID NO: 6594), GIPEPXX (SEQ ID NO: 6440):KPLS-AA17-LYV (SEQ ID NO: 6594), SIPKAXX (SEQ ID NO: 6450):KPLS-AA17-LYV (SEQ ID NO: 6594), HVTKPTX (SEQ ID NO: 6443):KPLS-AA17-LYV (SEQ ID NO: 6594), YVPKPXX (SEQ ID NO: 6454):KPLS-AA17-LYV (SEQ ID NO: 6594), TVPKPXX (SEQ ID NO: 6453):KPLS-AA17-LYV (SEQ ID NO: 6594), AVPKAXX (SEQ ID NO: 6439):KPLS-AA17-LYV (SEQ ID NO: 6594), KVGKAXX (SEQ ID NO: 6446):KPLS-AA17-LYV (SEQ ID NO: 6594), KASKAXX (SEQ ID NO: 6444):KPLS-AA17-LYV (SEQ ID NO: 6594), GSAGPXX (SEQ ID NO: 6441):KPLS-AA17-LYV (SEQ ID NO: 6594), AAPASXX (SEQ ID NO: 6436):KPLS-AA17-LYV (SEQ ID NO: 6594), STPPTXX (SEQ ID NO: 6452):KPLS-AA17-LYV (SEQ ID NO: 6594), HVPKPXX (SEQ ID NO: 6442):KPLS-AA17-LYV (SEQ ID NO: 6594), ASAAPXX (SEQ ID NO: 6437):KPLS-AA17-LYV (SEQ ID NO: 6594), ASASPXX (SEQ ID NO: 6438):KPLS-AA17-LYV (SEQ ID NO: 6594), NDEGLEX (SEQ ID NO: 6447):KPLS-AA17-LYV (SEQ ID NO: 6594), SSVKXQP (SEQ ID NO: 6451):KPLS-AA17-LYV (SEQ ID NO: 6594), RNVQXRP (SEQ ID NO: 6448):KPLS-AA17-LYV (SEQ ID NO: 6594), KIPKAXX (SEQ ID NO: 6445):EPLP-AA17-VYY (SEQ ID NO: 6592), GIPEPXX (SEQ ID NO: 6440):EPLP-AA17-VYY (SEQ ID NO: 6592), SIPKAXX (SEQ ID NO: 6450):EPLP-AA17-VYY (SEQ ID NO: 6592), HVTKPTX (SEQ ID NO: 6443):EPLP-AA17-VYY (SEQ ID NO: 6592), YVPKPXX (SEQ ID NO: 6454):EPLP-AA17-VYY (SEQ ID NO: 6592), TVPKPXX (SEQ ID NO: 6453):EPLP-AA17-VYY (SEQ ID NO: 6592), AVPKAXX (SEQ ID NO: 6439):EPLP-AA17-VYY (SEQ ID NO: 6592), KVGKAXX (SEQ ID NO: 6446):EPLP-AA17-VYY (SEQ ID NO: 6592), KASKAXX (SEQ ID NO: 6444):EPLP-AA17-VYY (SEQ ID NO: 6592), GSAGPXX (SEQ ID NO: 6441):EPLP-AA17-VYY (SEQ ID NO: 6592), AAPASXX (SEQ ID NO: 6436):EPLP-AA17-VYY (SEQ ID NO: 6592), STPPTXX (SEQ ID NO: 6452):EPLP-AA17-VYY (SEQ ID NO: 6592), HVPKPXX (SEQ ID NO: 6442):EPLP-AA17-VYY (SEQ ID NO: 6592), RVPSTXX (SEQ ID NO: 6449):EPLP-AA17-VYY (SEQ ID NO: 6592), ASASPXX (SEQ ID NO: 6438):EPLP-AA17-VYY (SEQ ID NO: 6592), NDEGLEX (SEQ ID NO: 6447):EPLP-AA17-VYY (SEQ ID NO: 6592), SSVKXQP (SEQ ID NO: 6451):EPLP-AA17-VYY (SEQ ID NO: 6592), RNVQXRP (SEQ ID NO: 6448):EPLP-AA17-VYY (SEQ ID NO: 6592), KIPKAXX (SEQ ID NO: 6445):EPLT-AA17-LYY (SEQ ID NO: 6593), GIPEPXX (SEQ ID NO: 6440):EPLT-AA17-LYY (SEQ ID NO: 6593), SIPKAXX (SEQ ID NO: 6450):EPLT-AA17-LYY (SEQ ID NO: 6593), HVTKPTX (SEQ ID NO: 6443):EPLT-AA17-LYY (SEQ ID NO: 6593), YVPKPXX (SEQ ID NO: 6454):EPLT-AA17-LYY (SEQ ID NO: 6593), TVPKPXX (SEQ ID NO: 6453):EPLT-AA17-LYY (SEQ ID NO: 6593), AVPKAXX (SEQ ID NO: 6439):EPLT-AA17-LYY (SEQ ID NO: 6593), KVGKAXX (SEQ ID NO: 6446):EPLT-AA17-LYY (SEQ ID NO: 6593), KASKAXX (SEQ ID NO: 6444):EPLT-AA17-LYY (SEQ ID NO: 6593), GSAGPXX (SEQ ID NO: 6441):EPLT-AA17-LYY (SEQ ID NO: 6593), AAPASXX (SEQ ID NO: 6436):EPLT-AA17-LYY (SEQ ID NO: 6593), STPPTXX (SEQ ID NO: 6452):EPLT-AA17-LYY (SEQ ID NO: 6593), HVPKPXX (SEQ ID NO: 6442):EPLT-AA17-LYY (SEQ ID NO: 6593), RVPSTXX (SEQ ID NO: 6449):EPLT-AA17-LYY (SEQ ID NO: 6593), ASAAPXX (SEQ ID NO: 6437):EPLT-AA17-LYY (SEQ ID NO: 6593), ASASPXX (SEQ ID NO: 6438):EPLT-AA17-LYY (SEQ ID NO: 6593), NDEGLEX (SEQ ID NO: 6447):EPLT-AA17-LYY (SEQ ID NO: 6593), SSVKXQP (SEQ ID NO: 6451):EPLT-AA17-LYY (SEQ ID NO: 6593), RNVQXRP (SEQ ID NO: 6448):EPLT-AA17-LYY (SEQ ID NO: 6593), NDEGLEX (SEQ ID NO: 6447):SNIT-AA17-QIM (SEQ ID NO: 6600), GIPEPXX (SEQ ID NO: 6440):SNIT-AA17-QIM (SEQ ID NO: 6600), HVTKPTX (SEQ ID NO: 6443):SNIT-AA17-QIM (SEQ ID NO: 6600), YVPKPXX (SEQ ID NO: 6454):SNIT-AA17-QIM (SEQ ID NO: 6600), TVPKPXX (SEQ ID NO: 6453):SNIT-AA17-QIM (SEQ ID NO: 6600), AVPKAXX (SEQ ID NO: 6439):SNIT-AA17-QIM (SEQ ID NO: 6600), GSAGPXX (SEQ ID NO: 6441):SNIT-AA17-QIM (SEQ ID NO: 6600), AAPASXX (SEQ ID NO: 6436):SNIT-AA17-QIM (SEQ ID NO: 6600), HVPKPXX (SEQ ID NO: 6442):SNIT-AA17-QIM (SEQ ID NO: 6600), RVPSTXX (SEQ ID NO: 6449):SNIT-AA17-QIM (SEQ ID NO: 6600), ASAAPXX (SEQ ID NO: 6437):SNIT-AA17-QIM (SEQ ID NO: 6600), ASASPXX (SEQ ID NO: 6438):SNIT-AA17-QIM (SEQ ID NO: 6600), SSVKXQP (SEQ ID NO: 6451):SNIT-AA17-QIM (SEQ ID NO: 6600), RNVQXRP (SEQ ID NO: 6448):SNIT-AA17-QIM (SEQ ID NO: 6600), RNVQXRP (SEQ ID NO: 6448):RSVK-AA17-AKV (SEQ ID NO: 6597), KIPKAXX (SEQ ID NO: 6445):RSVK-AA17-AKV (SEQ ID NO: 6597), GIPEPXX (SEQ ID NO: 6440):RSVK-AA17-AKV (SEQ ID NO: 6597), SIPKAXX (SEQ ID NO: 6450):RSVK-AA17-AKV (SEQ ID NO: 6597), HVTKPTX (SEQ ID NO: 6443):RSVK-AA17-AKV (SEQ ID NO: 6597), YVPKPXX (SEQ ID NO: 6454):RSVK-AA17-AKV (SEQ ID NO: 6597), TVPKPXX (SEQ ID NO: 6453):RSVK-AA17-AKV (SEQ ID NO: 6597), AVPKAXX (SEQ ID NO: 6439):RSVK-AA17-AKV (SEQ ID NO: 6597), KVGKAXX (SEQ ID NO: 6446):RSVK-AA17-AKV (SEQ ID NO: 6597), KASKAXX (SEQ ID NO: 6444):RSVK-AA17-AKV (SEQ ID NO: 6597), GSAGPXX (SEQ ID NO: 6441):RSVK-AA17-AKV (SEQ ID NO: 6597), AAPASXX (SEQ ID NO: 6436):RSVK-AA17-AKV (SEQ ID NO: 6597), STPPTXX (SEQ ID NO: 6452):RSVK-AA17-AKV (SEQ ID NO: 6597), HVPKPXX (SEQ ID NO: 6442):RSVK-AA17-AKV (SEQ ID NO: 6597), RVPSTXX (SEQ ID NO: 6449):RSVK-AA17-AKV (SEQ ID NO: 6597), ASAAPXX (SEQ ID NO: 6437):RSVK-AA17-AKV (SEQ ID NO: 6597), ASASPXX (SEQ ID NO: 6438):RSVK-AA17-AKV (SEQ ID NO: 6597), NDEGLEX (SEQ ID NO: 6447):RSVK-AA17-AKV (SEQ ID NO: 6597), SSVKXQP (SEQ ID NO: 6451):RPVQ-AA17-RKI (SEQ ID NO: 6596), KIPKAXX (SEQ ID NO: 6445):RPVQ-AA17-RKI (SEQ ID NO: 6596), GIPEPXX (SEQ ID NO: 6440):RPVQ-AA17-RKI (SEQ ID NO: 6596), SIPKAXX (SEQ ID NO: 6450):RPVQ-AA17-RKI (SEQ ID NO: 6596), HVTKPTX (SEQ ID NO: 6443):RPVQ-AA17-RKI (SEQ ID NO: 6596), YVPKPXX (SEQ ID NO: 6454):RPVQ-AA17-RKI (SEQ ID NO: 6596), TVPKPXX (SEQ ID NO: 6453):RPVQ-AA17-RKI (SEQ ID NO: 6596), AVPKAXX (SEQ ID NO: 6439):RPVQ-AA17-RKI (SEQ ID NO: 6596), KVGKAXX (SEQ ID NO: 6446):RPVQ-AA17-RKI (SEQ ID NO: 6596), KASKAXX (SEQ ID NO: 6444):RPVQ-AA17-RKI (SEQ ID NO: 6596), GSAGPXX (SEQ ID NO: 6441):RPVQ-AA17-RKI (SEQ ID NO: 6596), AAPASXX (SEQ ID NO: 6436):RPVQ-AA17-RKI (SEQ ID NO: 6596), STPPTXX (SEQ ID NO: 6452):RPVQ-AA17-RKI (SEQ ID NO: 6596), HVPKPXX (SEQ ID NO: 6442):RPVQ-AA17-RKI (SEQ ID NO: 6596), RVPSTXX (SEQ ID NO: 6449):RPVQ-AA17-RKI (SEQ ID NO: 6596), ASAAPXX (SEQ ID NO: 6437):RPVQ-AA17-RKI (SEQ ID NO: 6596), ASASPXX (SEQ ID NO: 6438):RPVQ-AA17-RKI (SEQ ID NO: 6596) and NDEGLEX (SEQ ID NO: 6447):RPVQ-AA17-RKI (SEQ ID NO: 6596); and wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T).
In particular, in certain embodiments, the pair PEP12:PEP9 is selected from the group consisting of GIPEPXXVPTKM (SEQ ID NO: 6493):SAIS-AA17-LYL (SEQ ID NO: 6598), HVTKPTXVPTKL (SEQ ID NO: 6519):SAIS-AA17-LYL (SEQ ID NO: 6598), YVPKPXXVPTKL (SEQ ID NO: 6589):SAIS-AA17-LYL (SEQ ID NO: 6598), TVPKPXXVPTQL (SEQ ID NO: 6581):SAIS-AA17-LYL (SEQ ID NO: 6598), AVPKAXXVPTKL (SEQ ID NO: 6485):SAIS-AA17-LYL (SEQ ID NO: 6598), KVGKAXXVPTKL (SEQ ID NO: 6543):SAIS-AA17-LYL (SEQ ID NO: 6598), KASKAXXVPTKL (SEQ ID NO: 6527):SAIS-AA17-LYL (SEQ ID NO: 6598), GSAGPXXVPTKM (SEQ ID NO: 6501):SAIS-AA17-LYL (SEQ ID NO: 6598), AAPASXXVPTRL (SEQ ID NO: 6461):SAIS-AA17-LYL (SEQ ID NO: 6598), STPPTXXVPTRL (SEQ ID NO: 6573):SAIS-AA17-LYL (SEQ ID NO: 6598), HVPKPXXVPTKL (SEQ ID NO: 6509):SAIS-AA17-LYL (SEQ ID NO: 6598), RVPSTXXVPTKT (SEQ ID NO: 6555):SAIS-AA17-LYL (SEQ ID NO: 6598), ASAAPXXVPTAL (SEQ ID NO: 6469):SAIS-AA17-LYL (SEQ ID NO: 6598), ASASPXXVPTDL (SEQ ID NO: 6477):SAIS-AA17-LYL (SEQ ID NO: 6598), GIPEPXXVPEKM (SEQ ID NO: 6491):SAIS-AA17-LYL (SEQ ID NO: 6598), HVTKPTXAPTKL (SEQ ID NO: 6511):SAIS-AA17-LYL (SEQ ID NO: 6598), YVPKPXXAPTKL (SEQ ID NO: 6583):SAIS-AA17-LYL (SEQ ID NO: 6598), TVPKPXXAPTQL (SEQ ID NO: 6575):SAIS-AA17-LYL (SEQ ID NO: 6598), AVPKAXXAPTKL (SEQ ID NO: 6479):SAIS-AA17-LYL (SEQ ID NO: 6598), GSAGPXXTPTKM (SEQ ID NO: 6497):SAIS-AA17-LYL (SEQ ID NO: 6598), AAPASXXVPARL (SEQ ID NO: 6458):SAIS-AA17-LYL (SEQ ID NO: 6598), HVPKPXXAPTKL (SEQ ID NO: 6503):SAIS-AA17-LYL (SEQ ID NO: 6598), RVPSTXXAPVKT (SEQ ID NO: 6550):SAIS-AA17-LYL (SEQ ID NO: 6598), ASAAPXXVPQAL (SEQ ID NO: 6468):SAIS-AA17-LYL (SEQ ID NO: 6598), ASASPXXVSQDL (SEQ ID NO: 6478):SAIS-AA17-LYL (SEQ ID NO: 6598), ASASPXXVPQDL (SEQ ID NO: 6476):SAIS-AA17-LYL (SEQ ID NO: 6598), SSVKXQPSRVHH (SEQ ID NO: 6565):SAIS-AA17-LYL (SEQ ID NO: 6598), RNVQXRPTQVQL (SEQ ID NO: 6548):SAIS-AA17-LYL (SEQ ID NO: 6598), KIPKAXXVPEEL (SEQ ID NO: 6533):SSLS-AA17-LFF (SEQ ID NO: 6605), SIPKAXXVPEEL (SEQ ID NO: 6561):SSLS-AA17-LFF (SEQ ID NO: 6605), HVTKPTXVPEKL (SEQ ID NO: 6517):SSLS-AA17-LFF (SEQ ID NO: 6605), YVPKPXXVPEKL (SEQ ID NO: 6587):SSLS-AA17-LFF (SEQ ID NO: 6605), TVPKPXXVPEQL (SEQ ID NO: 6579):SSLS-AA17-LFF (SEQ ID NO: 6605), AVPKAXXVPEKL (SEQ ID NO: 6483):SSLS-AA17-LFF (SEQ ID NO: 6605), KVGKAXXVPEKL (SEQ ID NO: 6541):SSLS-AA17-LFF (SEQ ID NO: 6605), KASKAXXVPEKL (SEQ ID NO: 6525):SSLS-AA17-LFF (SEQ ID NO: 6605), GSAGPXXVPEKM (SEQ ID NO: 6499):SSLS-AA17-LFF (SEQ ID NO: 6605), AAPASXXVPERL (SEQ ID NO: 6459):SSLS-AA17-LFF (SEQ ID NO: 6605), STPPTXXVPERL (SEQ ID NO: 6571):SSLS-AA17-LFF (SEQ ID NO: 6605), HVPKPXXVPEKL (SEQ ID NO: 6507):SSLS-AA17-LFF (SEQ ID NO: 6605), RVPSTXXVPEKT (SEQ ID NO: 6553):SSLS-AA17-LFF (SEQ ID NO: 6605), ASAAPXXVPEAL (SEQ ID NO: 6467):SSLS-AA17-LFF (SEQ ID NO: 6605), ASASPXXVPEDL (SEQ ID NO: 6475):SSLS-AA17-LFF (SEQ ID NO: 6605), KIPKAXXVPTEL (SEQ ID NO: 6535):SSLS-AA17-LFF (SEQ ID NO: 6605), SIPKAXXVPTEL (SEQ ID NO: 6563):SSLS-AA17-LFF (SEQ ID NO: 6605), HVTKPTXAPTKL (SEQ ID NO: 6511):SSLS-AA17-LFF (SEQ ID NO: 6605), YVPKPXXAPTKL (SEQ ID NO: 6583):SSLS-AA17-LFF (SEQ ID NO: 6605), TVPKPXXAPTQL (SEQ ID NO: 6575):SSLS-AA17-LFF (SEQ ID NO: 6605), AVPKAXXAPTKL (SEQ ID NO: 6479):SSLS-AA17-LFF (SEQ ID NO: 6605), KVGKAXXVPTKL (SEQ ID NO: 6543):SSLS-AA17-LFF (SEQ ID NO: 6605), KASKAXXVPTKL (SEQ ID NO: 6527):SSLS-AA17-LFF (SEQ ID NO: 6605), GSAGPXXTPTKM (SEQ ID NO: 6497):SSLS-AA17-LFF (SEQ ID NO: 6605), AAPASXXVPARL (SEQ ID NO: 6458):SSLS-AA17-LFF (SEQ ID NO: 6605), STPPTXXVPTRL (SEQ ID NO: 6573):SSLS-AA17-LFF (SEQ ID NO: 6605), HVPKPXXAPTKL (SEQ ID NO: 6503):SSLS-AA17-LFF (SEQ ID NO: 6605), RVPSTXXAPVKT (SEQ ID NO: 6550):SSLS-AA17-LFF (SEQ ID NO: 6605), ASAAPXXVPQAL (SEQ ID NO: 6468):SSLS-AA17-LFF (SEQ ID NO: 6605), ASASPXXVSQDL (SEQ ID NO: 6478):SSLS-AA17-LFF (SEQ ID NO: 6605), ASASPXXVPQDL (SEQ ID NO: 6476):SSLS-AA17-LFF (SEQ ID NO: 6605), NDEGLEXVPTEE (SEQ ID NO: 6545):SSLS-AA17-LFF (SEQ ID NO: 6605), NDEGLEXVPTGQ (SEQ ID NO: 6546):SSLS-AA17-LFF (SEQ ID NO: 6605), SSVKXQPSRVHH (SEQ ID NO: 6565):SSLS-AA17-LFF (SEQ ID NO: 6605), RNVQXRPTQVQL (SEQ ID NO: 6548):SSLS-AA17-LFF (SEQ ID NO: 6605), KIPKAXXAPTEL (SEQ ID NO: 6529):NAIS-AA17-LYF (SEQ ID NO: 6595), GIPEPXXAPTKM (SEQ ID NO: 6487):NAIS-AA17-LYF (SEQ ID NO: 6595), SIPKAXXAPTEL (SEQ ID NO: 6557):NAIS-AA17-LYF (SEQ ID NO: 6595), AVPKAXXAPTKL (SEQ ID NO: 6479):NAIS-AA17-LYF (SEQ ID NO: 6595), KVGKAXXAPTKL (SEQ ID NO: 6537):NAIS-AA17-LYF (SEQ ID NO: 6595), KASKAXXAPTKL (SEQ ID NO: 6521):NAIS-AA17-LYF (SEQ ID NO: 6595), GSAGPXXAPTKM (SEQ ID NO: 6495):NAIS-AA17-LYF (SEQ ID NO: 6595), AAPASXXAPTRL (SEQ ID NO: 6455):NAIS-AA17-LYF (SEQ ID NO: 6595), STPPTXXAPTRL (SEQ ID NO: 6567):NAIS-AA17-LYF (SEQ ID NO: 6595), RVPSTXXAPTKT (SEQ ID NO: 6549):NAIS-AA17-LYF (SEQ ID NO: 6595), ASAAPXXAPTAL (SEQ ID NO: 6463):NAIS-AA17-LYF (SEQ ID NO: 6595), ASASPXXAPTDL (SEQ ID NO: 6471):NAIS-AA17-LYF (SEQ ID NO: 6595), KIPKAXXVPTEL (SEQ ID NO: 6535):NAIS-AA17-LYF (SEQ ID NO: 6595), GIPEPXXVPEKM (SEQ ID NO: 6491):NAIS-AA17-LYF (SEQ ID NO: 6595), SIPKAXXVPTEL (SEQ ID NO: 6563):NAIS-AA17-LYF (SEQ ID NO: 6595), KVGKAXXVPTKL (SEQ ID NO: 6543):NAIS-AA17-LYF (SEQ ID NO: 6595), KASKAXXVPTKL (SEQ ID NO: 6527):NAIS-AA17-LYF (SEQ ID NO: 6595), GSAGPXXTPTKM (SEQ ID NO: 6497):NAIS-AA17-LYF (SEQ ID NO: 6595), AAPASXXVPARL (SEQ ID NO: 6458):NAIS-AA17-LYF (SEQ ID NO: 6595), STPPTXXVPTRL (SEQ ID NO: 6573):NAIS-AA17-LYF (SEQ ID NO: 6595), RVPSTXXAPVKT (SEQ ID NO: 6550):NAIS-AA17-LYF (SEQ ID NO: 6595), ASAAPXXVPQAL (SEQ ID NO: 6468):NAIS-AA17-LYF (SEQ ID NO: 6595), ASASPXXVSQDL (SEQ ID NO: 6478):NAIS-AA17-LYF (SEQ ID NO: 6595), ASASPXXVPQDL (SEQ ID NO: 6476):NAIS-AA17-LYF (SEQ ID NO: 6595), NDEGLEXVPTEE (SEQ ID NO: 6545):NAIS-AA17-LYF (SEQ ID NO: 6595), NDEGLEXVPTGQ (SEQ ID NO: 6546):NAIS-AA17-LYF (SEQ ID NO: 6595), SSVKXQPSRVHH (SEQ ID NO: 6565):NAIS-AA17-LYF (SEQ ID NO: 6595), RNVQXRPTQVQL (SEQ ID NO: 6548):NAIS-AA17-LYF (SEQ ID NO: 6595), KIPKAXXAPTEL (SEQ ID NO: 6529):SATS-AA17-LYY (SEQ ID NO: 6599), GIPEPXXAPTKM (SEQ ID NO: 6487):SATS-AA17-LYY (SEQ ID NO: 6599), SIPKAXXAPTEL (SEQ ID NO: 6557):SATS-AA17-LYY (SEQ ID NO: 6599), HVTKPTXAPTKL (SEQ ID NO: 6511):SATS-AA17-LYY (SEQ ID NO: 6599), YVPKPXXAPTKL (SEQ ID NO: 6583):SATS-AA17-LYY (SEQ ID NO: 6599), TVPKPXXAPTQL (SEQ ID NO: 6575):SATS-AA17-LYY (SEQ ID NO: 6599), KVGKAXXAPTKL (SEQ ID NO: 6537):SATS-AA17-LYY (SEQ ID NO: 6599), KASKAXXAPTKL (SEQ ID NO: 6521):SATS-AA17-LYY (SEQ ID NO: 6599), GSAGPXXAPTKM (SEQ ID NO: 6495):SATS-AA17-LYY (SEQ ID NO: 6599), AAPASXXAPTRL (SEQ ID NO: 6455):SATS-AA17-LYY (SEQ ID NO: 6599), STPPTXXAPTRL (SEQ ID NO: 6567):SATS-AA17-LYY (SEQ ID NO: 6599), HVPKPXXAPTKL (SEQ ID NO: 6503):SATS-AA17-LYY (SEQ ID NO: 6599), RVPSTXXAPTKT (SEQ ID NO: 6549):SATS-AA17-LYY (SEQ ID NO: 6599), ASAAPXXAPTAL (SEQ ID NO: 6463):SATS-AA17-LYY (SEQ ID NO: 6599), ASASPXXAPTDL (SEQ ID NO: 6471):SATS-AA17-LYY (SEQ ID NO: 6599), KIPKAXXVPTEL (SEQ ID NO: 6535):SATS-AA17-LYY (SEQ ID NO: 6599), GIPEPXXVPEKM (SEQ ID NO: 6491):SATS-AA17-LYY (SEQ ID NO: 6599), SIPKAXXVPTEL (SEQ ID NO: 6563):SATS-AA17-LYY (SEQ ID NO: 6599), KVGKAXXVPTKL (SEQ ID NO: 6543):SATS-AA17-LYY (SEQ ID NO: 6599), KASKAXXVPTKL (SEQ ID NO: 6527):SATS-AA17-LYY (SEQ ID NO: 6599), GSAGPXXTPTKM (SEQ ID NO: 6497):SATS-AA17-LYY (SEQ ID NO: 6599), AAPASXXVPARL (SEQ ID NO: 6458):SATS-AA17-LYY (SEQ ID NO: 6599), STPPTXXVPTRL (SEQ ID NO: 6573):SATS-AA17-LYY (SEQ ID NO: 6599), RVPSTXXAPVKT (SEQ ID NO: 6550):SATS-AA17-LYY (SEQ ID NO: 6599), ASAAPXXVPQAL (SEQ ID NO: 6468):SATS-AA17-LYY (SEQ ID NO: 6599), ASASPXXVSQDL (SEQ ID NO: 6478):SATS-AA17-LYY (SEQ ID NO: 6599), ASASPXXVPQDL (SEQ ID NO: 6476):SATS-AA17-LYY (SEQ ID NO: 6599), NDEGLEXVPTEE (SEQ ID NO: 6545):SATS-AA17-LYY (SEQ ID NO: 6599), NDEGLEXVPTGQ (SEQ ID NO: 6546):SATS-AA17-LYY (SEQ ID NO: 6599), SSVKXQPSRVHH (SEQ ID NO: 6565):SATS-AA17-LYY (SEQ ID NO: 6599), RNVQXRPTQVQL (SEQ ID NO: 6548):SATS-AA17-LYY (SEQ ID NO: 6599), KIPKAXXVPTEL (SEQ ID NO: 6535):SPIS-AA17-LYK (SEQ ID NO: 6604), GIPEPXXVPTKM (SEQ ID NO: 6493):SPIS-AA17-LYK (SEQ ID NO: 6604), SIPKAXXVPTEL (SEQ ID NO: 6563):SPIS-AA17-LYK (SEQ ID NO: 6604), HVTKPTXVPTKL (SEQ ID NO: 6519):SPIS-AA17-LYK (SEQ ID NO: 6604), YVPKPXXVPTKL (SEQ ID NO: 6589):SPIS-AA17-LYK (SEQ ID NO: 6604), TVPKPXXVPTQL (SEQ ID NO: 6581):SPIS-AA17-LYK (SEQ ID NO: 6604), AVPKAXXVPTKL (SEQ ID NO: 6485):SPIS-AA17-LYK (SEQ ID NO: 6604), KASKAXXVPTKL (SEQ ID NO: 6527):SPIS-AA17-LYK (SEQ ID NO: 6604), GSAGPXXVPTKM (SEQ ID NO: 6501):SPIS-AA17-LYK (SEQ ID NO: 6604), AAPASXXVPTRL (SEQ ID NO: 6461):SPIS-AA17-LYK (SEQ ID NO: 6604), STPPTXXVPTRL (SEQ ID NO: 6573):SPIS-AA17-LYK (SEQ ID NO: 6604), HVPKPXXVPTKL (SEQ ID NO: 6509):SPIS-AA17-LYK (SEQ ID NO: 6604), RVPSTXXVPTKT (SEQ ID NO: 6555):SPIS-AA17-LYK (SEQ ID NO: 6604), ASAAPXXVPTAL (SEQ ID NO: 6469):SPIS-AA17-LYK (SEQ ID NO: 6604), ASASPXXVPTDL (SEQ ID NO: 6477):SPIS-AA17-LYK (SEQ ID NO: 6604), GIPEPXXVPEKM (SEQ ID NO: 6491):SPIS-AA17-LYK (SEQ ID NO: 6604), HVTKPTXAPTKL (SEQ ID NO: 6511):SPIS-AA17-LYK (SEQ ID NO: 6604), YVPKPXXAPTKL (SEQ ID NO: 6583):SPIS-AA17-LYK (SEQ ID NO: 6604), TVPKPXXAPTQL (SEQ ID NO: 6575):SPIS-AA17-LYK (SEQ ID NO: 6604), AVPKAXXAPTKL (SEQ ID NO: 6479):SPIS-AA17-LYK (SEQ ID NO: 6604), GSAGPXXTPTKM (SEQ ID NO: 6497):SPIS-AA17-LYK (SEQ ID NO: 6604), AAPASXXVPARL (SEQ ID NO: 6458):SPIS-AA17-LYK (SEQ ID NO: 6604), HVPKPXXAPTKL (SEQ ID NO: 6503):SPIS-AA17-LYK (SEQ ID NO: 6604), RVPSTXXAPVKT (SEQ ID NO: 6550):SPIS-AA17-LYK (SEQ ID NO: 6604), ASAAPXXVPQAL (SEQ ID NO: 6468):SPIS-AA17-LYK (SEQ ID NO: 6604), ASASPXXVSQDL (SEQ ID NO: 6478):SPIS-AA17-LYK (SEQ ID NO: 6604), ASASPXXVPQDL (SEQ ID NO: 6476):SPIS-AA17-LYK (SEQ ID NO: 6604), SSVKXQPSRVHH (SEQ ID NO: 6565):SPIS-AA17-LYK (SEQ ID NO: 6604), RNVQXRPTQVQL (SEQ ID NO: 6548):SPIS-AA17-LYK (SEQ ID NO: 6604), KIPKAXXVPTEL (SEQ ID NO: 6535):EPIS-AA17-LYL (SEQ ID NO: 6591), GIPEPXXVPTKM (SEQ ID NO: 6493):EPIS-AA17-LYL (SEQ ID NO: 6591), SIPKAXXVPTEL (SEQ ID NO: 6563):EPIS-AA17-LYL (SEQ ID NO: 6591), HVTKPTXVPTKL (SEQ ID NO: 6519):EPIS-AA17-LYL (SEQ ID NO: 6591), YVPKPXXVPTKL (SEQ ID NO: 6589):EPIS-AA17-LYL (SEQ ID NO: 6591), TVPKPXXVPTQL (SEQ ID NO: 6581):EPIS-AA17-LYL (SEQ ID NO: 6591), AVPKAXXVPTKL (SEQ ID NO: 6485):EPIS-AA17-LYL (SEQ ID NO: 6591), KVGKAXXVPTKL (SEQ ID NO: 6543):EPIS-AA17-LYL (SEQ ID NO: 6591), GSAGPXXVPTKM (SEQ ID NO: 6501):EPIS-AA17-LYL (SEQ ID NO: 6591), AAPASXXVPTRL (SEQ ID NO: 6461):EPIS-AA17-LYL (SEQ ID NO: 6591), STPPTXXVPTRL (SEQ ID NO: 6573):EPIS-AA17-LYL (SEQ ID NO: 6591), HVPKPXXVPTKL (SEQ ID NO: 6509):EPIS-AA17-LYL (SEQ ID NO: 6591), RVPSTXXVPTKT (SEQ ID NO: 6555):EPIS-AA17-LYL (SEQ ID NO: 6591), ASAAPXXVPTAL (SEQ ID NO: 6469):EPIS-AA17-LYL (SEQ ID NO: 6591), ASASPXXVPTDL (SEQ ID NO: 6477):EPIS-AA17-LYL (SEQ ID NO: 6591), GIPEPXXVPEKM (SEQ ID NO: 6491):EPIS-AA17-LYL (SEQ ID NO: 6591), HVTKPTXAPTKL (SEQ ID NO: 6511):EPIS-AA17-LYL (SEQ ID NO: 6591), YVPKPXXAPTKL (SEQ ID NO: 6583):EPIS-AA17-LYL (SEQ ID NO: 6591), TVPKPXXAPTQL (SEQ ID NO: 6575):EPIS-AA17-LYL (SEQ ID NO: 6591), AVPKAXXAPTKL (SEQ ID NO: 6479):EPIS-AA17-LYL (SEQ ID NO: 6591), GSAGPXXTPTKM (SEQ ID NO: 6497):EPIS-AA17-LYL (SEQ ID NO: 6591), AAPASXXVPARL (SEQ ID NO: 6458):EPIS-AA17-LYL (SEQ ID NO: 6591), HVPKPXXAPTKL (SEQ ID NO: 6503):EPIS-AA17-LYL (SEQ ID NO: 6591), RVPSTXXAPVKT (SEQ ID NO: 6550):EPIS-AA17-LYL (SEQ ID NO: 6591), ASAAPXXVPQAL (SEQ ID NO: 6468):EPIS-AA17-LYL (SEQ ID NO: 6591), ASASPXXVSQDL (SEQ ID NO: 6478):EPIS-AA17-LYL (SEQ ID NO: 6591), ASASPXXVPQDL (SEQ ID NO: 6476):EPIS-AA17-LYL (SEQ ID NO: 6591), SSVKXQPSRVHH (SEQ ID NO: 6565):EPIS-AA17-LYL (SEQ ID NO: 6591), RNVQXRPTQVQL (SEQ ID NO: 6548):EPIS-AA17-LYL (SEQ ID NO: 6591), KIPKAXXTPTEL (SEQ ID NO: 6531):SPIN-AA17-LYF (SEQ ID NO: 6601), GIPEPXXTPTKM (SEQ ID NO: 6489):SPIN-AA17-LYF (SEQ ID NO: 6601), SIPKAXXTPTEL (SEQ ID NO: 6559):SPIN-AA17-LYF (SEQ ID NO: 6601), HVTKPTXTPTKL (SEQ ID NO: 6514):SPIN-AA17-LYF (SEQ ID NO: 6601), YVPKPXXTPTKL (SEQ ID NO: 6585):SPIN-AA17-LYF (SEQ ID NO: 6601), TVPKPXXTPTQL (SEQ ID NO: 6577):SPIN-AA17-LYF (SEQ ID NO: 6601), AVPKAXXTPTKL (SEQ ID NO: 6481):SPIN-AA17-LYF (SEQ ID NO: 6601), KVGKAXXTPTKL (SEQ ID NO: 6539):SPIN-AA17-LYF (SEQ ID NO: 6601), KASKAXXTPTKL (SEQ ID NO: 6523):SPIN-AA17-LYF (SEQ ID NO: 6601), AAPASXXTPTRL (SEQ ID NO: 6457):SPIN-AA17-LYF (SEQ ID NO: 6601), STPPTXXTPTRL (SEQ ID NO: 6569):SPIN-AA17-LYF (SEQ ID NO: 6601), HVPKPXXTPTKL (SEQ ID NO: 6505):SPIN-AA17-LYF (SEQ ID NO: 6601), RVPSTXXTPTKT (SEQ ID NO: 6551):SPIN-AA17-LYF (SEQ ID NO: 6601), ASAAPXXTPTAL (SEQ ID NO: 6465):SPIN-AA17-LYF (SEQ ID NO: 6601), ASASPXXTPTDL (SEQ ID NO: 6473):SPIN-AA17-LYF (SEQ ID NO: 6601), KIPKAXXVPTEL (SEQ ID NO: 6535):SPIN-AA17-LYF (SEQ ID NO: 6601), GIPEPXXVPEKM (SEQ ID NO: 6491):SPIN-AA17-LYF (SEQ ID NO: 6601), SIPKAXXVPTEL (SEQ ID NO: 6563):SPIN-AA17-LYF (SEQ ID NO: 6601), HVTKPTXAPTKL (SEQ ID NO: 6511):SPIN-AA17-LYF (SEQ ID NO: 6601), YVPKPXXAPTKL (SEQ ID NO: 6583):SPIN-AA17-LYF (SEQ ID NO: 6601), TVPKPXXAPTQL (SEQ ID NO: 6575):SPIN-AA17-LYF (SEQ ID NO: 6601), AVPKAXXAPTKL (SEQ ID NO: 6479):SPIN-AA17-LYF (SEQ ID NO: 6601), KVGKAXXVPTKL (SEQ ID NO: 6543):SPIN-AA17-LYF (SEQ ID NO: 6601), KASKAXXVPTKL (SEQ ID NO: 6527):SPIN-AA17-LYF (SEQ ID NO: 6601), AAPASXXVPARL (SEQ ID NO: 6458):SPIN-AA17-LYF (SEQ ID NO: 6601), STPPTXXVPTRL (SEQ ID NO: 6573):SPIN-AA17-LYF (SEQ ID NO: 6601), HVPKPXXAPTKL (SEQ ID NO: 6503):SPIN-AA17-LYF (SEQ ID NO: 6601), RVPSTXXAPVKT (SEQ ID NO: 6550):SPIN-AA17-LYF (SEQ ID NO: 6601), ASAAPXXVPQAL (SEQ ID NO: 6468):SPIN-AA17-LYF (SEQ ID NO: 6601), ASASPXXVSQDL (SEQ ID NO: 6478):SPIN-AA17-LYF (SEQ ID NO: 6601), ASASPXXVPQDL (SEQ ID NO: 6476):SPIN-AA17-LYF (SEQ ID NO: 6601), NDEGLEXVPTEE (SEQ ID NO: 6545):SPIN-AA17-LYF (SEQ ID NO: 6601), NDEGLEXVPTGQ (SEQ ID NO: 6546):SPIN-AA17-LYF (SEQ ID NO: 6601), SSVKXQPSRVHH (SEQ ID NO: 6565):SPIN-AA17-LYF (SEQ ID NO: 6601), RNVQXRPTQVQL (SEQ ID NO: 6548):SPIN-AA17-LYF (SEQ ID NO: 6601), KIPKAXXVPAEL (SEQ ID NO: 6532):SPIS-AA17-LYI (SEQ ID NO: 6603), GIPEPXXVPAKM (SEQ ID NO: 6490):SPIS-AA17-LYI (SEQ ID NO: 6603), SIPKAXXVPAEL (SEQ ID NO: 6560):SPIS-AA17-LYI (SEQ ID NO: 6603), HVTKPTXVPAKL (SEQ ID NO: 6516):SPIS-AA17-LYI (SEQ ID NO: 6603), YVPKPXXVPAKL (SEQ ID NO: 6586):SPIS-AA17-LYI (SEQ ID NO: 6603), TVPKPXXVPAQL (SEQ ID NO: 6578):SPIS-AA17-LYI (SEQ ID NO: 6603), AVPKAXXVPAKL (SEQ ID NO: 6482):SPIS-AA17-LYI (SEQ ID NO: 6603), KVGKAXXVPAKL (SEQ ID NO: 6540):SPIS-AA17-LYI (SEQ ID NO: 6603), KASKAXXVPAKL (SEQ ID NO: 6524):SPIS-AA17-LYI (SEQ ID NO: 6603), GSAGPXXVPAKM (SEQ ID NO: 6498):SPIS-AA17-LYI (SEQ ID NO: 6603), STPPTXXVPARL (SEQ ID NO: 6570):SPIS-AA17-LYI (SEQ ID NO: 6603), HVPKPXXVPAKL (SEQ ID NO: 6506):SPIS-AA17-LYI (SEQ ID NO: 6603), RVPSTXXVPAKT (SEQ ID NO: 6552):SPIS-AA17-LYI (SEQ ID NO: 6603), ASAAPXXVPAAL (SEQ ID NO: 6466):SPIS-AA17-LYI (SEQ ID NO: 6603), ASASPXXVPADL (SEQ ID NO: 6474):SPIS-AA17-LYI (SEQ ID NO: 6603), KIPKAXXVPTEL (SEQ ID NO: 6535):SPIS-AA17-LYI (SEQ ID NO: 6603), GIPEPXXVPEKM (SEQ ID NO: 6491):SPIS-AA17-LYI (SEQ ID NO: 6603), SIPKAXXVPTEL (SEQ ID NO: 6563):SPIS-AA17-LYI (SEQ ID NO: 6603), HVTKPTXAPTKL (SEQ ID NO: 6511):SPIS-AA17-LYI (SEQ ID NO: 6603), YVPKPXXAPTKL (SEQ ID NO: 6583):SPIS-AA17-LYI (SEQ ID NO: 6603), TVPKPXXAPTQL (SEQ ID NO: 6575):SPIS-AA17-LYI (SEQ ID NO: 6603), AVPKAXXAPTKL (SEQ ID NO: 6479):SPIS-AA17-LYI (SEQ ID NO: 6603), KVGKAXXVPTKL (SEQ ID NO: 6543):SPIS-AA17-LYI (SEQ ID NO: 6603), KASKAXXVPTKL (SEQ ID NO: 6527):SPIS-AA17-LYI (SEQ ID NO: 6603), GSAGPXXTPTKM (SEQ ID NO: 6497):SPIS-AA17-LYI (SEQ ID NO: 6603), STPPTXXVPTRL (SEQ ID NO: 6573):SPIS-AA17-LYI (SEQ ID NO: 6603), HVPKPXXAPTKL (SEQ ID NO: 6503):SPIS-AA17-LYI (SEQ ID NO: 6603), RVPSTXXAPVKT (SEQ ID NO: 6550):SPIS-AA17-LYI (SEQ ID NO: 6603), ASAAPXXVPQAL (SEQ ID NO: 6468):SPIS-AA17-LYI (SEQ ID NO: 6603), ASASPXXVSQDL (SEQ ID NO: 6478):SPIS-AA17-LYI (SEQ ID NO: 6603), ASASPXXVPQDL (SEQ ID NO: 6476):SPIS-AA17-LYI (SEQ ID NO: 6603), NDEGLEXVPTEE (SEQ ID NO: 6545):SPIS-AA17-LYI (SEQ ID NO: 6603), NDEGLEXVPTGQ (SEQ ID NO: 6546):SPIS-AA17-LYI (SEQ ID NO: 6603), SSVKXQPSRVHH (SEQ ID NO: 6565):SPIS-AA17-LYI (SEQ ID NO: 6603), RNVQXRPTQVQL (SEQ ID NO: 6548):SPIS-AA17-LYI (SEQ ID NO: 6603), KIPKAXXVPTEL (SEQ ID NO: 6535):SPIS-AA17-LFI (SEQ ID NO: 6602), GIPEPXXVPTKM (SEQ ID NO: 6493):SPIS-AA17-LFI (SEQ ID NO: 6602), SIPKAXXVPTEL (SEQ ID NO: 6563):SPIS-AA17-LFI (SEQ ID NO: 6602), HVTKPTXVPTKL (SEQ ID NO: 6519):SPIS-AA17-LFI (SEQ ID NO: 6602), YVPKPXXVPTKL (SEQ ID NO: 6589):SPIS-AA17-LFI (SEQ ID NO: 6602), TVPKPXXVPTQL (SEQ ID NO: 6581):SPIS-AA17-LFI (SEQ ID NO: 6602), AVPKAXXVPTKL (SEQ ID NO: 6485):SPIS-AA17-LFI (SEQ ID NO: 6602), KVGKAXXVPTKL (SEQ ID NO: 6543):SPIS-AA17-LFI (SEQ ID NO: 6602), KASKAXXVPTKL (SEQ ID NO: 6527):SPIS-AA17-LFI (SEQ ID NO: 6602), GSAGPXXVPTKM (SEQ ID NO: 6501):SPIS-AA17-LFI (SEQ ID NO: 6602), AAPASXXVPTRL (SEQ ID NO: 6461):SPIS-AA17-LFI (SEQ ID NO: 6602), HVPKPXXVPTKL (SEQ ID NO: 6509):SPIS-AA17-LFI (SEQ ID NO: 6602), RVPSTXXVPTKT (SEQ ID NO: 6555):SPIS-AA17-LFI (SEQ ID NO: 6602), ASAAPXXVPTAL (SEQ ID NO: 6469):SPIS-AA17-LFI (SEQ ID NO: 6602), ASASPXXVPTDL (SEQ ID NO: 6477):SPIS-AA17-LFI (SEQ ID NO: 6602), GIPEPXXVPEKM (SEQ ID NO: 6491):SPIS-AA17-LFI (SEQ ID NO: 6602), HVTKPTXAPTKL (SEQ ID NO: 6511):SPIS-AA17-LFI (SEQ ID NO: 6602), YVPKPXXAPTKL (SEQ ID NO: 6583):SPIS-AA17-LFI (SEQ ID NO: 6602), TVPKPXXAPTQL (SEQ ID NO: 6575):SPIS-AA17-LFI (SEQ ID NO: 6602), AVPKAXXAPTKL (SEQ ID NO: 6479):SPIS-AA17-LFI (SEQ ID NO: 6602), GSAGPXXTPTKM (SEQ ID NO: 6497):SPIS-AA17-LFI (SEQ ID NO: 6602), AAPASXXVPARL (SEQ ID NO: 6458):SPIS-AA17-LFI (SEQ ID NO: 6602), HVPKPXXAPTKL (SEQ ID NO: 6503):SPIS-AA17-LFI (SEQ ID NO: 6602), RVPSTXXAPVKT (SEQ ID NO: 6550):SPIS-AA17-LFI (SEQ ID NO: 6602), ASAAPXXVPQAL (SEQ ID NO: 6468):SPIS-AA17-LFI (SEQ ID NO: 6602), ASASPXXVSQDL (SEQ ID NO: 6478):SPIS-AA17-LFI (SEQ ID NO: 6602), ASASPXXVPQDL (SEQ ID NO: 6476):SPIS-AA17-LFI (SEQ ID NO: 6602), SSVKXQPSRVHH (SEQ ID NO: 6565):SPIS-AA17-LFI (SEQ ID NO: 6602), RNVQXRPTQVQL (SEQ ID NO: 6548):SPIS-AA17-LFI (SEQ ID NO: 6602), KIPKAXXAPVEL (SEQ ID NO: 6530):KPLS-AA17-LYV (SEQ ID NO: 6594), GIPEPXXAPVKM (SEQ ID NO: 6488):KPLS-AA17-LYV (SEQ ID NO: 6594), SIPKAXXAPVEL (SEQ ID NO: 6558):KPLS-AA17-LYV (SEQ ID NO: 6594), HVTKPTXAPVKL (SEQ ID NO: 6512):KPLS-AA17-LYV (SEQ ID NO: 6594), YVPKPXXAPVKL (SEQ ID NO: 6584):KPLS-AA17-LYV (SEQ ID NO: 6594), TVPKPXXAPVQL (SEQ ID NO: 6576):KPLS-AA17-LYV (SEQ ID NO: 6594), AVPKAXXAPVKL (SEQ ID NO: 6480):KPLS-AA17-LYV (SEQ ID NO: 6594), KVGKAXXAPVKL (SEQ ID NO: 6538):KPLS-AA17-LYV (SEQ ID NO: 6594), KASKAXXAPVKL (SEQ ID NO: 6522):KPLS-AA17-LYV (SEQ ID NO: 6594), GSAGPXXAPVKM (SEQ ID NO: 6496):KPLS-AA17-LYV (SEQ ID NO: 6594), AAPASXXAPVRL (SEQ ID NO: 6456):KPLS-AA17-LYV (SEQ ID NO: 6594), STPPTXXAPVRL (SEQ ID NO: 6568):KPLS-AA17-LYV (SEQ ID NO: 6594), HVPKPXXAPVKL (SEQ ID NO: 6504):KPLS-AA17-LYV (SEQ ID NO: 6594), ASAAPXXAPVAL (SEQ ID NO: 6464):KPLS-AA17-LYV (SEQ ID NO: 6594), ASASPXXAPVDL (SEQ ID NO: 6472):KPLS-AA17-LYV (SEQ ID NO: 6594), KIPKAXXVPTEL (SEQ ID NO: 6535):KPLS-AA17-LYV (SEQ ID NO: 6594), GIPEPXXVPEKM (SEQ ID NO: 6491):KPLS-AA17-LYV (SEQ ID NO: 6594), SIPKAXXVPTEL (SEQ ID NO: 6563):KPLS-AA17-LYV (SEQ ID NO: 6594), HVTKPTXAPTKL (SEQ ID NO: 6511):KPLS-AA17-LYV (SEQ ID NO: 6594), YVPKPXXAPTKL (SEQ ID NO: 6583):KPLS-AA17-LYV (SEQ ID NO: 6594), TVPKPXXAPTQL (SEQ ID NO: 6575):KPLS-AA17-LYV (SEQ ID NO: 6594), AVPKAXXAPTKL (SEQ ID NO: 6479):KPLS-AA17-LYV (SEQ ID NO: 6594), KVGKAXXVPTKL (SEQ ID NO: 6543):KPLS-AA17-LYV (SEQ ID NO: 6594), KASKAXXVPTKL (SEQ ID NO: 6527):KPLS-AA17-LYV (SEQ ID NO: 6594), GSAGPXXTPTKM (SEQ ID NO: 6497):KPLS-AA17-LYV (SEQ ID NO: 6594), AAPASXXVPARL (SEQ ID NO: 6458):KPLS-AA17-LYV (SEQ ID NO: 6594), STPPTXXVPTRL (SEQ ID NO: 6573):KPLS-AA17-LYV (SEQ ID NO: 6594), HVPKPXXAPTKL (SEQ ID NO: 6503):KPLS-AA17-LYV (SEQ ID NO: 6594), ASAAPXXVPQAL (SEQ ID NO: 6468):KPLS-AA17-LYV (SEQ ID NO: 6594), ASASPXXVSQDL (SEQ ID NO: 6478):KPLS-AA17-LYV (SEQ ID NO: 6594), ASASPXXVPQDL (SEQ ID NO: 6476):KPLS-AA17-LYV (SEQ ID NO: 6594), NDEGLEXVPTEE (SEQ ID NO: 6545):KPLS-AA17-LYV (SEQ ID NO: 6594), NDEGLEXVPTGQ (SEQ ID NO: 6546):KPLS-AA17-LYV (SEQ ID NO: 6594), SSVKXQPSRVHH (SEQ ID NO: 6565):KPLS-AA17-LYV (SEQ ID NO: 6594), RNVQXRPTQVQL (SEQ ID NO: 6548):KPLS-AA17-LYV (SEQ ID NO: 6594), KIPKAXXVPQEL (SEQ ID NO: 6534):EPLP-AA17-VYY (SEQ ID NO: 6592), GIPEPXXVPQKM (SEQ ID NO: 6492):EPLP-AA17-VYY (SEQ ID NO: 6592), SIPKAXXVPQEL (SEQ ID NO: 6562):EPLP-AA17-VYY (SEQ ID NO: 6592), HVTKPTXVPQKL (SEQ ID NO: 6518):EPLP-AA17-VYY (SEQ ID NO: 6592), YVPKPXXVPQKL (SEQ ID NO: 6588):EPLP-AA17-VYY (SEQ ID NO: 6592), TVPKPXXVPQQL (SEQ ID NO: 6580):EPLP-AA17-VYY (SEQ ID NO: 6592), AVPKAXXVPQKL (SEQ ID NO: 6484):EPLP-AA17-VYY (SEQ ID NO: 6592), KVGKAXXVPQKL (SEQ ID NO: 6542):EPLP-AA17-VYY (SEQ ID NO: 6592), KASKAXXVPQKL (SEQ ID NO: 6526):EPLP-AA17-VYY (SEQ ID NO: 6592), GSAGPXXVPQKM (SEQ ID NO: 6500):EPLP-AA17-VYY (SEQ ID NO: 6592), AAPASXXVPQRL (SEQ ID NO: 6460):EPLP-AA17-VYY (SEQ ID NO: 6592), STPPTXXVPQRL (SEQ ID NO: 6572):EPLP-AA17-VYY (SEQ ID NO: 6592), HVPKPXXVPQKL (SEQ ID NO: 6508):EPLP-AA17-VYY (SEQ ID NO: 6592), RVPSTXXVPQKT (SEQ ID NO: 6554):EPLP-AA17-VYY (SEQ ID NO: 6592), ASASPXXVPQDL (SEQ ID NO: 6476):EPLP-AA17-VYY (SEQ ID NO: 6592), KIPKAXXVPTEL (SEQ ID NO: 6535):EPLP-AA17-VYY (SEQ ID NO: 6592), GIPEPXXVPEKM (SEQ ID NO: 6491):EPLP-AA17-VYY (SEQ ID NO: 6592), SIPKAXXVPTEL (SEQ ID NO: 6563):EPLP-AA17-VYY (SEQ ID NO: 6592), HVTKPTXAPTKL (SEQ ID NO: 6511):EPLP-AA17-VYY (SEQ ID NO: 6592), YVPKPXXAPTKL (SEQ ID NO: 6583):EPLP-AA17-VYY (SEQ ID NO: 6592), TVPKPXXAPTQL (SEQ ID NO: 6575):EPLP-AA17-VYY (SEQ ID NO: 6592), AVPKAXXAPTKL (SEQ ID NO: 6479):EPLP-AA17-VYY (SEQ ID NO: 6592), KVGKAXXVPTKL (SEQ ID NO: 6543):EPLP-AA17-VYY (SEQ ID NO: 6592), KASKAXXVPTKL (SEQ ID NO: 6527):EPLP-AA17-VYY (SEQ ID NO: 6592), GSAGPXXTPTKM (SEQ ID NO: 6497):EPLP-AA17-VYY (SEQ ID NO: 6592), AAPASXXVPARL (SEQ ID NO: 6458):EPLP-AA17-VYY (SEQ ID NO: 6592), STPPTXXVPTRL (SEQ ID NO: 6573):EPLP-AA17-VYY (SEQ ID NO: 6592), HVPKPXXAPTKL (SEQ ID NO: 6503):EPLP-AA17-VYY (SEQ ID NO: 6592), RVPSTXXAPVKT (SEQ ID NO: 6550):EPLP-AA17-VYY (SEQ ID NO: 6592), ASASPXXVSQDL (SEQ ID NO: 6478):EPLP-AA17-VYY (SEQ ID NO: 6592), NDEGLEXVPTEE (SEQ ID NO: 6545):EPLP-AA17-VYY (SEQ ID NO: 6592), NDEGLEXVPTGQ (SEQ ID NO: 6546):EPLP-AA17-VYY (SEQ ID NO: 6592), SSVKXQPSRVHH (SEQ ID NO: 6565):EPLP-AA17-VYY (SEQ ID NO: 6592), RNVQXRPTQVQL (SEQ ID NO: 6548):EPLP-AA17-VYY (SEQ ID NO: 6592), KIPKAXXVSQEL (SEQ ID NO: 6536):EPLT-AA17-LYY (SEQ ID NO: 6593), GIPEPXXVSQKM (SEQ ID NO: 6494):EPLT-AA17-LYY (SEQ ID NO: 6593), SIPKAXXVSQEL (SEQ ID NO: 6564):EPLT-AA17-LYY (SEQ ID NO: 6593), HVTKPTXVSQKL (SEQ ID NO: 6520):EPLT-AA17-LYY (SEQ ID NO: 6593), YVPKPXXVSQKL (SEQ ID NO: 6590):EPLT-AA17-LYY (SEQ ID NO: 6593), TVPKPXXVSQQL (SEQ ID NO: 6582):EPLT-AA17-LYY (SEQ ID NO: 6593), AVPKAXXVSQKL (SEQ ID NO: 6486):EPLT-AA17-LYY (SEQ ID NO: 6593), KVGKAXXVSQKL (SEQ ID NO: 6544):EPLT-AA17-LYY (SEQ ID NO: 6593), KASKAXXVSQKL (SEQ ID NO: 6528):EPLT-AA17-LYY (SEQ ID NO: 6593), GSAGPXXVSQKM (SEQ ID NO: 6502):EPLT-AA17-LYY (SEQ ID NO: 6593), AAPASXXVSQRL (SEQ ID NO: 6462):EPLT-AA17-LYY (SEQ ID NO: 6593), STPPTXXVSQRL (SEQ ID NO: 6574):EPLT-AA17-LYY (SEQ ID NO: 6593), HVPKPXXVSQKL (SEQ ID NO: 6510):EPLT-AA17-LYY (SEQ ID NO: 6593), RVPSTXXVSQKT (SEQ ID NO: 6556):EPLT-AA17-LYY (SEQ ID NO: 6593), ASAAPXXVSQAL (SEQ ID NO: 6470):EPLT-AA17-LYY (SEQ ID NO: 6593), ASASPXXVSQDL (SEQ ID NO: 6478):EPLT-AA17-LYY (SEQ ID NO: 6593), KIPKAXXVPTEL (SEQ ID NO: 6535):EPLT-AA17-LYY (SEQ ID NO: 6593), GIPEPXXVPEKM (SEQ ID NO: 6491):EPLT-AA17-LYY (SEQ ID NO: 6593), SIPKAXXVPTEL (SEQ ID NO: 6563):EPLT-AA17-LYY (SEQ ID NO: 6593), HVTKPTXAPTKL (SEQ ID NO: 6511):EPLT-AA17-LYY (SEQ ID NO: 6593), YVPKPXXAPTKL (SEQ ID NO: 6583):EPLT-AA17-LYY (SEQ ID NO: 6593), TVPKPXXAPTQL (SEQ ID NO: 6575):EPLT-AA17-LYY (SEQ ID NO: 6593), AVPKAXXAPTKL (SEQ ID NO: 6479):EPLT-AA17-LYY (SEQ ID NO: 6593), KVGKAXXVPTKL (SEQ ID NO: 6543):EPLT-AA17-LYY (SEQ ID NO: 6593), KASKAXXVPTKL (SEQ ID NO: 6527):EPLT-AA17-LYY (SEQ ID NO: 6593), GSAGPXXTPTKM (SEQ ID NO: 6497):EPLT-AA17-LYY (SEQ ID NO: 6593), AAPASXXVPARL (SEQ ID NO: 6458):EPLT-AA17-LYY (SEQ ID NO: 6593), STPPTXXVPTRL (SEQ ID NO: 6573):EPLT-AA17-LYY (SEQ ID NO: 6593), HVPKPXXAPTKL (SEQ ID NO: 6503):EPLT-AA17-LYY (SEQ ID NO: 6593), RVPSTXXAPVKT (SEQ ID NO: 6550):EPLT-AA17-LYY (SEQ ID NO: 6593), ASAAPXXVPQAL (SEQ ID NO: 6468):EPLT-AA17-LYY (SEQ ID NO: 6593), NDEGLEXVPTEE (SEQ ID NO: 6545):EPLT-AA17-LYY (SEQ ID NO: 6593), NDEGLEXVPTGQ (SEQ ID NO: 6546):EPLT-AA17-LYY (SEQ ID NO: 6593), SSVKXQPSRVHH (SEQ ID NO: 6565):EPLT-AA17-LYY (SEQ ID NO: 6593), RNVQXRPTQVQL (SEQ ID NO: 6548):EPLT-AA17-LYY (SEQ ID NO: 6593), KIPKAXXVPQEL (SEQ ID NO: 6534):EPLT-AA17-LYY (SEQ ID NO: 6593), GIPEPXXVPQKM (SEQ ID NO: 6492):EPLT-AA17-LYY (SEQ ID NO: 6593), SIPKAXXVPQEL (SEQ ID NO: 6562):EPLT-AA17-LYY (SEQ ID NO: 6593), HVTKPTXVPQKL (SEQ ID NO: 6518):EPLT-AA17-LYY (SEQ ID NO: 6593), YVPKPXXVPQKL (SEQ ID NO: 6588):EPLT-AA17-LYY (SEQ ID NO: 6593), TVPKPXXVPQQL (SEQ ID NO: 6580):EPLT-AA17-LYY (SEQ ID NO: 6593), AVPKAXXVPQKL (SEQ ID NO: 6484):EPLT-AA17-LYY (SEQ ID NO: 6593), KVGKAXXVPQKL (SEQ ID NO: 6542):EPLT-AA17-LYY (SEQ ID NO: 6593), KASKAXXVPQKL (SEQ ID NO: 6526):EPLT-AA17-LYY (SEQ ID NO: 6593), GSAGPXXVPQKM (SEQ ID NO: 6500):EPLT-AA17-LYY (SEQ ID NO: 6593), AAPASXXVPQRL (SEQ ID NO: 6460):EPLT-AA17-LYY (SEQ ID NO: 6593), STPPTXXVPQRL (SEQ ID NO: 6572):EPLT-AA17-LYY (SEQ ID NO: 6593), HVPKPXXVPQKL (SEQ ID NO: 6508):EPLT-AA17-LYY (SEQ ID NO: 6593), RVPSTXXVPQKT (SEQ ID NO: 6554):EPLT-AA17-LYY (SEQ ID NO: 6593), ASASPXXVPQDL (SEQ ID NO: 6476):EPLT-AA17-LYY (SEQ ID NO: 6593), NDEGLEXVPTGQ (SEQ ID NO: 6546):SNIT-AA17-QIM (SEQ ID NO: 6600), GIPEPXXVPEKM (SEQ ID NO: 6491):SNIT-AA17-QIM (SEQ ID NO: 6600), HVTKPTXAPTKL (SEQ ID NO: 6511):SNIT-AA17-QIM (SEQ ID NO: 6600), YVPKPXXAPTKL (SEQ ID NO: 6583):SNIT-AA17-QIM (SEQ ID NO: 6600), TVPKPXXAPTQL (SEQ ID NO: 6575):SNIT-AA17-QIM (SEQ ID NO: 6600), AVPKAXXAPTKL (SEQ ID NO: 6479):SNIT-AA17-QIM (SEQ ID NO: 6600), GSAGPXXTPTKM (SEQ ID NO: 6497):SNIT-AA17-QIM (SEQ ID NO: 6600), AAPASXXVPARL (SEQ ID NO: 6458):SNIT-AA17-QIM (SEQ ID NO: 6600), HVPKPXXAPTKL (SEQ ID NO: 6503):SNIT-AA17-QIM (SEQ ID NO: 6600), RVPSTXXAPVKT (SEQ ID NO: 6550):SNIT-AA17-QIM (SEQ ID NO: 6600), ASAAPXXVPQAL (SEQ ID NO: 6468):SNIT-AA17-QIM (SEQ ID NO: 6600), ASASPXXVSQDL (SEQ ID NO: 6478):SNIT-AA17-QIM (SEQ ID NO: 6600), ASASPXXVPQDL (SEQ ID NO: 6476):SNIT-AA17-QIM (SEQ ID NO: 6600), SSVKXQPSRVHH (SEQ ID NO: 6565):SNIT-AA17-QIM (SEQ ID NO: 6600), RNVQXRPTQVQL (SEQ ID NO: 6548):SNIT-AA17-QIM (SEQ ID NO: 6600), RNVQXRPSRVQL (SEQ ID NO: 6547):RSVK-AA17-AKV (SEQ ID NO: 6597), KIPKAXXVPTEL (SEQ ID NO: 6535):RSVK-AA17-AKV (SEQ ID NO: 6597), GIPEPXXVPEKM (SEQ ID NO: 6491):RSVK-AA17-AKV (SEQ ID NO: 6597), SIPKAXXVPTEL (SEQ ID NO: 6563):RSVK-AA17-AKV (SEQ ID NO: 6597), HVTKPTXAPTKL (SEQ ID NO: 6511):RSVK-AA17-AKV (SEQ ID NO: 6597), YVPKPXXAPTKL (SEQ ID NO: 6583):RSVK-AA17-AKV (SEQ ID NO: 6597), TVPKPXXAPTQL (SEQ ID NO: 6575):RSVK-AA17-AKV (SEQ ID NO: 6597), AVPKAXXAPTKL (SEQ ID NO: 6479):RSVK-AA17-AKV (SEQ ID NO: 6597), KVGKAXXVPTKL (SEQ ID NO: 6543):RSVK-AA17-AKV (SEQ ID NO: 6597), KASKAXXVPTKL (SEQ ID NO: 6527):RSVK-AA17-AKV (SEQ ID NO: 6597), GSAGPXXTPTKM (SEQ ID NO: 6497):RSVK-AA17-AKV (SEQ ID NO: 6597), AAPASXXVPARL (SEQ ID NO: 6458):RSVK-AA17-AKV (SEQ ID NO: 6597), STPPTXXVPTRL (SEQ ID NO: 6573):RSVK-AA17-AKV (SEQ ID NO: 6597), HVPKPXXAPTKL (SEQ ID NO: 6503):RSVK-AA17-AKV (SEQ ID NO: 6597), RVPSTXXAPVKT (SEQ ID NO: 6550):RSVK-AA17-AKV (SEQ ID NO: 6597), ASAAPXXVPQAL (SEQ ID NO: 6468):RSVK-AA17-AKV (SEQ ID NO: 6597), ASASPXXVSQDL (SEQ ID NO: 6478):RSVK-AA17-AKV (SEQ ID NO: 6597), ASASPXXVPQDL (SEQ ID NO: 6476):RSVK-AA17-AKV (SEQ ID NO: 6597), NDEGLEXVPTEE (SEQ ID NO: 6545):RSVK-AA17-AKV (SEQ ID NO: 6597), NDEGLEXVPTGQ (SEQ ID NO: 6546):RSVK-AA17-AKV (SEQ ID NO: 6597), RNVQXRPTQVOL (SEQ ID NO: 6548):RSVK-AA17-AKV (SEQ ID NO: 6597), SSVKXQPTQVHH (SEQ ID NO: 6566):RPVQ-AA17-RKI (SEQ ID NO: 6596), KIPKAXXVPTEL (SEQ ID NO: 6535):RPVQ-AA17-RKI (SEQ ID NO: 6596), GIPEPXXVPEKM (SEQ ID NO: 6491):RPVQ-AA17-RKI (SEQ ID NO: 6596), SIPKAXXVPTEL (SEQ ID NO: 6563):RPVQ-AA17-RKI (SEQ ID NO: 6596), HVTKPTXAPTKL (SEQ ID NO: 6511):RPVQ-AA17-RKI (SEQ ID NO: 6596), YVPKPXXAPTKL (SEQ ID NO: 6583):RPVQ-AA17-RKI (SEQ ID NO: 6596), TVPKPXXAPTQL (SEQ ID NO: 6575):RPVQ-AA17-RKI (SEQ ID NO: 6596), AVPKAXXAPTKL (SEQ ID NO: 6479):RPVQ-AA17-RKI (SEQ ID NO: 6596), KVGKAXXVPTKL (SEQ ID NO: 6543):RPVQ-AA17-RKI (SEQ ID NO: 6596), KASKAXXVPTKL (SEQ ID NO: 6527):RPVQ-AA17-RKI (SEQ ID NO: 6596), GSAGPXXTPTKM (SEQ ID NO: 6497):RPVQ-AA17-RKI (SEQ ID NO: 6596), AAPASXXVPARL (SEQ ID NO: 6458):RPVQ-AA17-RKI (SEQ ID NO: 6596), STPPTXXVPTRL (SEQ ID NO: 6573):RPVQ-AA17-RKI (SEQ ID NO: 6596), HVPKPXXAPTKL (SEQ ID NO: 6503):RPVQ-AA17-RKI (SEQ ID NO: 6596), RVPSTXXAPVKT (SEQ ID NO: 6550):RPVQ-AA17-RKI (SEQ ID NO: 6596), ASAAPXXVPQAL (SEQ ID NO: 6468):RPVQ-AA17-RKI (SEQ ID NO: 6596), ASASPXXVSQDL (SEQ ID NO: 6478):RPVQ-AA17-RKI (SEQ ID NO: 6596), ASASPXXVPQDL (SEQ ID NO: 6476):RPVQ-AA17-RKI (SEQ ID NO: 6596), NDEGLEXVPTEE (SEQ ID NO: 6545):RPVQ-AA17-RKI (SEQ ID NO: 6596), NDEGLEXVPTGQ (SEQ ID NO: 6546):RPVQ-AA17-RKI (SEQ ID NO: 6596) and SSVKXQPSRVHH (SEQ ID NO: 6565):RPVQ-AA17-RKI (SEQ ID NO: 6596); and wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T).
In certain embodiments, the triplet PEP7:PEP3:PEP1 is selected from the group consisting of GIPEPXX (SEQ ID NO: 6440):VPT:SAIS (SEQ ID NO: 6360), HVTKPTX (SEQ ID NO: 6443):VPT:SAIS (SEQ ID NO: 6360), YVPKPXX (SEQ ID NO: 6454):VPT:SAIS (SEQ ID NO: 6360), TVPKPXX (SEQ ID NO: 6453):VPT:SAIS (SEQ ID NO: 6360), AVPKAXX (SEQ ID NO: 6439):VPT:SAIS (SEQ ID NO: 6360), KVGKAXX (SEQ ID NO: 6446):VPT:SAIS (SEQ ID NO: 6360), KASKAXX (SEQ ID NO: 6444):VPT:SAIS (SEQ ID NO: 6360), GSAGPXX (SEQ ID NO: 6441):VPT:SAIS (SEQ ID NO: 6360), AAPASXX (SEQ ID NO: 6436):VPT:SAIS (SEQ ID NO: 6360), STPPTXX (SEQ ID NO: 6452):VPT:SAIS (SEQ ID NO: 6360), HVPKPXX (SEQ ID NO: 6442):VPT:SAIS (SEQ ID NO: 6360), RVPSTXX (SEQ ID NO: 6449):VPT:SAIS (SEQ ID NO: 6360), ASAAPXX (SEQ ID NO: 6437):VPT:SAIS (SEQ ID NO: 6360), ASASPXX (SEQ ID NO: 6438):VPT:SAIS (SEQ ID NO: 6360), GIPEPXX (SEQ ID NO: 6440):VPE:SAIS (SEQ ID NO: 6360), HVTKPTX (SEQ ID NO: 6443):APT:SAIS (SEQ ID NO: 6360), YVPKPXX (SEQ ID NO: 6454):APT:SAIS (SEQ ID NO: 6360), TVPKPXX (SEQ ID NO: 6453):APT:SAIS (SEQ ID NO: 6360), AVPKAXX (SEQ ID NO: 6439):APT:SAIS (SEQ ID NO: 6360), GSAGPXX (SEQ ID NO: 6441):TPT:SAIS (SEQ ID NO: 6360), AAPASXX (SEQ ID NO: 6436):VPA:SAIS (SEQ ID NO: 6360), HVPKPXX (SEQ ID NO: 6442):APT:SAIS (SEQ ID NO: 6360), RVPSTXX (SEQ ID NO: 6449):APV:SAIS (SEQ ID NO: 6360), ASAAPXX (SEQ ID NO: 6437):VPQ:SAIS (SEQ ID NO: 6360), ASASPXX (SEQ ID NO: 6438):VSQ:SAIS (SEQ ID NO: 6360), ASASPXX (SEQ ID NO: 6438):VPQ:SAIS (SEQ ID NO: 6360), SSVKXQP (SEQ ID NO: 6451):SRV:SAIS (SEQ ID NO: 6360), RNVQXRP (SEQ ID NO: 6448):TQV:SAIS (SEQ ID NO: 6360), KIPKAXX (SEQ ID NO: 6445):VPE:SSLS (SEQ ID NO: 6365), SIPKAXX (SEQ ID NO: 6450):VPE:SSLS (SEQ ID NO: 6365), HVTKPTX (SEQ ID NO: 6443):VPE:SSLS (SEQ ID NO: 6365), YVPKPXX (SEQ ID NO: 6454):VPE:SSLS (SEQ ID NO: 6365), TVPKPXX (SEQ ID NO: 6453):VPE:SSLS (SEQ ID NO: 6365), AVPKAXX (SEQ ID NO: 6439):VPE:SSLS (SEQ ID NO: 6365), KVGKAXX (SEQ ID NO: 6446):VPE:SSLS (SEQ ID NO: 6365), KASKAXX (SEQ ID NO: 6444):VPE:SSLS (SEQ ID NO: 6365), GSAGPXX (SEQ ID NO: 6441):VPE:SSLS (SEQ ID NO: 6365), AAPASXX (SEQ ID NO: 6436):VPE:SSLS (SEQ ID NO: 6365), STPPTXX (SEQ ID NO: 6452):VPE:SSLS (SEQ ID NO: 6365), HVPKPXX (SEQ ID NO: 6442):VPE:SSLS (SEQ ID NO: 6365), RVPSTXX (SEQ ID NO: 6449):VPE:SSLS (SEQ ID NO: 6365), ASAAPXX (SEQ ID NO: 6437):VPE:SSLS (SEQ ID NO: 6365), ASASPXX (SEQ ID NO: 6438):VPE:SSLS (SEQ ID NO: 6365), KIPKAXX (SEQ ID NO: 6445):VPT:SSLS (SEQ ID NO: 6365), SIPKAXX (SEQ ID NO: 6450):VPT:SSLS (SEQ ID NO: 6365), HVTKPTX (SEQ ID NO: 6443):APT:SSLS (SEQ ID NO: 6365), YVPKPXX (SEQ ID NO: 6454):APT:SSLS (SEQ ID NO: 6365), TVPKPXX (SEQ ID NO: 6453):APT:SSLS (SEQ ID NO: 6365), AVPKAXX (SEQ ID NO: 6439):APT:SSLS (SEQ ID NO: 6365), KVGKAXX (SEQ ID NO: 6446):VPT:SSLS (SEQ ID NO: 6365), KASKAXX (SEQ ID NO: 6444):VPT:SSLS (SEQ ID NO: 6365), GSAGPXX (SEQ ID NO: 6441):TPT:SSLS (SEQ ID NO: 6365), AAPASXX (SEQ ID NO: 6436):VPA:SSLS (SEQ ID NO: 6365), STPPTXX (SEQ ID NO: 6452):VPT:SSLS (SEQ ID NO: 6365), HVPKPXX (SEQ ID NO: 6442):APT:SSLS (SEQ ID NO: 6365), RVPSTXX (SEQ ID NO: 6449):APV:SSLS (SEQ ID NO: 6365), ASAAPXX (SEQ ID NO: 6437):VPQ:SSLS (SEQ ID NO: 6365), ASASPXX (SEQ ID NO: 6438):VSQ:SSLS (SEQ ID NO: 6365), ASASPXX (SEQ ID NO: 6438):VPQ:SSLS (SEQ ID NO: 6365), NDEGLEX (SEQ ID NO: 6447):VPT:SSLS (SEQ ID NO: 6365), SSVKXQP (SEQ ID NO: 6451):SRV:SSLS (SEQ ID NO: 6365), RNVQXRP (SEQ ID NO: 6448):TQV:SSLS (SEQ ID NO: 6365), KIPKAXX (SEQ ID NO: 6445):APT:NAIS (SEQ ID NO: 6357), GIPEPXX (SEQ ID NO: 6440):APT:NAIS (SEQ ID NO: 6357), SIPKAXX (SEQ ID NO: 6450):APT:NAIS (SEQ ID NO: 6357), AVPKAXX (SEQ ID NO: 6439):APT:NAIS (SEQ ID NO: 6357), KVGKAXX (SEQ ID NO: 6446)APT:NAIS (SEQ ID NO: 6357), KASKAXX (SEQ ID NO: 6444):APT:NAIS (SEQ ID NO: 6357), GSAGPXX (SEQ ID NO: 6441):APT:NAIS (SEQ ID NO: 6357), AAPASXX (SEQ ID NO: 6436):APT:NAIS (SEQ ID NO: 6357), STPPTXX (SEQ ID NO: 6452):APT:NAIS (SEQ ID NO: 6357), RVPSTXX (SEQ ID NO: 6449)APT:NAIS (SEQ ID NO: 6357), ASAAPXX (SEQ ID NO: 6437):APT:NAIS (SEQ ID NO: 6357), ASASPXX (SEQ ID NO: 6438):APT:NAIS (SEQ ID NO: 6357), KIPKAXX (SEQ ID NO: 6445):VPT:NAIS (SEQ ID NO: 6357), GIPEPXX (SEQ ID NO: 6440):VPE:NAIS (SEQ ID NO: 6357), SIPKAXX (SEQ ID NO: 6450):VPT:NAIS (SEQ ID NO: 6357), KVGKAXX (SEQ ID NO: 6446):VPT:NAIS (SEQ ID NO: 6357), KASKAXX (SEQ ID NO: 6444):VPT:NAIS (SEQ ID NO: 6357), GSAGPXX (SEQ ID NO: 6441):TPT:NAIS (SEQ ID NO: 6357), AAPASXX (SEQ ID NO: 6436):VPA:NAIS (SEQ ID NO: 6357), STPPTXX (SEQ ID NO: 6452):VPT:NAIS (SEQ ID NO: 6357), RVPSTXX (SEQ ID NO: 6449):APV:NAIS (SEQ ID NO: 6357), ASAAPXX (SEQ ID NO: 6437):VPQ:NAIS (SEQ ID NO: 6357), ASASPXX (SEQ ID NO: 6438):VSQ:NAIS (SEQ ID NO: 6357), ASASPXX (SEQ ID NO: 6438):VPQ:NAIS (SEQ ID NO: 6357), NDEGLEX (SEQ ID NO: 6447):VPT:NAIS (SEQ ID NO: 6357), SSVKXQP (SEQ ID NO: 6451):SRV:NAIS (SEQ ID NO: 6357), RNVQXRP (SEQ ID NO: 6448):TQV:NAIS (SEQ ID NO: 6357), KIPKAXX (SEQ ID NO: 6445):APT:SATS (SEQ ID NO: 6361), GIPEPXX (SEQ ID NO: 6440):APT:SATS (SEQ ID NO: 6361), SIPKAXX (SEQ ID NO: 6450):APT:SATS (SEQ ID NO: 6361), HVTKPTX (SEQ ID NO: 6443):APT:SATS (SEQ ID NO: 6361), YVPKPXX (SEQ ID NO: 6454):APT:SATS (SEQ ID NO: 6361), TVPKPXX (SEQ ID NO: 6453):APT:SATS (SEQ ID NO: 6361), KVGKAXX (SEQ ID NO: 6446):APT:SATS (SEQ ID NO: 6361), KASKAXX (SEQ ID NO: 6444):APT:SATS (SEQ ID NO: 6361), GSAGPXX (SEQ ID NO: 6441)APT:SATS (SEQ ID NO: 6361), AAPASXX (SEQ ID NO: 6436):APT:SATS (SEQ ID NO: 6361), STPPTXX (SEQ ID NO: 6452):APT:SATS (SEQ ID NO: 6361), HVPKPXX (SEQ ID NO: 6442)APT:SATS (SEQ ID NO: 6361), RVPSTXX (SEQ ID NO: 6449):APT:SATS (SEQ ID NO: 6361), ASAAPXX (SEQ ID NO: 6437):APT:SATS (SEQ ID NO: 6361), ASASPXX (SEQ ID NO: 6438):APT:SATS (SEQ ID NO: 6361), KIPKAXX (SEQ ID NO: 6445):VPT:SATS (SEQ ID NO: 6361), GIPEPXX (SEQ ID NO: 6440):VPE:SATS (SEQ ID NO: 6361), SIPKAXX (SEQ ID NO: 6450):VPT:SATS (SEQ ID NO: 6361), KVGKAXX (SEQ ID NO: 6446):VPT:SATS (SEQ ID NO: 6361), KASKAXX (SEQ ID NO: 6444):VPT:SATS (SEQ ID NO: 6361), GSAGPXX (SEQ ID NO: 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6451):SRV:SPIS (SEQ ID NO: 6364), RNVQXRP (SEQ ID NO: 6448):TQV:SPIS (SEQ ID NO: 6364), KIPKAXX (SEQ ID NO: 6445):VPT:EPIS (SEQ ID NO: 6353), GIPEPXX (SEQ ID NO: 6440):VPT:EPIS (SEQ ID NO: 6353), SIPKAXX (SEQ ID NO: 6450):VPT:EPIS (SEQ ID NO: 6353), HVTKPTX (SEQ ID NO: 6443):VPT:EPIS (SEQ ID NO: 6353), YVPKPXX (SEQ ID NO: 6454):VPT:EPIS (SEQ ID NO: 6353), TVPKPXX (SEQ ID NO: 6453):VPT:EPIS (SEQ ID NO: 6353), AVPKAXX (SEQ ID NO: 6439):VPT:EPIS (SEQ ID NO: 6353), KVGKAXX (SEQ ID NO: 6446):VPT:EPIS (SEQ ID NO: 6353), GSAGPXX (SEQ ID NO: 6441):VPT:EPIS (SEQ ID NO: 6353), AAPASXX (SEQ ID NO: 6436):VPT:EPIS (SEQ ID NO: 6353), STPPTXX (SEQ ID NO: 6452):VPT:EPIS (SEQ ID NO: 6353), HVPKPXX (SEQ ID NO: 6442):VPT:EPIS (SEQ ID NO: 6353), RVPSTXX (SEQ ID NO: 6449):VPT:EPIS (SEQ ID NO: 6353), ASAAPXX (SEQ ID NO: 6437):VPT:EPIS (SEQ ID NO: 6353), ASASPXX (SEQ ID NO: 6438):VPT:EPIS (SEQ ID NO: 6353), GIPEPXX (SEQ ID NO: 6440):VPE:EPIS (SEQ ID NO: 6353), HVTKPTX (SEQ ID NO: 6443)APT:EPIS (SEQ ID NO: 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6441):VPA:SPIS (SEQ ID NO: 6364), STPPTXX (SEQ ID NO: 6452):VPA:SPIS (SEQ ID NO: 6364), HVPKPXX (SEQ ID NO: 6442):VPA:SPIS (SEQ ID NO: 6364), RVPSTXX (SEQ ID NO: 6449):VPA:SPIS (SEQ ID NO: 6364), ASAAPXX (SEQ ID NO: 6437):VPA:SPIS (SEQ ID NO: 6364), ASASPXX (SEQ ID NO: 6438):VPA:SPIS (SEQ ID NO: 6364), KVGKAXX (SEQ ID NO: 6446):VPT:SPIS (SEQ ID NO: 6364), NDEGLEX (SEQ ID NO: 6447):VPT:SPIS (SEQ ID NO: 6364), KIPKAXX (SEQ ID NO: 6445):APV:KPLS (SEQ ID NO: 6356), GIPEPXX (SEQ ID NO: 6440):APV:KPLS (SEQ ID NO: 6356), SIPKAXX (SEQ ID NO: 6450):APV:KPLS (SEQ ID NO: 6356), HVTKPTX (SEQ ID NO: 6443):APV:KPLS (SEQ ID NO: 6356), YVPKPXX (SEQ ID NO: 6454):APV:KPLS (SEQ ID NO: 6356), TVPKPXX (SEQ ID NO: 6453):APV:KPLS (SEQ ID NO: 6356), AVPKAXX (SEQ ID NO: 6439):APV:KPLS (SEQ ID NO: 6356), KVGKAXX (SEQ ID NO: 6446):APV:KPLS (SEQ ID NO: 6356), KASKAXX (SEQ ID NO: 6444):APV:KPLS (SEQ ID NO: 6356), GSAGPXX (SEQ ID NO: 6441)APV:KPLS (SEQ ID NO: 6356), AAPASXX (SEQ ID NO: 6436):APV:KPLS (SEQ ID NO: 6356), STPPTXX (SEQ ID NO: 6452)APV:KPLS (SEQ ID NO: 6356), HVPKPXX (SEQ ID NO: 6442)APV:KPLS (SEQ ID NO: 6356), ASAAPXX (SEQ ID NO: 6437):APV:KPLS (SEQ ID NO: 6356), ASASPXX (SEQ ID NO: 6438):APV:KPLS (SEQ ID NO: 6356), KIPKAXX (SEQ ID NO: 6445):VPT:KPLS (SEQ ID NO: 6356), GIPEPXX (SEQ ID NO: 6440):VPE:KPLS (SEQ ID NO: 6356), SIPKAXX (SEQ ID NO: 6450):VPT:KPLS (SEQ ID NO: 6356), HVTKPTX (SEQ ID NO: 6443):APT:KPLS (SEQ ID NO: 6356), YVPKPXX (SEQ ID NO: 6454):APT:KPLS (SEQ ID NO: 6356), TVPKPXX (SEQ ID NO: 6453):APT:KPLS (SEQ ID NO: 6356), AVPKAXX (SEQ ID NO: 6439):APT:KPLS (SEQ ID NO: 6356), KVGKAXX (SEQ ID NO: 6446):VPT:KPLS (SEQ ID NO: 6356), KASKAXX (SEQ ID NO: 6444):VPT:KPLS (SEQ ID NO: 6356), GSAGPXX (SEQ ID NO: 6441):TPT:KPLS (SEQ ID NO: 6356), AAPASXX (SEQ ID NO: 6436):VPA:KPLS (SEQ ID NO: 6356), STPPTXX (SEQ ID NO: 6452):VPT:KPLS (SEQ ID NO: 6356), HVPKPXX (SEQ ID NO: 6442):APT:KPLS (SEQ ID NO: 6356), ASAAPXX (SEQ ID NO: 6437):VPQ:KPLS (SEQ ID NO: 6356), ASASPXX (SEQ ID NO: 6438):VSQ:KPLS (SEQ ID NO: 6356), ASASPXX (SEQ ID NO: 6438):VPQ:KPLS (SEQ ID NO: 6356), NDEGLEX (SEQ ID NO: 6447):VPT:KPLS (SEQ ID NO: 6356), SSVKXQP (SEQ ID NO: 6451):SRV:KPLS (SEQ ID NO: 6356), RNVQXRP (SEQ ID NO: 6448):TQV:KPLS (SEQ ID NO: 6356), KIPKAXX (SEQ ID NO: 6445):VPQ:EPLP (SEQ ID NO: 6354), GIPEPXX (SEQ ID NO: 6440):VPQ:EPLP (SEQ ID NO: 6354), SIPKAXX (SEQ ID NO: 6450):VPQ:EPLP (SEQ ID NO: 6354), HVTKPTX (SEQ ID NO: 6443):VPQ:EPLP (SEQ ID NO: 6354), YVPKPXX (SEQ ID NO: 6454):VPQ:EPLP (SEQ ID NO: 6354), TVPKPXX (SEQ ID NO: 6453):VPQ:EPLP (SEQ ID NO: 6354), AVPKAXX (SEQ ID NO: 6439):VPQ:EPLP (SEQ ID NO: 6354), KVGKAXX (SEQ ID NO: 6446):VPQ:EPLP (SEQ ID NO: 6354), KASKAXX (SEQ ID NO: 6444):VPQ:EPLP (SEQ ID NO: 6354), GSAGPXX (SEQ ID NO: 6441):VPQ:EPLP (SEQ ID NO: 6354), AAPASXX (SEQ ID NO: 6436):VPQ:EPLP (SEQ ID NO: 6354), STPPTXX (SEQ ID NO: 6452):VPQ:EPLP (SEQ ID NO: 6354), HVPKPXX (SEQ ID NO: 6442):VPQ:EPLP (SEQ ID NO: 6354), RVPSTXX (SEQ ID NO: 6449):VPQ:EPLP (SEQ ID NO: 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6448):TQV:EPLP (SEQ ID NO: 6354), KIPKAXX (SEQ ID NO: 6445):VSQ:EPLT (SEQ ID NO: 6355), GIPEPXX (SEQ ID NO: 6440):VSQ:EPLT (SEQ ID NO: 6355), SIPKAXX (SEQ ID NO: 6450):VSQ:EPLT (SEQ ID NO: 6355), HVTKPTX (SEQ ID NO: 6443):VSQ:EPLT (SEQ ID NO: 6355), YVPKPXX (SEQ ID NO: 6454):VSQ:EPLT (SEQ ID NO: 6355), TVPKPXX (SEQ ID NO: 6453):VSQ:EPLT (SEQ ID NO: 6355), AVPKAXX (SEQ ID NO: 6439):VSQ:EPLT (SEQ ID NO: 6355), KVGKAXX (SEQ ID NO: 6446):VSQ:EPLT (SEQ ID NO: 6355), KASKAXX (SEQ ID NO: 6444):VSQ:EPLT (SEQ ID NO: 6355), GSAGPXX (SEQ ID NO: 6441):VSQ:EPLT (SEQ ID NO: 6355), AAPASXX (SEQ ID NO: 6436):VSQ:EPLT (SEQ ID NO: 6355), STPPTXX (SEQ ID NO: 6452):VSQ:EPLT (SEQ ID NO: 6355), HVPKPXX (SEQ ID NO: 6442):VSQ:EPLT (SEQ ID NO: 6355), RVPSTXX (SEQ ID NO: 6449):VSQ:EPLT (SEQ ID NO: 6355), ASAAPXX (SEQ ID NO: 6437):VSQ:EPLT (SEQ ID NO: 6355), ASASPXX (SEQ ID NO: 6438):VSQ:EPLT (SEQ ID NO: 6355), KIPKAXX (SEQ ID NO: 6445):VPT:EPLT (SEQ ID NO: 6355), GIPEPXX (SEQ ID NO: 6440):VPE:EPLT (SEQ ID NO: 6355), SIPKAXX (SEQ ID NO: 6450):VPT:EPLT (SEQ ID NO: 6355), HVTKPTX (SEQ ID NO: 6443):APT:EPLT (SEQ ID NO: 6355), YVPKPXX (SEQ ID NO: 6454):APT:EPLT (SEQ ID NO: 6355), TVPKPXX (SEQ ID NO: 6453)APT:EPLT (SEQ ID NO: 6355), AVPKAXX (SEQ ID NO: 6439):APT:EPLT (SEQ ID NO: 6355), KVGKAXX (SEQ ID NO: 6446):VPT:EPLT (SEQ ID NO: 6355), KASKAXX (SEQ ID NO: 6444):VPT:EPLT (SEQ ID NO: 6355), GSAGPXX (SEQ ID NO: 6441):TPT:EPLT (SEQ ID NO: 6355), AAPASXX (SEQ ID NO: 6436):VPA:EPLT (SEQ ID NO: 6355), STPPTXX (SEQ ID NO: 6452):VPT:EPLT (SEQ ID NO: 6355), HVPKPXX (SEQ ID NO: 6442):APT:EPLT (SEQ ID NO: 6355), RVPSTXX (SEQ ID NO: 6449):APV:EPLT (SEQ ID NO: 6355), ASAAPXX (SEQ ID NO: 6437):VPQ:EPLT (SEQ ID NO: 6355), NDEGLEX (SEQ ID NO: 6447):VPT:EPLT (SEQ ID NO: 6355), SSVKXQP (SEQ ID NO: 6451):SRV:EPLT (SEQ ID NO: 6355), RNVQXRP (SEQ ID NO: 6448):TQV:EPLT (SEQ ID NO: 6355), KIPKAXX (SEQ ID NO: 6445):VPQ:EPLT (SEQ ID NO: 6355), GIPEPXX (SEQ ID NO: 6440):VPQ:EPLT (SEQ ID NO: 6355), SIPKAXX (SEQ ID NO: 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6362), GSAGPXX (SEQ ID NO: 6441):TPT:SNIT (SEQ ID NO: 6362), AAPASXX (SEQ ID NO: 6436):VPA:SNIT (SEQ ID NO: 6362), HVPKPXX (SEQ ID NO: 6442):APT:SNIT (SEQ ID NO: 6362), RVPSTXX (SEQ ID NO: 6449):APV:SNIT (SEQ ID NO: 6362), ASAAPXX (SEQ ID NO: 6437):VPQ:SNIT (SEQ ID NO: 6362), ASASPXX (SEQ ID NO: 6438):VSQ:SNIT (SEQ ID NO: 6362), ASASPXX (SEQ ID NO: 6438):VPQ:SNIT (SEQ ID NO: 6362), SSVKXQP (SEQ ID NO: 6451):SRV:SNIT (SEQ ID NO: 6362), RNVQXRP (SEQ ID NO: 6448):TQV:SNIT (SEQ ID NO: 6362), RNVQXRP (SEQ ID NO: 6448):SRV:RSVK (SEQ ID NO: 6359), KIPKAXX (SEQ ID NO: 6445):VPT:RSVK (SEQ ID NO: 6359), GIPEPXX (SEQ ID NO: 6440):VPE:RSVK (SEQ ID NO: 6359), SIPKAXX (SEQ ID NO: 6450):VPT:RSVK (SEQ ID NO: 6359), HVTKPTX (SEQ ID NO: 6443):APT:RSVK (SEQ ID NO: 6359), YVPKPXX (SEQ ID NO: 6454)APT:RSVK (SEQ ID NO: 6359), TVPKPXX (SEQ ID NO: 6453):APT:RSVK (SEQ ID NO: 6359), AVPKAXX (SEQ ID NO: 6439):APT:RSVK (SEQ ID NO: 6359), KVGKAXX (SEQ ID NO: 6446):VPT:RSVK (SEQ ID NO: 6359), KASKAXX (SEQ ID NO: 6444):VPT:RSVK (SEQ ID NO: 6359), GSAGPXX (SEQ ID NO: 6441):TPT:RSVK (SEQ ID NO: 6359), AAPASXX (SEQ ID NO: 6436):VPA:RSVK (SEQ ID NO: 6359), STPPTXX (SEQ ID NO: 6452):VPT:RSVK (SEQ ID NO: 6359), HVPKPXX (SEQ ID NO: 6442):APT:RSVK (SEQ ID NO: 6359), RVPSTXX (SEQ ID NO: 6449):APV:RSVK (SEQ ID NO: 6359), ASAAPXX (SEQ ID NO: 6437):VPQ:RSVK (SEQ ID NO: 6359), ASASPXX (SEQ ID NO: 6438):VSQ:RSVK (SEQ ID NO: 6359), ASASPXX (SEQ ID NO: 6438):VPQ:RSVK (SEQ ID NO: 6359), NDEGLEX (SEQ ID NO: 6447):VPT:RSVK (SEQ ID NO: 6359), RNVQXRP (SEQ ID NO: 6448):TQV:RSVK (SEQ ID NO: 6359), SSVKXQP (SEQ ID NO: 6451):TQV:RPVQ (SEQ ID NO: 6358), KIPKAXX (SEQ ID NO: 6445):VPT:RPVQ (SEQ ID NO: 6358), GIPEPXX (SEQ ID NO: 6440):VPE:RPVQ (SEQ ID NO: 6358), SIPKAXX (SEQ ID NO: 6450):VPT:RPVQ (SEQ ID NO: 6358), HVTKPTX (SEQ ID NO: 6443):APT:RPVQ (SEQ ID NO: 6358), YVPKPXX (SEQ ID NO: 6454):APT:RPVQ (SEQ ID NO: 6358), TVPKPXX (SEQ ID NO: 6453):APT:RPVQ (SEQ ID NO: 6358), AVPKAXX (SEQ ID NO: 6439):APT:RPVQ (SEQ ID NO: 6358), KVGKAXX (SEQ ID NO: 6446):VPT:RPVQ (SEQ ID NO: 6358), KASKAXX (SEQ ID NO: 6444):VPT:RPVQ (SEQ ID NO: 6358), GSAGPXX (SEQ ID NO: 6441):TPT:RPVQ (SEQ ID NO: 6358), AAPASXX (SEQ ID NO: 6436):VPA:RPVQ (SEQ ID NO: 6358), STPPTXX (SEQ ID NO: 6452):VPT:RPVQ (SEQ ID NO: 6358), HVPKPXX (SEQ ID NO: 6442):APT:RPVQ (SEQ ID NO: 6358), RVPSTXX (SEQ ID NO: 6449):APV:RPVQ (SEQ ID NO: 6358), ASAAPXX (SEQ ID NO: 6437):VPQ:RPVQ (SEQ ID NO: 6358), ASASPXX (SEQ ID NO: 6438):VSQ:RPVQ (SEQ ID NO: 6358), ASASPXX (SEQ ID NO: 6438):VPQ:RPVQ (SEQ ID NO: 6358), NDEGLEX (SEQ ID NO: 6447):VPT:RPVQ (SEQ ID NO: 6358) and SSVKXQP (SEQ ID NO: 6451):SRV:RPVQ (SEQ ID NO: 6358).
In certain embodiments, the triplet PEP7:PEP3:PEP12 is selected from the group consisting of GIPEPXX (SEQ ID NO: 6440):VPT:SAIS-AA17-LYL (SEQ ID NO: 6598), HVTKPTX (SEQ ID NO: 6443):VPT:SAIS-AA17-LYL (SEQ ID NO: 6598), YVPKPXX (SEQ ID NO: 6454):VPT:SAIS-AA17-LYL (SEQ ID NO: 6598), TVPKPXX (SEQ ID NO: 6453):VPT:SAIS-AA17-LYL (SEQ ID NO: 6598), AVPKAXX (SEQ ID NO: 6439):VPT:SAIS-AA17-LYL (SEQ ID NO: 6598), KVGKAXX (SEQ ID NO: 6446):VPT:SAIS-AA17-LYL (SEQ ID NO: 6598), KASKAXX (SEQ ID NO: 6444):VPT:SAIS-AA17-LYL (SEQ ID NO: 6598), GSAGPXX (SEQ ID NO: 6441):VPT:SAIS-AA17-LYL (SEQ ID NO: 6598), AAPASXX (SEQ ID NO: 6436):VPT:SAIS-AA17-LYL (SEQ ID NO: 6598), STPPTXX (SEQ ID NO: 6452):VPT:SAIS-AA17-LYL (SEQ ID NO: 6598), HVPKPXX (SEQ ID NO: 6442):VPT:SAIS-AA17-LYL (SEQ ID NO: 6598), RVPSTXX (SEQ ID NO: 6449):VPT:SAIS-AA17-LYL (SEQ ID NO: 6598), ASAAPXX (SEQ ID NO: 6437):VPT:SAIS-AA17-LYL (SEQ ID NO: 6598), ASASPXX (SEQ ID NO: 6438):VPT:SAIS-AA17-LYL (SEQ ID NO: 6598), GIPEPXX (SEQ ID NO: 6440):VPE:SAIS-AA17-LYL (SEQ ID NO: 6598), HVTKPTX (SEQ ID NO: 6443):APT:SAIS-AA17-LYL (SEQ ID NO: 6598), YVPKPXX (SEQ ID NO: 6454):APT:SAIS-AA17-LYL (SEQ ID NO: 6598), TVPKPXX (SEQ ID NO: 6453):APT:SAIS-AA17-LYL (SEQ ID NO: 6598), AVPKAXX (SEQ ID NO: 6439):APT:SAIS-AA17-LYL (SEQ ID NO: 6598), GSAGPXX (SEQ ID NO: 6441):TPT:SAIS-AA17-LYL (SEQ ID NO: 6598), AAPASXX (SEQ ID NO: 6436):VPA:SAIS-AA17-LYL (SEQ ID NO: 6598), HVPKPXX (SEQ ID NO: 6442):APT:SAIS-AA17-LYL (SEQ ID NO: 6598), RVPSTXX (SEQ ID NO: 6449):APV:SAIS-AA17-LYL (SEQ ID NO: 6598), ASAAPXX (SEQ ID NO: 6437):VPQ:SAIS-AA17-LYL (SEQ ID NO: 6598), ASASPXX (SEQ ID NO: 6438):VSQ:SAIS-AA17-LYL (SEQ ID NO: 6598), ASASPXX (SEQ ID NO: 6438):VPQ:SAIS-AA17-LYL (SEQ ID NO: 6598), SSVKXQP (SEQ ID NO: 6451):SRV:SAIS-AA17-LYL (SEQ ID NO: 6598), RNVQXRP (SEQ ID NO: 6448):TQV:SAIS-AA17-LYL (SEQ ID NO: 6598), KIPKAXX (SEQ ID NO: 6445):VPE:SSLS-AA17-LFF (SEQ ID NO: 6605), SIPKAXX (SEQ ID NO: 6450):VPE:SSLS-AA17-LFF (SEQ ID NO: 6605), HVTKPTX (SEQ ID NO: 6443):VPE:SSLS-AA17-LFF (SEQ ID NO: 6605), YVPKPXX (SEQ ID NO: 6454):VPE:SSLS-AA17-LFF (SEQ ID NO: 6605), TVPKPXX (SEQ ID NO: 6453):VPE:SSLS-AA17-LFF (SEQ ID NO: 6605), AVPKAXX (SEQ ID NO: 6439):VPE:SSLS-AA17-LFF (SEQ ID NO: 6605), KVGKAXX (SEQ ID NO: 6446):VPE:SSLS-AA17-LFF (SEQ ID NO: 6605), KASKAXX (SEQ ID NO: 6444):VPE:SSLS-AA17-LFF (SEQ ID NO: 6605), GSAGPXX (SEQ ID NO: 6441):VPE:SSLS-AA17-LFF (SEQ ID NO: 6605), AAPASXX (SEQ ID NO: 6436):VPE:SSLS-AA17-LFF (SEQ ID NO: 6605), STPPTXX (SEQ ID NO: 6452):VPE:SSLS-AA17-LFF (SEQ ID NO: 6605), HVPKPXX (SEQ ID NO: 6442):VPE:SSLS-AA17-LFF (SEQ ID NO: 6605), RVPSTXX (SEQ ID NO: 6449):VPE:SSLS-AA17-LFF (SEQ ID NO: 6605), ASAAPXX (SEQ ID NO: 6437):VPE:SSLS-AA17-LFF (SEQ ID NO: 6605), ASASPXX (SEQ ID NO: 6438):VPE:SSLS-AA17-LFF (SEQ ID NO: 6605), KIPKAXX (SEQ ID NO: 6445):VPT:SSLS-AA17-LFF (SEQ ID NO: 6605), SIPKAXX (SEQ ID NO: 6450):VPT:SSLS-AA17-LFF (SEQ ID NO: 6605), HVTKPTX (SEQ ID NO: 6443):APT:SSLS-AA17-LFF (SEQ ID NO: 6605), YVPKPXX (SEQ ID NO: 6454):APT:SSLS-AA17-LFF (SEQ ID NO: 6605), TVPKPXX (SEQ ID NO: 6453):APT:SSLS-AA17-LFF (SEQ ID NO: 6605), AVPKAXX (SEQ ID NO: 6439):APT:SSLS-AA17-LFF (SEQ ID NO: 6605), KVGKAXX (SEQ ID NO: 6446):VPT:SSLS-AA17-LFF (SEQ ID NO: 6605), KASKAXX (SEQ ID NO: 6444):VPT:SSLS-AA17-LFF (SEQ ID NO: 6605), GSAGPXX (SEQ ID NO: 6441):TPT:SSLS-AA17-LFF (SEQ ID NO: 6605), AAPASXX (SEQ ID NO: 6436):VPA:SSLS-AA17-LFF (SEQ ID NO: 6605), STPPTXX (SEQ ID NO: 6452):VPT:SSLS-AA17-LFF (SEQ ID NO: 6605), HVPKPXX (SEQ ID NO: 6442)APT:SSLS-AA17-LFF (SEQ ID NO: 6605), RVPSTXX (SEQ ID NO: 6449):APV:SSLS-AA17-LFF (SEQ ID NO: 6605), ASAAPXX (SEQ ID NO: 6437):VPQ:SSLS-AA17-LFF (SEQ ID NO: 6605), ASASPXX (SEQ ID NO: 6438):VSQ:SSLS-AA17-LFF (SEQ ID NO: 6605), ASASPXX (SEQ ID NO: 6438):VPQ:SSLS-AA17-LFF (SEQ ID NO: 6605), NDEGLEX (SEQ ID NO: 6447):VPT:SSLS-AA17-LFF (SEQ ID NO: 6605), SSVKXQP (SEQ ID NO: 6451):SRV:SSLS-AA17-LFF (SEQ ID NO: 6605), RNVQXRP (SEQ ID NO: 6448):TQV:SSLS-AA17-LFF (SEQ ID NO: 6605), KIPKAXX (SEQ ID NO: 6445):APT:NAIS-AA17-LYF (SEQ ID NO: 6595), GIPEPXX (SEQ ID NO: 6440):APT:NAIS-AA17-LYF (SEQ ID NO: 6595), SIPKAXX (SEQ ID NO: 6450):APT:NAIS-AA17-LYF (SEQ ID NO: 6595), AVPKAXX (SEQ ID NO: 6439)APT:NAIS-AA17-LYF (SEQ ID NO: 6595), KVGKAXX (SEQ ID NO: 6446):APT:NAIS-AA17-LYF (SEQ ID NO: 6595), KASKAXX (SEQ ID NO: 6444):APT:NAIS-AA17-LYF (SEQ ID NO: 6595), GSAGPXX (SEQ ID NO: 6441):APT:NAIS-AA17-LYF (SEQ ID NO: 6595), AAPASXX (SEQ ID NO: 6436):APT:NAIS-AA17-LYF (SEQ ID NO: 6595), STPPTXX (SEQ ID NO: 6452):APT:NAIS-AA17-LYF (SEQ ID NO: 6595), RVPSTXX (SEQ ID NO: 6449):APT:NAIS-AA17-LYF (SEQ ID NO: 6595), ASAAPXX (SEQ ID NO: 6437)-APT:NAIS-AA17-LYF (SEQ ID NO: 6595), ASASPXX (SEQ ID NO: 6438):APT:NAIS-AA17-LYF (SEQ ID NO: 6595), KIPKAXX (SEQ ID NO: 6445):VPT:NAIS-AA17-LYF (SEQ ID NO: 6595), GIPEPXX (SEQ ID NO: 6440):VPE:NAIS-AA17-LYF (SEQ ID NO: 6595), SIPKAXX (SEQ ID NO: 6450):VPT:NAIS-AA17-LYF (SEQ ID NO: 6595), KVGKAXX (SEQ ID NO: 6446):VPT:NAIS-AA17-LYF (SEQ ID NO: 6595), KASKAXX (SEQ ID NO: 6444):VPT:NAIS-AA17-LYF (SEQ ID NO: 6595), GSAGPXX (SEQ ID NO: 6441):TPT:NAIS-AA17-LYF (SEQ ID NO: 6595), AAPASXX (SEQ ID NO: 6436):VPA:NAIS-AA17-LYF (SEQ ID NO: 6595), STPPTXX (SEQ ID NO: 6452):VPT:NAIS-AA17-LYF (SEQ ID NO: 6595), RVPSTXX (SEQ ID NO: 6449):APV:NAIS-AA17-LYF (SEQ ID NO: 6595), ASAAPXX (SEQ ID NO: 6437):VPQ:NAIS-AA17-LYF (SEQ ID NO: 6595), ASASPXX (SEQ ID NO: 6438):VSQ:NAIS-AA17-LYF (SEQ ID NO: 6595), ASASPXX (SEQ ID NO: 6438):VPQ:NAIS-AA17-LYF (SEQ ID NO: 6595), NDEGLEX (SEQ ID NO: 6447):VPT:NAIS-AA17-LYF (SEQ ID NO: 6595), SSVKXQP (SEQ ID NO: 6451):SRV:NAIS-AA17-LYF (SEQ ID NO: 6595), RNVQXRP (SEQ ID NO: 6448):TQV:NAIS-AA17-LYF (SEQ ID NO: 6595), KIPKAXX (SEQ ID NO: 6445):APT:SATS-AA17-LYY (SEQ ID NO: 6599), GIPEPXX (SEQ ID NO: 6440):APT:SATS-AA17-LYY (SEQ ID NO: 6599), SIPKAXX (SEQ ID NO: 6450):APT:SATS-AA17-LYY (SEQ ID NO: 6599), HVTKPTX (SEQ ID NO: 6443)APT:SATS-AA17-LYY (SEQ ID NO: 6599), YVPKPXX (SEQ ID NO: 6454):APT:SATS-AA17-LYY (SEQ ID NO: 6599), TVPKPXX (SEQ ID NO: 6453):APT:SATS-AA17-LYY (SEQ ID NO: 6599), KVGKAXX (SEQ ID NO: 6446):APT:SATS-AA17-LYY (SEQ ID NO: 6599), KASKAXX (SEQ ID NO: 6444):APT:SATS-AA17-LYY (SEQ ID NO: 6599), GSAGPXX (SEQ ID NO: 6441):APT:SATS-AA17-LYY (SEQ ID NO: 6599), AAPASXX (SEQ ID NO: 6436):APT:SATS-AA17-LYY (SEQ ID NO: 6599), STPPTXX (SEQ ID NO: 6452):APT:SATS-AA17-LYY (SEQ ID NO: 6599), HVPKPXX (SEQ ID NO: 6442):APT:SATS-AA17-LYY (SEQ ID NO: 6599), RVPSTXX (SEQ ID NO: 6449):APT:SATS-AA17-LYY (SEQ ID NO: 6599), ASAAPXX (SEQ ID NO: 6437):APT:SATS-AA17-LYY (SEQ ID NO: 6599), ASASPXX (SEQ ID NO: 6438):APT:SATS-AA17-LYY (SEQ ID NO: 6599), KIPKAXX (SEQ ID NO: 6445):VPT:SATS-AA17-LYY (SEQ ID NO: 6599), GIPEPXX (SEQ ID NO: 6440):VPE:SATS-AA17-LYY (SEQ ID NO: 6599), SIPKAXX (SEQ ID NO: 6450):VPT:SATS-AA17-LYY (SEQ ID NO: 6599), KVGKAXX (SEQ ID NO: 6446):VPT:SATS-AA17-LYY (SEQ ID NO: 6599), KASKAXX (SEQ ID NO: 6444):VPT:SATS-AA17-LYY (SEQ ID NO: 6599), GSAGPXX (SEQ ID NO: 6441):TPT:SATS-AA17-LYY (SEQ ID NO: 6599), AAPASXX (SEQ ID NO: 6436):VPA:SATS-AA17-LYY (SEQ ID NO: 6599), STPPTXX (SEQ ID NO: 6452):VPT:SATS-AA17-LYY (SEQ ID NO: 6599), RVPSTXX (SEQ ID NO: 6449):APV:SATS-AA17-LYY (SEQ ID NO: 6599), ASAAPXX (SEQ ID NO: 6437):VPQ:SATS-AA17-LYY (SEQ ID NO: 6599), ASASPXX (SEQ ID NO: 6438):VSQ:SATS-AA17-LYY (SEQ ID NO: 6599), ASASPXX (SEQ ID NO: 6438):VPQ:SATS-AA17-LYY (SEQ ID NO: 6599), NDEGLEX (SEQ ID NO: 6447):VPT:SATS-AA17-LYY (SEQ ID NO: 6599), SSVKXQP (SEQ ID NO: 6451):SRV:SATS-AA17-LYY (SEQ ID NO: 6599), RNVQXRP (SEQ ID NO: 6448):TQV:SATS-AA17-LYY (SEQ ID NO: 6599), KIPKAXX (SEQ ID NO: 6445):VPT:SPIS-AA17-LYK (SEQ ID NO: 6604), GIPEPXX (SEQ ID NO: 6440):VPT:SPIS-AA17-LYK (SEQ ID NO: 6604), SIPKAXX (SEQ ID NO: 6450):VPT:SPIS-AA17-LYK (SEQ ID NO: 6604), HVTKPTX (SEQ ID NO: 6443):VPT:SPIS-AA17-LYK (SEQ ID NO: 6604), YVPKPXX (SEQ ID NO: 6454):VPT:SPIS-AA17-LYK (SEQ ID NO: 6604), TVPKPXX (SEQ ID NO: 6453):VPT:SPIS-AA17-LYK (SEQ ID NO: 6604), AVPKAXX (SEQ ID NO: 6439):VPT:SPIS-AA17-LYK (SEQ ID NO: 6604), KASKAXX (SEQ ID NO: 6444):VPT:SPIS-AA17-LYK (SEQ ID NO: 6604), GSAGPXX (SEQ ID NO: 6441):VPT:SPIS-AA17-LYK (SEQ ID NO: 6604), AAPASXX (SEQ ID NO: 6436):VPT:SPIS-AA17-LYK (SEQ ID NO: 6604), STPPTXX (SEQ ID NO: 6452):VPT:SPIS-AA17-LYK (SEQ ID NO: 6604), HVPKPXX (SEQ ID NO: 6442):VPT:SPIS-AA17-LYK (SEQ ID NO: 6604), RVPSTXX (SEQ ID NO: 6449):VPT:SPIS-AA17-LYK (SEQ ID NO: 6604), ASAAPXX (SEQ ID NO: 6437):VPT:SPIS-AA17-LYK (SEQ ID NO: 6604), ASASPXX (SEQ ID NO: 6438):VPT:SPIS-AA17-LYK (SEQ ID NO: 6604), GIPEPXX (SEQ ID NO: 6440):VPE:SPIS-AA17-LYK (SEQ ID NO: 6604), HVTKPTX (SEQ ID NO: 6443):APT:SPIS-AA17-LYK (SEQ ID NO: 6604), YVPKPXX (SEQ ID NO: 6454):APT:SPIS-AA17-LYK (SEQ ID NO: 6604), TVPKPXX (SEQ ID NO: 6453):APT:SPIS-AA17-LYK (SEQ ID NO: 6604), AVPKAXX (SEQ ID NO: 6439)APT:SPIS-AA17-LYK (SEQ ID NO: 6604), GSAGPXX (SEQ ID NO: 6441):TPT:SPIS-AA17-LYK (SEQ ID NO: 6604), AAPASXX (SEQ ID NO: 6436):VPA:SPIS-AA17-LYK (SEQ ID NO: 6604), HVPKPXX (SEQ ID NO: 6442):APT:SPIS-AA17-LYK (SEQ ID NO: 6604), RVPSTXX (SEQ ID NO: 6449):APV:SPIS-AA17-LYK (SEQ ID NO: 6604), ASAAPXX (SEQ ID NO: 6437):VPQ:SPIS-AA17-LYK (SEQ ID NO: 6604), ASASPXX (SEQ ID NO: 6438):VSQ:SPIS-AA17-LYK (SEQ ID NO: 6604), ASASPXX (SEQ ID NO: 6438):VPQ:SPIS-AA17-LYK (SEQ ID NO: 6604), SSVKXQP (SEQ ID NO: 6451):SRV:SPIS-AA17-LYK (SEQ ID NO: 6604), RNVQXRP (SEQ ID NO: 6448):TQV:SPIS-AA17-LYK (SEQ ID NO: 6604), KIPKAXX (SEQ ID NO: 6445):VPT:EPIS-AA17-LYL (SEQ ID NO: 6591), GIPEPXX (SEQ ID NO: 6440):VPT:EPIS-AA17-LYL (SEQ ID NO: 6591), SIPKAXX (SEQ ID NO: 6450):VPT:EPIS-AA17-LYL (SEQ ID NO: 6591), HVTKPTX (SEQ ID NO: 6443):VPT:EPIS-AA17-LYL (SEQ ID NO: 6591), YVPKPXX (SEQ ID NO: 6454):VPT:EPIS-AA17-LYL (SEQ ID NO: 6591), TVPKPXX (SEQ ID NO: 6453):VPT:EPIS-AA17-LYL (SEQ ID NO: 6591), AVPKAXX (SEQ ID NO: 6439):VPT:EPIS-AA17-LYL (SEQ ID NO: 6591), KVGKAXX (SEQ ID NO: 6446):VPT:EPIS-AA17-LYL (SEQ ID NO: 6591), GSAGPXX (SEQ ID NO: 6441):VPT:EPIS-AA17-LYL (SEQ ID NO: 6591), AAPASXX (SEQ ID NO: 6436):VPT:EPIS-AA17-LYL (SEQ ID NO: 6591), STPPTXX (SEQ ID NO: 6452):VPT:EPIS-AA17-LYL (SEQ ID NO: 6591), HVPKPXX (SEQ ID NO: 6442):VPT:EPIS-AA17-LYL (SEQ ID NO: 6591), RVPSTXX (SEQ ID NO: 6449):VPT:EPIS-AA17-LYL (SEQ ID NO: 6591), ASAAPXX (SEQ ID NO: 6437):VPT:EPIS-AA17-LYL (SEQ ID NO: 6591), ASASPXX (SEQ ID NO: 6438):VPT:EPIS-AA17-LYL (SEQ ID NO: 6591), GIPEPXX (SEQ ID NO: 6440):VPE:EPIS-AA17-LYL (SEQ ID NO: 6591), HVTKPTX (SEQ ID NO: 6443):APT:EPIS-AA17-LYL (SEQ ID NO: 6591), YVPKPXX (SEQ ID NO: 6454):APT:EPIS-AA17-LYL (SEQ ID NO: 6591), TVPKPXX (SEQ ID NO: 6453):APT:EPIS-AA17-LYL (SEQ ID NO: 6591), AVPKAXX (SEQ ID NO: 6439):APT:EPIS-AA17-LYL (SEQ ID NO: 6591), GSAGPXX (SEQ ID NO: 6441):TPT:EPIS-AA17-LYL (SEQ ID NO: 6591), AAPASXX (SEQ ID NO: 6436):VPA:EPIS-AA17-LYL (SEQ ID NO: 6591), HVPKPXX (SEQ ID NO: 6442):APT:EPIS-AA17-LYL (SEQ ID NO: 6591), RVPSTXX (SEQ ID NO: 6449):APV:EPIS-AA17-LYL (SEQ ID NO: 6591), ASAAPXX (SEQ ID NO: 6437):VPQ:EPIS-AA17-LYL (SEQ ID NO: 6591), ASASPXX (SEQ ID NO: 6438):VSQ:EPIS-AA17-LYL (SEQ ID NO: 6591), ASASPXX (SEQ ID NO: 6438):VPQ:EPIS-AA17-LYL (SEQ ID NO: 6591), SSVKXQP (SEQ ID NO: 6451):SRV:EPIS-AA17-LYL (SEQ ID NO: 6591), RNVQXRP (SEQ ID NO: 6448):TQV:EPIS-AA17-LYL (SEQ ID NO: 6591), KIPKAXX (SEQ ID NO: 6445):TPT:SPIN-AA17-LYF (SEQ ID NO: 6601), GIPEPXX (SEQ ID NO: 6440):TPT:SPIN-AA17-LYF (SEQ ID NO: 6601), SIPKAXX (SEQ ID NO: 6450):TPT:SPIN-AA17-LYF (SEQ ID NO: 6601), HVTKPTX (SEQ ID NO: 6443):TPT:SPIN-AA17-LYF (SEQ ID NO: 6601), YVPKPXX (SEQ ID NO: 6454):TPT:SPIN-AA17-LYF (SEQ ID NO: 6601), TVPKPXX (SEQ ID NO: 6453):TPT:SPIN-AA17-LYF (SEQ ID NO: 6601), AVPKAXX (SEQ ID NO: 6439):TPT:SPIN-AA17-LYF (SEQ ID NO: 6601), KVGKAXX (SEQ ID NO: 6446):TPT:SPIN-AA17-LYF (SEQ ID NO: 6601), KASKAXX (SEQ ID NO: 6444):TPT:SPIN-AA17-LYF (SEQ ID NO: 6601), AAPASXX (SEQ ID NO: 6436):TPT:SPIN-AA17-LYF (SEQ ID NO: 6601), STPPTXX (SEQ ID NO: 6452):TPT:SPIN-AA17-LYF (SEQ ID NO: 6601), HVPKPXX (SEQ ID NO: 6442):TPT:SPIN-AA17-LYF (SEQ ID NO: 6601), RVPSTXX (SEQ ID NO: 6449):TPT:SPIN-AA17-LYF (SEQ ID NO: 6601), ASAAPXX (SEQ ID NO: 6437):TPT:SPIN-AA17-LYF (SEQ ID NO: 6601), ASASPXX (SEQ ID NO: 6438):TPT:SPIN-AA17-LYF (SEQ ID NO: 6601), KIPKAXX (SEQ ID NO: 6445):VPT:SPIN-AA17-LYF (SEQ ID NO: 6601), GIPEPXX (SEQ ID NO: 6440):VPE:SPIN-AA17-LYF (SEQ ID NO: 6601), SIPKAXX (SEQ ID NO: 6450):VPT:SPIN-AA17-LYF (SEQ ID NO: 6601), HVTKPTX (SEQ ID NO: 6443):APT:SPIN-AA17-LYF (SEQ ID NO: 6601), YVPKPXX (SEQ ID NO: 6454):APT:SPIN-AA17-LYF (SEQ ID NO: 6601), TVPKPXX (SEQ ID NO: 6453):APT:SPIN-AA17-LYF (SEQ ID NO: 6601), AVPKAXX (SEQ ID NO: 6439)APT:SPIN-AA17-LYF (SEQ ID NO: 6601), KVGKAXX (SEQ ID NO: 6446):VPT:SPIN-AA17-LYF (SEQ ID NO: 6601), KASKAXX (SEQ ID NO: 6444):VPT:SPIN-AA17-LYF (SEQ ID NO: 6601), AAPASXX (SEQ ID NO: 6436):VPA:SPIN-AA17-LYF (SEQ ID NO: 6601), STPPTXX (SEQ ID NO: 6452):VPT:SPIN-AA17-LYF (SEQ ID NO: 6601), HVPKPXX (SEQ ID NO: 6442)APT:SPIN-AA17-LYF (SEQ ID NO: 6601), RVPSTXX (SEQ ID NO: 6449)APV:SPIN-AA17-LYF (SEQ ID NO: 6601), ASAAPXX (SEQ ID NO: 6437):VPQ:SPIN-AA17-LYF (SEQ ID NO: 6601), ASASPXX (SEQ ID NO: 6438):VSQ:SPIN-AA17-LYF (SEQ ID NO: 6601), ASASPXX (SEQ ID NO: 6438):VPQ:SPIN-AA17-LYF (SEQ ID NO: 6601), NDEGLEX (SEQ ID NO: 6447):VPT:SPIN-AA17-LYF (SEQ ID NO: 6601), SSVKXQP (SEQ ID NO: 6451):SRV:SPIN-AA17-LYF (SEQ ID NO: 6601), RNVQXRP (SEQ ID NO: 6448):TQV:SPIN-AA17-LYF (SEQ ID NO: 6601), KIPKAXX (SEQ ID NO: 6445):VPA:SPIS-AA17-LYI (SEQ ID NO: 6603), GIPEPXX (SEQ ID NO: 6440):VPA:SPIS-AA17-LYI (SEQ ID NO: 6603), SIPKAXX (SEQ ID NO: 6450):VPA:SPIS-AA17-LYI (SEQ ID NO: 6603), HVTKPTX (SEQ ID NO: 6443):VPA:SPIS-AA17-LYI (SEQ ID NO: 6603), YVPKPXX (SEQ ID NO: 6454):VPA:SPIS-AA17-LYI (SEQ ID NO: 6603), TVPKPXX (SEQ ID NO: 6453):VPA:SPIS-AA17-LYI (SEQ ID NO: 6603), AVPKAXX (SEQ ID NO: 6439):VPA:SPIS-AA17-LYI (SEQ ID NO: 6603), KVGKAXX (SEQ ID NO: 6446):VPA:SPIS-AA17-LYI (SEQ ID NO: 6603), KASKAXX (SEQ ID NO: 6444):VPA:SPIS-AA17-LYI (SEQ ID NO: 6603), GSAGPXX (SEQ ID NO: 6441):VPA:SPIS-AA17-LYI (SEQ ID NO: 6603), STPPTXX (SEQ ID NO: 6452):VPA:SPIS-AA17-LYI (SEQ ID NO: 6603), HVPKPXX (SEQ ID NO: 6442):VPA:SPIS-AA17-LYI (SEQ ID NO: 6603), RVPSTXX (SEQ ID NO: 6449):VPA:SPIS-AA17-LYI (SEQ ID NO: 6603), ASAAPXX (SEQ ID NO: 6437):VPA:SPIS-AA17-LYI (SEQ ID NO: 6603), ASASPXX (SEQ ID NO: 6438):VPA:SPIS-AA17-LYI (SEQ ID NO: 6603), KIPKAXX (SEQ ID NO: 6445):VPT:SPIS-AA17-LYI (SEQ ID NO: 6603), GIPEPXX (SEQ ID NO: 6440):VPE:SPIS-AA17-LYI (SEQ ID NO: 6603), SIPKAXX (SEQ ID NO: 6450):VPT:SPIS-AA17-LYI (SEQ ID NO: 6603), HVTKPTX (SEQ ID NO: 6443):APT:SPIS-AA17-LYI (SEQ ID NO: 6603), YVPKPXX (SEQ ID NO: 6454):APT:SPIS-AA17-LYI (SEQ ID NO: 6603), TVPKPXX (SEQ ID NO: 6453):APT:SPIS-AA17-LYI (SEQ ID NO: 6603), AVPKAXX (SEQ ID NO: 6439):APT:SPIS-AA17-LYI (SEQ ID NO: 6603), KVGKAXX (SEQ ID NO: 6446):VPT:SPIS-AA17-LYI (SEQ ID NO: 6603), KASKAXX (SEQ ID NO: 6444):VPT:SPIS-AA17-LYI (SEQ ID NO: 6603), GSAGPXX (SEQ ID NO: 6441):TPT:SPIS-AA17-LYI (SEQ ID NO: 6603), STPPTXX (SEQ ID NO: 6452):VPT:SPIS-AA17-LYI (SEQ ID NO: 6603), HVPKPXX (SEQ ID NO: 6442):APT:SPIS-AA17-LYI (SEQ ID NO: 6603), RVPSTXX (SEQ ID NO: 6449):APV:SPIS-AA17-LYI (SEQ ID NO: 6603), ASAAPXX (SEQ ID NO: 6437):VPQ:SPIS-AA17-LYI (SEQ ID NO: 6603), ASASPXX (SEQ ID NO: 6438):VSQ:SPIS-AA17-LYI (SEQ ID NO: 6603), ASASPXX (SEQ ID NO: 6438):VPQ:SPIS-AA17-LYI (SEQ ID NO: 6603), NDEGLEX (SEQ ID NO: 6447):VPT:SPIS-AA17-LYI (SEQ ID NO: 6603), SSVKXQP (SEQ ID NO: 6451):SRV:SPIS-AA17-LYI (SEQ ID NO: 6603), RNVQXRP (SEQ ID NO: 6448):TQV:SPIS-AA17-LYI (SEQ ID NO: 6603), KIPKAXX (SEQ ID NO: 6445):VPT:SPIS-AA17-LFI (SEQ ID NO: 6602), GIPEPXX (SEQ ID NO: 6440):VPT:SPIS-AA17-LFI (SEQ ID NO: 6602), SIPKAXX (SEQ ID NO: 6450):VPT:SPIS-AA17-LFI (SEQ ID NO: 6602), HVTKPTX (SEQ ID NO: 6443):VPT:SPIS-AA17-LFI (SEQ ID NO: 6602), YVPKPXX (SEQ ID NO: 6454):VPT:SPIS-AA17-LFI (SEQ ID NO: 6602), TVPKPXX (SEQ ID NO: 6453):VPT:SPIS-AA17-LFI (SEQ ID NO: 6602), AVPKAXX (SEQ ID NO: 6439):VPT:SPIS-AA17-LFI (SEQ ID NO: 6602), KVGKAXX (SEQ ID NO: 6446):VPT:SPIS-AA17-LFI (SEQ ID NO: 6602), KASKAXX (SEQ ID NO: 6444):VPT:SPIS-AA17-LFI (SEQ ID NO: 6602), GSAGPXX (SEQ ID NO: 6441):VPT:SPIS-AA17-LFI (SEQ ID NO: 6602), AAPASXX (SEQ ID NO: 6436):VPT:SPIS-AA17-LFI (SEQ ID NO: 6602), HVPKPXX (SEQ ID NO: 6442):VPT:SPIS-AA17-LFI (SEQ ID NO: 6602), RVPSTXX (SEQ ID NO: 6449):VPT:SPIS-AA17-LFI (SEQ ID NO: 6602), ASAAPXX (SEQ ID NO: 6437):VPT:SPIS-AA17-LFI (SEQ ID NO: 6602), ASASPXX (SEQ ID NO: 6438):VPT:SPIS-AA17-LFI (SEQ ID NO: 6602), GIPEPXX (SEQ ID NO: 6440):VPE:SPIS-AA17-LFI (SEQ ID NO: 6602), HVTKPTX (SEQ ID NO: 6443):APT:SPIS-AA17-LFI (SEQ ID NO: 6602), YVPKPXX (SEQ ID NO: 6454):APT:SPIS-AA17-LFI (SEQ ID NO: 6602), TVPKPXX (SEQ ID NO: 6453):APT:SPIS-AA17-LFI (SEQ ID NO: 6602), AVPKAXX (SEQ ID NO: 6439):APT:SPIS-AA17-LFI (SEQ ID NO: 6602), GSAGPXX (SEQ ID NO: 6441):TPT:SPIS-AA17-LFI (SEQ ID NO: 6602), AAPASXX (SEQ ID NO: 6436):VPA:SPIS-AA17-LFI (SEQ ID NO: 6602), HVPKPXX (SEQ ID NO: 6442):APT:SPIS-AA17-LFI (SEQ ID NO: 6602), RVPSTXX (SEQ ID NO: 6449):APV:SPIS-AA17-LFI (SEQ ID NO: 6602), ASAAPXX (SEQ ID NO: 6437):VPQ:SPIS-AA17-LFI (SEQ ID NO: 6602), ASASPXX (SEQ ID NO: 6438):VSQ:SPIS-AA17-LFI (SEQ ID NO: 6602), ASASPXX (SEQ ID NO: 6438):VPQ:SPIS-AA17-LFI (SEQ ID NO: 6602), SSVKXQP (SEQ ID NO: 6451):SRV:SPIS-AA17-LFI (SEQ ID NO: 6602), RNVQXRP (SEQ ID NO: 6448):TQV:SPIS-AA17-LFI (SEQ ID NO: 6602), KIPKAXX (SEQ ID NO: 6445):APV:KPLS-AA17-LYV (SEQ ID NO: 6594), GIPEPXX (SEQ ID NO: 6440):APV:KPLS-AA17-LYV (SEQ ID NO: 6594), SIPKAXX (SEQ ID NO: 6450):APV:KPLS-AA17-LYV (SEQ ID NO: 6594), HVTKPTX (SEQ ID NO: 6443):APV:KPLS-AA17-LYV (SEQ ID NO: 6594), YVPKPXX (SEQ ID NO: 6454):APV:KPLS-AA17-LYV (SEQ ID NO: 6594), TVPKPXX (SEQ ID NO: 6453):APV:KPLS-AA17-LYV (SEQ ID NO: 6594), AVPKAXX (SEQ ID NO: 6439):APV:KPLS-AA17-LYV (SEQ ID NO: 6594), KVGKAXX (SEQ ID NO: 6446):APV:KPLS-AA17-LYV (SEQ ID NO: 6594), KASKAXX (SEQ ID NO: 6444):APV:KPLS-AA17-LYV (SEQ ID NO: 6594), GSAGPXX (SEQ ID NO: 6441)APV:KPLS-AA17-LYV (SEQ ID NO: 6594), AAPASXX (SEQ ID NO: 6436):APV:KPLS-AA17-LYV (SEQ ID NO: 6594), STPPTXX (SEQ ID NO: 6452):APV:KPLS-AA17-LYV (SEQ ID NO: 6594), HVPKPXX (SEQ ID NO: 6442):APV:KPLS-AA17-LYV (SEQ ID NO: 6594), ASAAPXX (SEQ ID NO: 6437):APV:KPLS-AA17-LYV (SEQ ID NO: 6594), ASASPXX (SEQ ID NO: 6438):APV:KPLS-AA17-LYV (SEQ ID NO: 6594), KIPKAXX (SEQ ID NO: 6445):VPT:KPLS-AA17-LYV (SEQ ID NO: 6594), GIPEPXX (SEQ ID NO: 6440):VPE:KPLS-AA17-LYV (SEQ ID NO: 6594), SIPKAXX (SEQ ID NO: 6450):VPT:KPLS-AA17-LYV (SEQ ID NO: 6594), HVTKPTX (SEQ ID NO: 6443):APT:KPLS-AA17-LYV (SEQ ID NO: 6594), YVPKPXX (SEQ ID NO: 6454):APT:KPLS-AA17-LYV (SEQ ID NO: 6594), TVPKPXX (SEQ ID NO: 6453):APT:KPLS-AA17-LYV (SEQ ID NO: 6594), AVPKAXX (SEQ ID NO: 6439):APT:KPLS-AA17-LYV (SEQ ID NO: 6594), KVGKAXX (SEQ ID NO: 6446):VPT:KPLS-AA17-LYV (SEQ ID NO: 6594), KASKAXX (SEQ ID NO: 6444):VPT:KPLS-AA17-LYV (SEQ ID NO: 6594), GSAGPXX (SEQ ID NO: 6441):TPT:KPLS-AA17-LYV (SEQ ID NO: 6594), AAPASXX (SEQ ID NO: 6436):VPA:KPLS-AA17-LYV (SEQ ID NO: 6594), STPPTXX (SEQ ID NO: 6452):VPT:KPLS-AA17-LYV (SEQ ID NO: 6594), HVPKPXX (SEQ ID NO: 6442):APT:KPLS-AA17-LYV (SEQ ID NO: 6594), ASAAPXX (SEQ ID NO: 6437):VPQ:KPLS-AA17-LYV (SEQ ID NO: 6594), ASASPXX (SEQ ID NO: 6438):VSQ:KPLS-AA17-LYV (SEQ ID NO: 6594), ASASPXX (SEQ ID NO: 6438):VPQ:KPLS-AA17-LYV (SEQ ID NO: 6594), NDEGLEX (SEQ ID NO: 6447):VPT:KPLS-AA17-LYV (SEQ ID NO: 6594), SSVKXQP (SEQ ID NO: 6451):SRV:KPLS-AA17-LYV (SEQ ID NO: 6594), RNVQXRP (SEQ ID NO: 6448):TQV:KPLS-AA17-LYV (SEQ ID NO: 6594), KIPKAXX (SEQ ID NO: 6445):VPQ:EPLP-AA17-VYY (SEQ ID NO: 6592), GIPEPXX (SEQ ID NO: 6440):VPQ:EPLP-AA17-VYY (SEQ ID NO: 6592), SIPKAXX (SEQ ID NO: 6450):VPQ:EPLP-AA17-VYY (SEQ ID NO: 6592), HVTKPTX (SEQ ID NO: 6443):VPQ:EPLP-AA17-VYY (SEQ ID NO: 6592), YVPKPXX (SEQ ID NO: 6454):VPQ:EPLP-AA17-VYY (SEQ ID NO: 6592), TVPKPXX (SEQ ID NO: 6453):VPQ:EPLP-AA17-VYY (SEQ ID NO: 6592), AVPKAXX (SEQ ID NO: 6439):VPQ:EPLP-AA17-VYY (SEQ ID NO: 6592), KVGKAXX (SEQ ID NO: 6446):VPQ:EPLP-AA17-VYY (SEQ ID NO: 6592), KASKAXX (SEQ ID NO: 6444):VPQ:EPLP-AA17-VYY (SEQ ID NO: 6592), GSAGPXX (SEQ ID NO: 6441):VPQ:EPLP-AA17-VYY (SEQ ID NO: 6592), AAPASXX (SEQ ID NO: 6436):VPQ:EPLP-AA17-VYY (SEQ ID NO: 6592), STPPTXX (SEQ ID NO: 6452):VPQ:EPLP-AA17-VYY (SEQ ID NO: 6592), HVPKPXX (SEQ ID NO: 6442):VPQ:EPLP-AA17-VYY (SEQ ID NO: 6592), RVPSTXX (SEQ ID NO: 6449):VPQ:EPLP-AA17-VYY (SEQ ID NO: 6592), ASASPXX (SEQ ID NO: 6438):VPQ:EPLP-AA17-VYY (SEQ ID NO: 6592), KIPKAXX (SEQ ID NO: 6445):VPT:EPLP-AA17-VYY (SEQ ID NO: 6592), GIPEPXX (SEQ ID NO: 6440):VPE:EPLP-AA17-VYY (SEQ ID NO: 6592), SIPKAXX (SEQ ID NO: 6450):VPT:EPLP-AA17-VYY (SEQ ID NO: 6592), HVTKPTX (SEQ ID NO: 6443):APT:EPLP-AA17-VYY (SEQ ID NO: 6592), YVPKPXX (SEQ ID NO: 6454):APT:EPLP-AA17-VYY (SEQ ID NO: 6592), TVPKPXX (SEQ ID NO: 6453):APT:EPLP-AA17-VYY (SEQ ID NO: 6592), AVPKAXX (SEQ ID NO: 6439):APT:EPLP-AA17-VYY (SEQ ID NO: 6592), KVGKAXX (SEQ ID NO: 6446):VPT:EPLP-AA17-VYY (SEQ ID NO: 6592), KASKAXX (SEQ ID NO: 6444):VPT:EPLP-AA17-VYY (SEQ ID NO: 6592), GSAGPXX (SEQ ID NO: 6441):TPT:EPLP-AA17-VYY (SEQ ID NO: 6592), AAPASXX (SEQ ID NO: 6436):VPA:EPLP-AA17-VYY (SEQ ID NO: 6592), STPPTXX (SEQ ID NO: 6452):VPT:EPLP-AA17-VYY (SEQ ID NO: 6592), HVPKPXX (SEQ ID NO: 6442):APT:EPLP-AA17-VYY (SEQ ID NO: 6592), RVPSTXX (SEQ ID NO: 6449):APV:EPLP-AA17-VYY (SEQ ID NO: 6592), ASASPXX (SEQ ID NO: 6438):VSQ:EPLP-AA17-VYY (SEQ ID NO: 6592), NDEGLEX (SEQ ID NO: 6447):VPT:EPLP-AA17-VYY (SEQ ID NO: 6592), SSVKXQP (SEQ ID NO: 6451):SRV:EPLP-AA17-VYY (SEQ ID NO: 6592), RNVQXRP (SEQ ID NO: 6448):TQV:EPLP-AA17-VYY (SEQ ID NO: 6592), KIPKAXX (SEQ ID NO: 6445):VSQ:EPLT-AA17-LYY (SEQ ID NO: 6593), GIPEPXX (SEQ ID NO: 6440):VSQ:EPLT-AA17-LYY (SEQ ID NO: 6593), SIPKAXX (SEQ ID NO: 6450):VSQ:EPLT-AA17-LYY (SEQ ID NO: 6593), HVTKPTX (SEQ ID NO: 6443):VSQ:EPLT-AA17-LYY (SEQ ID NO: 6593), YVPKPXX (SEQ ID NO: 6454):VSQ:EPLT-AA17-LYY (SEQ ID NO: 6593), TVPKPXX (SEQ ID NO: 6453):VSQ:EPLT-AA17-LYY (SEQ ID NO: 6593), AVPKAXX (SEQ ID NO: 6439):VSQ:EPLT-AA17-LYY (SEQ ID NO: 6593), KVGKAXX (SEQ ID NO: 6446):VSQ:EPLT-AA17-LYY (SEQ ID NO: 6593), KASKAXX (SEQ ID NO: 6444):VSQ:EPLT-AA17-LYY (SEQ ID NO: 6593), GSAGPXX (SEQ ID NO: 6441):VSQ:EPLT-AA17-LYY (SEQ ID NO: 6593), AAPASXX (SEQ ID NO: 6436):VSQ:EPLT-AA17-LYY (SEQ ID NO: 6593), STPPTXX (SEQ ID NO: 6452):VSQ:EPLT-AA17-LYY (SEQ ID NO: 6593), HVPKPXX (SEQ ID NO: 6442):VSQ:EPLT-AA17-LYY (SEQ ID NO: 6593), RVPSTXX (SEQ ID NO: 6449):VSQ:EPLT-AA17-LYY (SEQ ID NO: 6593), ASAAPXX (SEQ ID NO: 6437):VSQ:EPLT-AA17-LYY (SEQ ID NO: 6593), ASASPXX (SEQ ID NO: 6438):VSQ:EPLT-AA17-LYY (SEQ ID NO: 6593), KIPKAXX (SEQ ID NO: 6445):VPT:EPLT-AA17-LYY (SEQ ID NO: 6593), GIPEPXX (SEQ ID NO: 6440):VPE:EPLT-AA17-LYY (SEQ ID NO: 6593), SIPKAXX (SEQ ID NO: 6450):VPT:EPLT-AA17-LYY (SEQ ID NO: 6593), HVTKPTX (SEQ ID NO: 6443):APT:EPLT-AA17-LYY (SEQ ID NO: 6593), YVPKPXX (SEQ ID NO: 6454):APT:EPLT-AA17-LYY (SEQ ID NO: 6593), TVPKPXX (SEQ ID NO: 6453):APT:EPLT-AA17-LYY (SEQ ID NO: 6593), AVPKAXX (SEQ ID NO: 6439):APT:EPLT-AA17-LYY (SEQ ID NO: 6593), KVGKAXX (SEQ ID NO: 6446):VPT:EPLT-AA17-LYY (SEQ ID NO: 6593), KASKAXX (SEQ ID NO: 6444):VPT:EPLT-AA17-LYY (SEQ ID NO: 6593), GSAGPXX (SEQ ID NO: 6441):TPT:EPLT-AA17-LYY (SEQ ID NO: 6593), AAPASXX (SEQ ID NO: 6436):VPA:EPLT-AA17-LYY (SEQ ID NO: 6593), STPPTXX (SEQ ID NO: 6452):VPT:EPLT-AA17-LYY (SEQ ID NO: 6593), HVPKPXX (SEQ ID NO: 6442):APT:EPLT-AA17-LYY (SEQ ID NO: 6593), RVPSTXX (SEQ ID NO: 6449):APV:EPLT-AA17-LYY (SEQ ID NO: 6593), ASAAPXX (SEQ ID NO: 6437):VPQ:EPLT-AA17-LYY (SEQ ID NO: 6593), NDEGLEX (SEQ ID NO: 6447):VPT:EPLT-AA17-LYY (SEQ ID NO: 6593), SSVKXQP (SEQ ID NO: 6451):SRV:EPLT-AA17-LYY (SEQ ID NO: 6593), RNVQXRP (SEQ ID NO: 6448):TQV:EPLT-AA17-LYY (SEQ ID NO: 6593), KIPKAXX (SEQ ID NO: 6445):VPQ:EPLT-AA17-LYY (SEQ ID NO: 6593), GIPEPXX (SEQ ID NO: 6440):VPQ:EPLT-AA17-LYY (SEQ ID NO: 6593), SIPKAXX (SEQ ID NO: 6450):VPQ:EPLT-AA17-LYY (SEQ ID NO: 6593), HVTKPTX (SEQ ID NO: 6443):VPQ:EPLT-AA17-LYY (SEQ ID NO: 6593), YVPKPXX (SEQ ID NO: 6454):VPQ:EPLT-AA17-LYY (SEQ ID NO: 6593), TVPKPXX (SEQ ID NO: 6453):VPQ:EPLT-AA17-LYY (SEQ ID NO: 6593), AVPKAXX (SEQ ID NO: 6439):VPQ:EPLT-AA17-LYY (SEQ ID NO: 6593), KVGKAXX (SEQ ID NO: 6446):VPQ:EPLT-AA17-LYY (SEQ ID NO: 6593), KASKAXX (SEQ ID NO: 6444):VPQ:EPLT-AA17-LYY (SEQ ID NO: 6593), GSAGPXX (SEQ ID NO: 6441):VPQ:EPLT-AA17-LYY (SEQ ID NO: 6593), AAPASXX (SEQ ID NO: 6436):VPQ:EPLT-AA17-LYY (SEQ ID NO: 6593), STPPTXX (SEQ ID NO: 6452):VPQ:EPLT-AA17-LYY (SEQ ID NO: 6593), HVPKPXX (SEQ ID NO: 6442):VPQ:EPLT-AA17-LYY (SEQ ID NO: 6593), RVPSTXX (SEQ ID NO: 6449):VPQ:EPLT-AA17-LYY (SEQ ID NO: 6593), ASASPXX (SEQ ID NO: 6438):VPQ:EPLT-AA17-LYY (SEQ ID NO: 6593), NDEGLEX (SEQ ID NO: 6447):VPT:SNIT-AA17-QIM (SEQ ID NO: 6600), GIPEPXX (SEQ ID NO: 6440):VPE:SNIT-AA17-QIM (SEQ ID NO: 6600), HVTKPTX (SEQ ID NO: 6443)APT:SNIT-AA17-QIM (SEQ ID NO: 6600), YVPKPXX (SEQ ID NO: 6454):APT:SNIT-AA17-QIM (SEQ ID NO: 6600), TVPKPXX (SEQ ID NO: 6453):APT:SNIT-AA17-QIM (SEQ ID NO: 6600), AVPKAXX (SEQ ID NO: 6439):APT:SNIT-AA17-QIM (SEQ ID NO: 6600), GSAGPXX (SEQ ID NO: 6441):TPT:SNIT-AA17-QIM (SEQ ID NO: 6600), AAPASXX (SEQ ID NO: 6436):VPA:SNIT-AA17-QIM (SEQ ID NO: 6600), HVPKPXX (SEQ ID NO: 6442):APT:SNIT-AA17-QIM (SEQ ID NO: 6600), RVPSTXX (SEQ ID NO: 6449):APV:SNIT-AA17-QIM (SEQ ID NO: 6600), ASAAPXX (SEQ ID NO: 6437):VPQ:SNIT-AA17-QIM (SEQ ID NO: 6600), ASASPXX (SEQ ID NO: 6438):VSQ:SNIT-AA17-QIM (SEQ ID NO: 6600), ASASPXX (SEQ ID NO: 6438):VPQ:SNIT-AA17-QIM (SEQ ID NO: 6600), SSVKXQP (SEQ ID NO: 6451):SRV:SNIT-AA17-QIM (SEQ ID NO: 6600), RNVQXRP (SEQ ID NO: 6448):TQV:SNIT-AA17-QIM (SEQ ID NO: 6600), RNVQXRP (SEQ ID NO: 6448):SRV:RSVK-AA17-AKV (SEQ ID NO: 6597), KIPKAXX (SEQ ID NO: 6445):VPT:RSVK-AA17-AKV (SEQ ID NO: 6597), GIPEPXX (SEQ ID NO: 6440):VPE:RSVK-AA17-AKV (SEQ ID NO: 6597), SIPKAXX (SEQ ID NO: 6450):VPT:RSVK-AA17-AKV (SEQ ID NO: 6597), HVTKPTX (SEQ ID NO: 6443):APT:RSVK-AA17-AKV (SEQ ID NO: 6597), YVPKPXX (SEQ ID NO: 6454):APT:RSVK-AA17-AKV (SEQ ID NO: 6597), TVPKPXX (SEQ ID NO: 6453):APT:RSVK-AA17-AKV (SEQ ID NO: 6597), AVPKAXX (SEQ ID NO: 6439):APT:RSVK-AA17-AKV (SEQ ID NO: 6597), KVGKAXX (SEQ ID NO: 6446):VPT:RSVK-AA17-AKV (SEQ ID NO: 6597), KASKAXX (SEQ ID NO: 6444):VPT:RSVK-AA17-AKV (SEQ ID NO: 6597), GSAGPXX (SEQ ID NO: 6441):TPT:RSVK-AA17-AKV (SEQ ID NO: 6597), AAPASXX (SEQ ID NO: 6436):VPA:RSVK-AA17-AKV (SEQ ID NO: 6597), STPPTXX (SEQ ID NO: 6452):VPT:RSVK-AA17-AKV (SEQ ID NO: 6597), HVPKPXX (SEQ ID NO: 6442):APT:RSVK-AA17-AKV (SEQ ID NO: 6597), RVPSTXX (SEQ ID NO: 6449):APV:RSVK-AA17-AKV (SEQ ID NO: 6597), ASAAPXX (SEQ ID NO: 6437):VPQ:RSVK-AA17-AKV (SEQ ID NO: 6597), ASASPXX (SEQ ID NO: 6438):VSQ:RSVK-AA17-AKV (SEQ ID NO: 6597), ASASPXX (SEQ ID NO: 6438):VPQ:RSVK-AA17-AKV (SEQ ID NO: 6597), NDEGLEX (SEQ ID NO: 6447):VPT:RSVK-AA17-AKV (SEQ ID NO: 6597), RNVQXRP (SEQ ID NO: 6448):TQV:RSVK-AA17-AKV (SEQ ID NO: 6597), SSVKXQP (SEQ ID NO: 6451):TQV:RPVQ-AA17-RKI (SEQ ID NO: 6596), KIPKAXX (SEQ ID NO: 6445):VPT:RPVQ-AA17-RKI (SEQ ID NO: 6596), GIPEPXX (SEQ ID NO: 6440):VPE:RPVQ-AA17-RKI (SEQ ID NO: 6596), SIPKAXX (SEQ ID NO: 6450):VPT:RPVQ-AA17-RKI (SEQ ID NO: 6596), HVTKPTX (SEQ ID NO: 6443):APT:RPVQ-AA17-RKI (SEQ ID NO: 6596), YVPKPXX (SEQ ID NO: 6454):APT:RPVQ-AA17-RKI (SEQ ID NO: 6596), TVPKPXX (SEQ ID NO: 6453):APT:RPVQ-AA17-RKI (SEQ ID NO: 6596), AVPKAXX (SEQ ID NO: 6439):APT:RPVQ-AA17-RKI (SEQ ID NO: 6596), KVGKAXX (SEQ ID NO: 6446):VPT:RPVQ-AA17-RKI (SEQ ID NO: 6596), KASKAXX (SEQ ID NO: 6444):VPT:RPVQ-AA17-RKI (SEQ ID NO: 6596), GSAGPXX (SEQ ID NO: 6441):TPT:RPVQ-AA17-RKI (SEQ ID NO: 6596), AAPASXX (SEQ ID NO: 6436):VPA:RPVQ-AA17-RKI (SEQ ID NO: 6596), STPPTXX (SEQ ID NO: 6452):VPT:RPVQ-AA17-RKI (SEQ ID NO: 6596), HVPKPXX (SEQ ID NO: 6442):APT:RPVQ-AA17-RKI (SEQ ID NO: 6596), RVPSTXX (SEQ ID NO: 6449):APV:RPVQ-AA17-RKI (SEQ ID NO: 6596), ASAAPXX (SEQ ID NO: 6437):VPQ:RPVQ-AA17-RKI (SEQ ID NO: 6596), ASASPXX (SEQ ID NO: 6438):VSQ:RPVQ-AA17-RKI (SEQ ID NO: 6596), ASASPXX (SEQ ID NO: 6438):VPQ:RPVQ-AA17-RKI (SEQ ID NO: 6596), NDEGLEX (SEQ ID NO: 6447):VPT:RPVQ-AA17-RKI (SEQ ID NO: 6596) and SSVKXQP (SEQ ID NO: 6451):SRV:RPVQ-AA17-RKI (SEQ ID NO: 6596); and wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T).
In certain embodiments, the triplet PEP7:PEP5:PEP1 is selected from the group consisting of GIPEPXX (SEQ ID NO: 6440):VPTKM (SEQ ID NO: 6424):SAIS (SEQ ID NO: 6360), HVTKPTX (SEQ ID NO: 6443):VPTKL (SEQ ID NO: 6423):SAIS (SEQ ID NO: 6360), YVPKPXX (SEQ ID NO: 6454):VPTKL (SEQ ID NO: 6423):SAIS (SEQ ID NO: 6360), TVPKPXX (SEQ ID NO: 6453):VPTQL (SEQ ID NO: 6426):SAIS (SEQ ID NO: 6360), AVPKAXX (SEQ ID NO: 6439):VPTKL (SEQ ID NO: 6423):SAIS (SEQ ID NO: 6360), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):SAIS (SEQ ID NO: 6360), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):SAIS (SEQ ID NO: 6360), GSAGPXX (SEQ ID NO: 6441):VPTKM (SEQ ID NO: 6424):SAIS (SEQ ID NO: 6360), AAPASXX (SEQ ID NO: 6436):VPTRL (SEQ ID NO: 6427):SAIS (SEQ ID NO: 6360), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):SAIS (SEQ ID NO: 6360), HVPKPXX (SEQ ID NO: 6442):VPTKL (SEQ ID NO: 6423):SAIS (SEQ ID NO: 6360), RVPSTXX (SEQ ID NO: 6449):VPTKT (SEQ ID NO: 6425):SAIS (SEQ ID NO: 6360), ASAAPXX (SEQ ID NO: 6437):VPTAL (SEQ ID NO: 6418):SAIS (SEQ ID NO: 6360), ASASPXX (SEQ ID NO: 6438):VPTDL (SEQ ID NO: 6419):SAIS (SEQ ID NO: 6360), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):SAIS (SEQ ID NO: 6360), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):SAIS (SEQ ID NO: 6360), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):SAIS (SEQ ID NO: 6360), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):SAIS (SEQ ID NO: 6360), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):SAIS (SEQ ID NO: 6360), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):SAIS (SEQ ID NO: 6360), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):SAIS (SEQ ID NO: 6360), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):SAIS (SEQ ID NO: 6360), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):SAIS (SEQ ID NO: 6360), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):SAIS (SEQ ID NO: 6360), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):SAIS (SEQ ID NO: 6360), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):SAIS (SEQ ID NO: 6360), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):SAIS (SEQ ID NO: 6360), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):SAIS (SEQ ID NO: 6360), KIPKAXX (SEQ ID NO: 6445):VPEEL (SEQ ID NO: 6404):SSLS (SEQ ID NO: 6365), SIPKAXX (SEQ ID NO: 6450):VPEEL (SEQ ID NO: 6404):SSLS (SEQ ID NO: 6365), HVTKPTX (SEQ ID NO: 6443):VPEKL (SEQ ID NO: 6405):SSLS (SEQ ID NO: 6365), YVPKPXX (SEQ ID NO: 6454):VPEKL (SEQ ID NO: 6405):SSLS (SEQ ID NO: 6365), TVPKPXX (SEQ ID NO: 6453):VPEQL (SEQ ID NO: 6408):SSLS (SEQ ID NO: 6365), AVPKAXX (SEQ ID NO: 6439):VPEKL (SEQ ID NO: 6405):SSLS (SEQ ID NO: 6365), KVGKAXX (SEQ ID NO: 6446):VPEKL (SEQ ID NO: 6405):SSLS (SEQ ID NO: 6365), KASKAXX (SEQ ID NO: 6444):VPEKL (SEQ ID NO: 6405):SSLS (SEQ ID NO: 6365), GSAGPXX (SEQ ID NO: 6441):VPEKM (SEQ ID NO: 6406):SSLS (SEQ ID NO: 6365), AAPASXX (SEQ ID NO: 6436):VPERL (SEQ ID NO: 6409):SSLS (SEQ ID NO: 6365), STPPTXX (SEQ ID NO: 6452):VPERL (SEQ ID NO: 6409):SSLS (SEQ ID NO: 6365), HVPKPXX (SEQ ID NO: 6442):VPEKL (SEQ ID NO: 6405):SSLS (SEQ ID NO: 6365), RVPSTXX (SEQ ID NO: 6449):VPEKT (SEQ ID NO: 6407):SSLS (SEQ ID NO: 6365), ASAAPXX (SEQ ID NO: 6437):VPEAL (SEQ ID NO: 6402):SSLS (SEQ ID NO: 6365), ASASPXX (SEQ ID NO: 6438):VPEDL (SEQ ID NO: 6403):SSLS (SEQ ID NO: 6365), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):SSLS (SEQ ID NO: 6365), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):SSLS (SEQ ID NO: 6365), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):SSLS (SEQ ID NO: 6365), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):SSLS (SEQ ID NO: 6365), TVPKPXX (SEQ ID NO: 6453)APTQL (SEQ ID NO: 6372):SSLS (SEQ ID NO: 6365), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):SSLS (SEQ ID NO: 6365), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):SSLS (SEQ ID NO: 6365), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):SSLS (SEQ ID NO: 6365), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):SSLS (SEQ ID NO: 6365), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):SSLS (SEQ ID NO: 6365), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):SSLS (SEQ ID NO: 6365), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):SSLS (SEQ ID NO: 6365), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):SSLS (SEQ ID NO: 6365), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):SSLS (SEQ ID NO: 6365), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):SSLS (SEQ ID NO: 6365), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):SSLS (SEQ ID NO: 6365), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):SSLS (SEQ ID NO: 6365), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):SSLS (SEQ ID NO: 6365), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):SSLS (SEQ ID NO: 6365), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):SSLS (SEQ ID NO: 6365), KIPKAXX (SEQ ID NO: 6445):APTEL (SEQ ID NO: 6368):NAIS (SEQ ID NO: 6357), GIPEPXX (SEQ ID NO: 6440):APTKM (SEQ ID NO: 6370):NAIS (SEQ ID NO: 6357), SIPKAXX (SEQ ID NO: 6450)APTEL (SEQ ID NO: 6368):NAIS (SEQ ID NO: 6357), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):NAIS (SEQ ID NO: 6357), KVGKAXX (SEQ ID NO: 6446):APTKL (SEQ ID NO: 6369):NAIS (SEQ ID NO: 6357), KASKAXX (SEQ ID NO: 6444):APTKL (SEQ ID NO: 6369):NAIS (SEQ ID NO: 6357), GSAGPXX (SEQ ID NO: 6441):APTKM (SEQ ID NO: 6370):NAIS (SEQ ID NO: 6357), AAPASXX (SEQ ID NO: 6436):APTRL (SEQ ID NO: 6373):NAIS (SEQ ID NO: 6357), STPPTXX (SEQ ID NO: 6452)APTRL (SEQ ID NO: 6373):NAIS (SEQ ID NO: 6357), RVPSTXX (SEQ ID NO: 6449):APTKT (SEQ ID NO: 6371):NAIS (SEQ ID NO: 6357), ASAAPXX (SEQ ID NO: 6437):APTAL (SEQ ID NO: 6366):NAIS (SEQ ID NO: 6357), ASASPXX (SEQ ID NO: 6438)APTDL (SEQ ID NO: 6367):NAIS (SEQ ID NO: 6357), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):NAIS (SEQ ID NO: 6357), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):NAIS (SEQ ID NO: 6357), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):NAIS (SEQ ID NO: 6357), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):NAIS (SEQ ID NO: 6357), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):NAIS (SEQ ID NO: 6357), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):NAIS (SEQ ID NO: 6357), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):NAIS (SEQ ID NO: 6357), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):NAIS (SEQ ID NO: 6357), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):NAIS (SEQ ID NO: 6357), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):NAIS (SEQ ID NO: 6357), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):NAIS (SEQ ID NO: 6357), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):NAIS (SEQ ID NO: 6357), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):NAIS (SEQ ID NO: 6357), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):NAIS (SEQ ID NO: 6357), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):NAIS (SEQ ID NO: 6357), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):NAIS (SEQ ID NO: 6357), KIPKAXX (SEQ ID NO: 6445):APTEL (SEQ ID NO: 6368):SATS (SEQ ID NO: 6361), GIPEPXX (SEQ ID NO: 6440):APTKM (SEQ ID NO: 6370):SATS (SEQ ID NO: 6361), SIPKAXX (SEQ ID NO: 6450):APTEL (SEQ ID NO: 6368):SATS (SEQ ID NO: 6361), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):SATS (SEQ ID NO: 6361), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):SATS (SEQ ID NO: 6361), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):SATS (SEQ ID NO: 6361), KVGKAXX (SEQ ID NO: 6446):APTKL (SEQ ID NO: 6369):SATS (SEQ ID NO: 6361), KASKAXX (SEQ ID NO: 6444):APTKL (SEQ ID NO: 6369):SATS (SEQ ID NO: 6361), GSAGPXX (SEQ ID NO: 6441):APTKM (SEQ ID NO: 6370):SATS (SEQ ID NO: 6361), AAPASXX (SEQ ID NO: 6436):APTRL (SEQ ID NO: 6373):SATS (SEQ ID NO: 6361), STPPTXX (SEQ ID NO: 6452):APTRL (SEQ ID NO: 6373):SATS (SEQ ID NO: 6361), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):SATS (SEQ ID NO: 6361), RVPSTXX (SEQ ID NO: 6449):APTKT (SEQ ID NO: 6371):SATS (SEQ ID NO: 6361), ASAAPXX (SEQ ID NO: 6437):APTAL (SEQ ID NO: 6366):SATS (SEQ ID NO: 6361), ASASPXX (SEQ ID NO: 6438):APTDL (SEQ ID NO: 6367):SATS (SEQ ID NO: 6361), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):SATS (SEQ ID NO: 6361), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):SATS (SEQ ID NO: 6361), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):SATS (SEQ ID NO: 6361), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):SATS (SEQ ID NO: 6361), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):SATS (SEQ ID NO: 6361), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):SATS (SEQ ID NO: 6361), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):SATS (SEQ ID NO: 6361), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):SATS (SEQ ID NO: 6361), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):SATS (SEQ ID NO: 6361), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):SATS (SEQ ID NO: 6361), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):SATS (SEQ ID NO: 6361), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):SATS (SEQ ID NO: 6361), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):SATS (SEQ ID NO: 6361), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):SATS (SEQ ID NO: 6361), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):SATS (SEQ ID NO: 6361), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):SATS (SEQ ID NO: 6361), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):SPIS (SEQ ID NO: 6364), GIPEPXX (SEQ ID NO: 6440):VPTKM (SEQ ID NO: 6424):SPIS (SEQ ID NO: 6364), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):SPIS (SEQ ID NO: 6364), HVTKPTX (SEQ ID NO: 6443):VPTKL (SEQ ID NO: 6423):SPIS (SEQ ID NO: 6364), YVPKPXX (SEQ ID NO: 6454):VPTKL (SEQ ID NO: 6423):SPIS (SEQ ID NO: 6364), TVPKPXX (SEQ ID NO: 6453):VPTQL (SEQ ID NO: 6426):SPIS (SEQ ID NO: 6364), AVPKAXX (SEQ ID NO: 6439):VPTKL (SEQ ID NO: 6423):SPIS (SEQ ID NO: 6364), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):SPIS (SEQ ID NO: 6364), GSAGPXX (SEQ ID NO: 6441):VPTKM (SEQ ID NO: 6424):SPIS (SEQ ID NO: 6364), AAPASXX (SEQ ID NO: 6436):VPTRL (SEQ ID NO: 6427):SPIS (SEQ ID NO: 6364), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):SPIS (SEQ ID NO: 6364), HVPKPXX (SEQ ID NO: 6442):VPTKL (SEQ ID NO: 6423):SPIS (SEQ ID NO: 6364), RVPSTXX (SEQ ID NO: 6449):VPTKT (SEQ ID NO: 6425):SPIS (SEQ ID NO: 6364), ASAAPXX (SEQ ID NO: 6437):VPTAL (SEQ ID NO: 6418):SPIS (SEQ ID NO: 6364), ASASPXX (SEQ ID NO: 6438):VPTDL (SEQ ID NO: 6419):SPIS (SEQ ID NO: 6364), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):SPIS (SEQ ID NO: 6364), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):SPIS (SEQ ID NO: 6364), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):SPIS (SEQ ID NO: 6364), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):SPIS (SEQ ID NO: 6364), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):SPIS (SEQ ID NO: 6364), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):SPIS (SEQ ID NO: 6364), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):SPIS (SEQ ID NO: 6364), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):SPIS (SEQ ID NO: 6364), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):SPIS (SEQ ID NO: 6364), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):SPIS (SEQ ID NO: 6364), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):SPIS (SEQ ID NO: 6364), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):SPIS (SEQ ID NO: 6364), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):SPIS (SEQ ID NO: 6364), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):SPIS (SEQ ID NO: 6364), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):EPIS (SEQ ID NO: 6353), GIPEPXX (SEQ ID NO: 6440):VPTKM (SEQ ID NO: 6424):EPIS (SEQ ID NO: 6353), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):EPIS (SEQ ID NO: 6353), HVTKPTX (SEQ ID NO: 6443):VPTKL (SEQ ID NO: 6423):EPIS (SEQ ID NO: 6353), YVPKPXX (SEQ ID NO: 6454):VPTKL (SEQ ID NO: 6423):EPIS (SEQ ID NO: 6353), TVPKPXX (SEQ ID NO: 6453):VPTQL (SEQ ID NO: 6426):EPIS (SEQ ID NO: 6353), AVPKAXX (SEQ ID NO: 6439):VPTKL (SEQ ID NO: 6423):EPIS (SEQ ID NO: 6353), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):EPIS (SEQ ID NO: 6353), GSAGPXX (SEQ ID NO: 6441):VPTKM (SEQ ID NO: 6424):EPIS (SEQ ID NO: 6353), AAPASXX (SEQ ID NO: 6436):VPTRL (SEQ ID NO: 6427):EPIS (SEQ ID NO: 6353), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):EPIS (SEQ ID NO: 6353), HVPKPXX (SEQ ID NO: 6442):VPTKL (SEQ ID NO: 6423):EPIS (SEQ ID NO: 6353), RVPSTXX (SEQ ID NO: 6449):VPTKT (SEQ ID NO: 6425):EPIS (SEQ ID NO: 6353), ASAAPXX (SEQ ID NO: 6437):VPTAL (SEQ ID NO: 6418):EPIS (SEQ ID NO: 6353), ASASPXX (SEQ ID NO: 6438):VPTDL (SEQ ID NO: 6419):EPIS (SEQ ID NO: 6353), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):EPIS (SEQ ID NO: 6353), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):EPIS (SEQ ID NO: 6353), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):EPIS (SEQ ID NO: 6353), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):EPIS (SEQ ID NO: 6353), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):EPIS (SEQ ID NO: 6353), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):EPIS (SEQ ID NO: 6353), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):EPIS (SEQ ID NO: 6353), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):EPIS (SEQ ID NO: 6353), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):EPIS (SEQ ID NO: 6353), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):EPIS (SEQ ID NO: 6353), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):EPIS (SEQ ID NO: 6353), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):EPIS (SEQ ID NO: 6353), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):EPIS (SEQ ID NO: 6353), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):EPIS (SEQ ID NO: 6353), KIPKAXX (SEQ ID NO: 6445):TPTEL (SEQ ID NO: 6386):SPIN (SEQ ID NO: 6363), GIPEPXX (SEQ ID NO: 6440):TPTKM (SEQ ID NO: 6388):SPIN (SEQ ID NO: 6363), SIPKAXX (SEQ ID NO: 6450):TPTEL (SEQ ID NO: 6386):SPIN (SEQ ID NO: 6363), HVTKPTX (SEQ ID NO: 6443):TPTKL (SEQ ID NO: 6387):SPIN (SEQ ID NO: 6363), YVPKPXX (SEQ ID NO: 6454):TPTKL (SEQ ID NO: 6387):SPIN (SEQ ID NO: 6363), TVPKPXX (SEQ ID NO: 6453):TPTQL (SEQ ID NO: 6390):SPIN (SEQ ID NO: 6363), AVPKAXX (SEQ ID NO: 6439):TPTKL (SEQ ID NO: 6387):SPIN (SEQ ID NO: 6363), KVGKAXX (SEQ ID NO: 6446):TPTKL (SEQ ID NO: 6387):SPIN (SEQ ID NO: 6363), KASKAXX (SEQ ID NO: 6444):TPTKL (SEQ ID NO: 6387):SPIN (SEQ ID NO: 6363), AAPASXX (SEQ ID NO: 6436):TPTRL (SEQ ID NO: 6391):SPIN (SEQ ID NO: 6363), STPPTXX (SEQ ID NO: 6452):TPTRL (SEQ ID NO: 6391):SPIN (SEQ ID NO: 6363), HVPKPXX (SEQ ID NO: 6442):TPTKL (SEQ ID NO: 6387):SPIN (SEQ ID NO: 6363), RVPSTXX (SEQ ID NO: 6449):TPTKT (SEQ ID NO: 6389):SPIN (SEQ ID NO: 6363), ASAAPXX (SEQ ID NO: 6437):TPTAL (SEQ ID NO: 6384):SPIN (SEQ ID NO: 6363), ASASPXX (SEQ ID NO: 6438):TPTDL (SEQ ID NO: 6385):SPIN (SEQ ID NO: 6363), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):SPIN (SEQ ID NO: 6363), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):SPIN (SEQ ID NO: 6363), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):SPIN (SEQ ID NO: 6363), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):SPIN (SEQ ID NO: 6363), YVPKPXX (SEQ ID NO: 6454)APTKL (SEQ ID NO: 6369):SPIN (SEQ ID NO: 6363), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):SPIN (SEQ ID NO: 6363), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):SPIN (SEQ ID NO: 6363), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):SPIN (SEQ ID NO: 6363), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):SPIN (SEQ ID NO: 6363), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):SPIN (SEQ ID NO: 6363), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):SPIN (SEQ ID NO: 6363), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):SPIN (SEQ ID NO: 6363), RVPSTXX (SEQ ID NO: 6449)APVKT (SEQ ID NO: 6379):SPIN (SEQ ID NO: 6363), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):SPIN (SEQ ID NO: 6363), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):SPIN (SEQ ID NO: 6363), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):SPIN (SEQ ID NO: 6363), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):SPIN (SEQ ID NO: 6363), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):SPIN (SEQ ID NO: 6363), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):SPIN (SEQ ID NO: 6363), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):SPIN (SEQ ID NO: 6363), KIPKAXX (SEQ ID NO: 6445):VPAEL (SEQ ID NO: 6396):SPIS (SEQ ID NO: 6364), GIPEPXX (SEQ ID NO: 6440):VPAKM (SEQ ID NO: 6398):SPIS (SEQ ID NO: 6364), SIPKAXX (SEQ ID NO: 6450):VPAEL (SEQ ID NO: 6396):SPIS (SEQ ID NO: 6364), HVTKPTX (SEQ ID NO: 6443):VPAKL (SEQ ID NO: 6397):SPIS (SEQ ID NO: 6364), YVPKPXX (SEQ ID NO: 6454):VPAKL (SEQ ID NO: 6397):SPIS (SEQ ID NO: 6364), TVPKPXX (SEQ ID NO: 6453):VPAQL (SEQ ID NO: 6400):SPIS (SEQ ID NO: 6364), AVPKAXX (SEQ ID NO: 6439):VPAKL (SEQ ID NO: 6397):SPIS (SEQ ID NO: 6364), KVGKAXX (SEQ ID NO: 6446):VPAKL (SEQ ID NO: 6397):SPIS (SEQ ID NO: 6364), KASKAXX (SEQ ID NO: 6444):VPAKL (SEQ ID NO: 6397):SPIS (SEQ ID NO: 6364), GSAGPXX (SEQ ID NO: 6441):VPAKM (SEQ ID NO: 6398):SPIS (SEQ ID NO: 6364), STPPTXX (SEQ ID NO: 6452):VPARL (SEQ ID NO: 6401):SPIS (SEQ ID NO: 6364), HVPKPXX (SEQ ID NO: 6442):VPAKL (SEQ ID NO: 6397):SPIS (SEQ ID NO: 6364), RVPSTXX (SEQ ID NO: 6449):VPAKT (SEQ ID NO: 6399):SPIS (SEQ ID NO: 6364), ASAAPXX (SEQ ID NO: 6437):VPAAL (SEQ ID NO: 6394):SPIS (SEQ ID NO: 6364), ASASPXX (SEQ ID NO: 6438):VPADL (SEQ ID NO: 6395):SPIS (SEQ ID NO: 6364), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):SPIS (SEQ ID NO: 6364), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):SPIS (SEQ ID NO: 6364), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):SPIS (SEQ ID NO: 6364), KIPKAXX (SEQ ID NO: 6445):APVEL (SEQ ID NO: 6376):KPLS (SEQ ID NO: 6356), GIPEPXX (SEQ ID NO: 6440):APVKM (SEQ ID NO: 6378):KPLS (SEQ ID NO: 6356), SIPKAXX (SEQ ID NO: 6450):APVEL (SEQ ID NO: 6376):KPLS (SEQ ID NO: 6356), HVTKPTX (SEQ ID NO: 6443):APVKL (SEQ ID NO: 6377):KPLS (SEQ ID NO: 6356), YVPKPXX (SEQ ID NO: 6454):APVKL (SEQ ID NO: 6377):KPLS (SEQ ID NO: 6356), TVPKPXX (SEQ ID NO: 6453):APVQL (SEQ ID NO: 6380):KPLS (SEQ ID NO: 6356), AVPKAXX (SEQ ID NO: 6439):APVKL (SEQ ID NO: 6377):KPLS (SEQ ID NO: 6356), KVGKAXX (SEQ ID NO: 6446):APVKL (SEQ ID NO: 6377):KPLS (SEQ ID NO: 6356), KASKAXX (SEQ ID NO: 6444):APVKL (SEQ ID NO: 6377):KPLS (SEQ ID NO: 6356), GSAGPXX (SEQ ID NO: 6441):APVKM (SEQ ID NO: 6378):KPLS (SEQ ID NO: 6356), AAPASXX (SEQ ID NO: 6436):APVRL (SEQ ID NO: 6381):KPLS (SEQ ID NO: 6356), STPPTXX (SEQ ID NO: 6452)APVRL (SEQ ID NO: 6381):KPLS (SEQ ID NO: 6356), HVPKPXX (SEQ ID NO: 6442):APVKL (SEQ ID NO: 6377):KPLS (SEQ ID NO: 6356), ASAAPXX (SEQ ID NO: 6437):APVAL (SEQ ID NO: 6374):KPLS (SEQ ID NO: 6356), ASASPXX (SEQ ID NO: 6438):APVDL (SEQ ID NO: 6375):KPLS (SEQ ID NO: 6356), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):KPLS (SEQ ID NO: 6356), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):KPLS (SEQ ID NO: 6356), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):KPLS (SEQ ID NO: 6356), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):KPLS (SEQ ID NO: 6356), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):KPLS (SEQ ID NO: 6356), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):KPLS (SEQ ID NO: 6356), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):KPLS (SEQ ID NO: 6356), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):KPLS (SEQ ID NO: 6356), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):KPLS (SEQ ID NO: 6356), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):KPLS (SEQ ID NO: 6356), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):KPLS (SEQ ID NO: 6356), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):KPLS (SEQ ID NO: 6356), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):KPLS (SEQ ID NO: 6356), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):KPLS (SEQ ID NO: 6356), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):KPLS (SEQ ID NO: 6356), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):KPLS (SEQ ID NO: 6356), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):KPLS (SEQ ID NO: 6356), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):KPLS (SEQ ID NO: 6356), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):KPLS (SEQ ID NO: 6356), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):KPLS (SEQ ID NO: 6356), KIPKAXX (SEQ ID NO: 6445):VPQEL (SEQ ID NO: 6412):EPLP (SEQ ID NO: 6354), GIPEPXX (SEQ ID NO: 6440):VPQKM (SEQ ID NO: 6414):EPLP (SEQ ID NO: 6354), SIPKAXX (SEQ ID NO: 6450):VPQEL (SEQ ID NO: 6412):EPLP (SEQ ID NO: 6354), HVTKPTX (SEQ ID NO: 6443):VPQKL (SEQ ID NO: 6413):EPLP (SEQ ID NO: 6354), YVPKPXX (SEQ ID NO: 6454):VPQKL (SEQ ID NO: 6413):EPLP (SEQ ID NO: 6354), TVPKPXX (SEQ ID NO: 6453):VPQQL (SEQ ID NO: 6416):EPLP (SEQ ID NO: 6354), AVPKAXX (SEQ ID NO: 6439):VPQKL (SEQ ID NO: 6413):EPLP (SEQ ID NO: 6354), KVGKAXX (SEQ ID NO: 6446):VPQKL (SEQ ID NO: 6413):EPLP (SEQ ID NO: 6354), KASKAXX (SEQ ID NO: 6444):VPQKL (SEQ ID NO: 6413):EPLP (SEQ ID NO: 6354), GSAGPXX (SEQ ID NO: 6441):VPQKM (SEQ ID NO: 6414):EPLP (SEQ ID NO: 6354), AAPASXX (SEQ ID NO: 6436):VPQRL (SEQ ID NO: 6417):EPLP (SEQ ID NO: 6354), STPPTXX (SEQ ID NO: 6452):VPQRL (SEQ ID NO: 6417):EPLP (SEQ ID NO: 6354), HVPKPXX (SEQ ID NO: 6442):VPQKL (SEQ ID NO: 6413):EPLP (SEQ ID NO: 6354), RVPSTXX (SEQ ID NO: 6449):VPQKT (SEQ ID NO: 6415):EPLP (SEQ ID NO: 6354), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):EPLP (SEQ ID NO: 6354), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):EPLP (SEQ ID NO: 6354), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):EPLP (SEQ ID NO: 6354), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):EPLP (SEQ ID NO: 6354), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):EPLP (SEQ ID NO: 6354), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):EPLP (SEQ ID NO: 6354), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):EPLP (SEQ ID NO: 6354), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):EPLP (SEQ ID NO: 6354), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):EPLP (SEQ ID NO: 6354), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):EPLP (SEQ ID NO: 6354), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):EPLP (SEQ ID NO: 6354), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):EPLP (SEQ ID NO: 6354), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):EPLP (SEQ ID NO: 6354), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):EPLP (SEQ ID NO: 6354), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):EPLP (SEQ ID NO: 6354), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):EPLP (SEQ ID NO: 6354), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):EPLP (SEQ ID NO: 6354), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):EPLP (SEQ ID NO: 6354), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):EPLP (SEQ ID NO: 6354), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):EPLP (SEQ ID NO: 6354), KIPKAXX (SEQ ID NO: 6445):VSQEL (SEQ ID NO: 6430):EPLT (SEQ ID NO: 6355), GIPEPXX (SEQ ID NO: 6440):VSQKM (SEQ ID NO: 6432):EPLT (SEQ ID NO: 6355), SIPKAXX (SEQ ID NO: 6450):VSQEL (SEQ ID NO: 6430):EPLT (SEQ ID NO: 6355), HVTKPTX (SEQ ID NO: 6443):VSQKL (SEQ ID NO: 6431):EPLT (SEQ ID NO: 6355), YVPKPXX (SEQ ID NO: 6454):VSQKL (SEQ ID NO: 6431):EPLT (SEQ ID NO: 6355), TVPKPXX (SEQ ID NO: 6453):VSQOL (SEQ ID NO: 6434):EPLT (SEQ ID NO: 6355), AVPKAXX (SEQ ID NO: 6439):VSQKL (SEQ ID NO: 6431):EPLT (SEQ ID NO: 6355), KVGKAXX (SEQ ID NO: 6446):VSQKL (SEQ ID NO: 6431):EPLT (SEQ ID NO: 6355), KASKAXX (SEQ ID NO: 6444):VSQKL (SEQ ID NO: 6431):EPLT (SEQ ID NO: 6355), GSAGPXX (SEQ ID NO: 6441):VSQKM (SEQ ID NO: 6432):EPLT (SEQ ID NO: 6355), AAPASXX (SEQ ID NO: 6436):VSQRL (SEQ ID NO: 6435):EPLT (SEQ ID NO: 6355), STPPTXX (SEQ ID NO: 6452):VSQRL (SEQ ID NO: 6435):EPLT (SEQ ID NO: 6355), HVPKPXX (SEQ ID NO: 6442):VSQKL (SEQ ID NO: 6431):EPLT (SEQ ID NO: 6355), RVPSTXX (SEQ ID NO: 6449):VSQKT (SEQ ID NO: 6433):EPLT (SEQ ID NO: 6355), ASAAPXX (SEQ ID NO: 6437):VSQAL (SEQ ID NO: 6428):EPLT (SEQ ID NO: 6355), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):EPLT (SEQ ID NO: 6355), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):EPLT (SEQ ID NO: 6355), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):EPLT (SEQ ID NO: 6355), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):EPLT (SEQ ID NO: 6355), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):EPLT (SEQ ID NO: 6355), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):EPLT (SEQ ID NO: 6355), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):EPLT (SEQ ID NO: 6355), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):EPLT (SEQ ID NO: 6355), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):EPLT (SEQ ID NO: 6355), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):EPLT (SEQ ID NO: 6355), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):EPLT (SEQ ID NO: 6355), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):EPLT (SEQ ID NO: 6355), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):EPLT (SEQ ID NO: 6355), HVPKPXX (SEQ ID NO: 6442)APTKL (SEQ ID NO: 6369):EPLT (SEQ ID NO: 6355), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):EPLT (SEQ ID NO: 6355), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):EPLT (SEQ ID NO: 6355), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):EPLT (SEQ ID NO: 6355), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):EPLT (SEQ ID NO: 6355), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):EPLT (SEQ ID NO: 6355), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):EPLT (SEQ ID NO: 6355), KIPKAXX (SEQ ID NO: 6445):VPQEL (SEQ ID NO: 6412):EPLT (SEQ ID NO: 6355), GIPEPXX (SEQ ID NO: 6440):VPQKM (SEQ ID NO: 6414):EPLT (SEQ ID NO: 6355), SIPKAXX (SEQ ID NO: 6450):VPQEL (SEQ ID NO: 6412):EPLT (SEQ ID NO: 6355), HVTKPTX (SEQ ID NO: 6443):VPQKL (SEQ ID NO: 6413):EPLT (SEQ ID NO: 6355), YVPKPXX (SEQ ID NO: 6454):VPQKL (SEQ ID NO: 6413):EPLT (SEQ ID NO: 6355), TVPKPXX (SEQ ID NO: 6453):VPQQL (SEQ ID NO: 6416):EPLT (SEQ ID NO: 6355), AVPKAXX (SEQ ID NO: 6439):VPQKL (SEQ ID NO: 6413):EPLT (SEQ ID NO: 6355), KVGKAXX (SEQ ID NO: 6446):VPQKL (SEQ ID NO: 6413):EPLT (SEQ ID NO: 6355), KASKAXX (SEQ ID NO: 6444):VPQKL (SEQ ID NO: 6413):EPLT (SEQ ID NO: 6355), GSAGPXX (SEQ ID NO: 6441):VPQKM (SEQ ID NO: 6414):EPLT (SEQ ID NO: 6355), AAPASXX (SEQ ID NO: 6436):VPQRL (SEQ ID NO: 6417):EPLT (SEQ ID NO: 6355), STPPTXX (SEQ ID NO: 6452):VPQRL (SEQ ID NO: 6417):EPLT (SEQ ID NO: 6355), HVPKPXX (SEQ ID NO: 6442):VPQKL (SEQ ID NO: 6413):EPLT (SEQ ID NO: 6355), RVPSTXX (SEQ ID NO: 6449):VPQKT (SEQ ID NO: 6415):EPLT (SEQ ID NO: 6355), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):EPLT (SEQ ID NO: 6355), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):SNIT (SEQ ID NO: 6362), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):SNIT (SEQ ID NO: 6362), HVTKPTX (SEQ ID NO: 6443)APTKL (SEQ ID NO: 6369):SNIT (SEQ ID NO: 6362), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):SNIT (SEQ ID NO: 6362), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):SNIT (SEQ ID NO: 6362), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):SNIT (SEQ ID NO: 6362), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):SNIT (SEQ ID NO: 6362), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):SNIT (SEQ ID NO: 6362), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):SNIT (SEQ ID NO: 6362), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):SNIT (SEQ ID NO: 6362), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):SNIT (SEQ ID NO: 6362), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):SNIT (SEQ ID NO: 6362), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):SNIT (SEQ ID NO: 6362), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):SNIT (SEQ ID NO: 6362), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):SNIT (SEQ ID NO: 6362), RNVQXRP (SEQ ID NO: 6448):SRVQL (SEQ ID NO: 6383):RSVK (SEQ ID NO: 6359), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):RSVK (SEQ ID NO: 6359), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):RSVK (SEQ ID NO: 6359), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):RSVK (SEQ ID NO: 6359), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):RSVK (SEQ ID NO: 6359), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):RSVK (SEQ ID NO: 6359), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):RSVK (SEQ ID NO: 6359), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):RSVK (SEQ ID NO: 6359), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):RSVK (SEQ ID NO: 6359), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):RSVK (SEQ ID NO: 6359), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):RSVK (SEQ ID NO: 6359), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):RSVK (SEQ ID NO: 6359), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):RSVK (SEQ ID NO: 6359), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):RSVK (SEQ ID NO: 6359), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):RSVK (SEQ ID NO: 6359), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):RSVK (SEQ ID NO: 6359), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):RSVK (SEQ ID NO: 6359), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):RSVK (SEQ ID NO: 6359), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):RSVK (SEQ ID NO: 6359), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):RSVK (SEQ ID NO: 6359), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):RSVK (SEQ ID NO: 6359), SSVKXQP (SEQ ID NO: 6451):TQVHH (SEQ ID NO: 6392):RPVQ (SEQ ID NO: 6358), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):RPVQ (SEQ ID NO: 6358), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):RPVQ (SEQ ID NO: 6358), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):RPVQ (SEQ ID NO: 6358), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):RPVQ (SEQ ID NO: 6358), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):RPVQ (SEQ ID NO: 6358), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):RPVQ (SEQ ID NO: 6358), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):RPVQ (SEQ ID NO: 6358), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):RPVQ (SEQ ID NO: 6358), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):RPVQ (SEQ ID NO: 6358), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):RPVQ (SEQ ID NO: 6358), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):RPVQ (SEQ ID NO: 6358), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):RPVQ (SEQ ID NO: 6358), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):RPVQ (SEQ ID NO: 6358), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):RPVQ (SEQ ID NO: 6358), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):RPVQ (SEQ ID NO: 6358), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):RPVQ (SEQ ID NO: 6358), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):RPVQ (SEQ ID NO: 6358), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):RPVQ (SEQ ID NO: 6358), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):RPVQ (SEQ ID NO: 6358) and SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):RPVQ (SEQ ID NO: 6358).
In certain embodiments, the triplet PEP7:PEP5:PEP12 is selected from the group consisting of GIPEPXX (SEQ ID NO: 6440):VPTKM (SEQ ID NO: 6424):SAIS-AA17-LYL (SEQ ID NO: 6598), HVTKPTX (SEQ ID NO: 6443):VPTKL (SEQ ID NO: 6423):SAIS-AA17-LYL (SEQ ID NO: 6598), YVPKPXX (SEQ ID NO: 6454):VPTKL (SEQ ID NO: 6423):SAIS-AA17-LYL (SEQ ID NO: 6598), TVPKPXX (SEQ ID NO: 6453):VPTQL (SEQ ID NO: 6426):SAIS-AA17-LYL (SEQ ID NO: 6598), AVPKAXX (SEQ ID NO: 6439):VPTKL (SEQ ID NO: 6423):SAIS-AA17-LYL (SEQ ID NO: 6598), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):SAIS-AA17-LYL (SEQ ID NO: 6598), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):SAIS-AA17-LYL (SEQ ID NO: 6598), GSAGPXX (SEQ ID NO: 6441):VPTKM (SEQ ID NO: 6424):SAIS-AA17-LYL (SEQ ID NO: 6598), AAPASXX (SEQ ID NO: 6436):VPTRL (SEQ ID NO: 6427):SAIS-AA17-LYL (SEQ ID NO: 6598), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):SAIS-AA17-LYL (SEQ ID NO: 6598), HVPKPXX (SEQ ID NO: 6442):VPTKL (SEQ ID NO: 6423):SAIS-AA17-LYL (SEQ ID NO: 6598), RVPSTXX (SEQ ID NO: 6449):VPTKT (SEQ ID NO: 6425):SAIS-AA17-LYL (SEQ ID NO: 6598), ASAAPXX (SEQ ID NO: 6437):VPTAL (SEQ ID NO: 6418):SAIS-AA17-LYL (SEQ ID NO: 6598), ASASPXX (SEQ ID NO: 6438):VPTDL (SEQ ID NO: 6419):SAIS-AA17-LYL (SEQ ID NO: 6598), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):SAIS-AA17-LYL (SEQ ID NO: 6598), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):SAIS-AA17-LYL (SEQ ID NO: 6598), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):SAIS-AA17-LYL (SEQ ID NO: 6598), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):SAIS-AA17-LYL (SEQ ID NO: 6598), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):SAIS-AA17-LYL (SEQ ID NO: 6598), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):SAIS-AA17-LYL (SEQ ID NO: 6598), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):SAIS-AA17-LYL (SEQ ID NO: 6598), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):SAIS-AA17-LYL (SEQ ID NO: 6598), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):SAIS-AA17-LYL (SEQ ID NO: 6598), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):SAIS-AA17-LYL (SEQ ID NO: 6598), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):SAIS-AA17-LYL (SEQ ID NO: 6598), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):SAIS-AA17-LYL (SEQ ID NO: 6598), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):SAIS-AA17-LYL (SEQ ID NO: 6598), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):SAIS-AA17-LYL (SEQ ID NO: 6598), KIPKAXX (SEQ ID NO: 6445):VPEEL (SEQ ID NO: 6404):SSLS-AA17-LFF (SEQ ID NO: 6605), SIPKAXX (SEQ ID NO: 6450):VPEEL (SEQ ID NO: 6404):SSLS-AA17-LFF (SEQ ID NO: 6605), HVTKPTX (SEQ ID NO: 6443):VPEKL (SEQ ID NO: 6405):SSLS-AA17-LFF (SEQ ID NO: 6605), YVPKPXX (SEQ ID NO: 6454):VPEKL (SEQ ID NO: 6405):SSLS-AA17-LFF (SEQ ID NO: 6605), TVPKPXX (SEQ ID NO: 6453):VPEQL (SEQ ID NO: 6408):SSLS-AA17-LFF (SEQ ID NO: 6605), AVPKAXX (SEQ ID NO: 6439):VPEKL (SEQ ID NO: 6405):SSLS-AA17-LFF (SEQ ID NO: 6605), KVGKAXX (SEQ ID NO: 6446):VPEKL (SEQ ID NO: 6405):SSLS-AA17-LFF (SEQ ID NO: 6605), KASKAXX (SEQ ID NO: 6444):VPEKL (SEQ ID NO: 6405):SSLS-AA17-LFF (SEQ ID NO: 6605), GSAGPXX (SEQ ID NO: 6441):VPEKM (SEQ ID NO: 6406):SSLS-AA17-LFF (SEQ ID NO: 6605), AAPASXX (SEQ ID NO: 6436):VPERL (SEQ ID NO: 6409):SSLS-AA17-LFF (SEQ ID NO: 6605), STPPTXX (SEQ ID NO: 6452):VPERL (SEQ ID NO: 6409):SSLS-AA17-LFF (SEQ ID NO: 6605), HVPKPXX (SEQ ID NO: 6442):VPEKL (SEQ ID NO: 6405):SSLS-AA17-LFF (SEQ ID NO: 6605), RVPSTXX (SEQ ID NO: 6449):VPEKT (SEQ ID NO: 6407):SSLS-AA17-LFF (SEQ ID NO: 6605), ASAAPXX (SEQ ID NO: 6437):VPEAL (SEQ ID NO: 6402):SSLS-AA17-LFF (SEQ ID NO: 6605), ASASPXX (SEQ ID NO: 6438):VPEDL (SEQ ID NO: 6403):SSLS-AA17-LFF (SEQ ID NO: 6605), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):SSLS-AA17-LFF (SEQ ID NO: 6605), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):SSLS-AA17-LFF (SEQ ID NO: 6605), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):SSLS-AA17-LFF (SEQ ID NO: 6605), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):SSLS-AA17-LFF (SEQ ID NO: 6605), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):SSLS-AA17-LFF (SEQ ID NO: 6605), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):SSLS-AA17-LFF (SEQ ID NO: 6605), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):SSLS-AA17-LFF (SEQ ID NO: 6605), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):SSLS-AA17-LFF (SEQ ID NO: 6605), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):SSLS-AA17-LFF (SEQ ID NO: 6605), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):SSLS-AA17-LFF (SEQ ID NO: 6605), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):SSLS-AA17-LFF (SEQ ID NO: 6605), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):SSLS-AA17-LFF (SEQ ID NO: 6605), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):SSLS-AA17-LFF (SEQ ID NO: 6605), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):SSLS-AA17-LFF (SEQ ID NO: 6605), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):SSLS-AA17-LFF (SEQ ID NO: 6605), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):SSLS-AA17-LFF (SEQ ID NO: 6605), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):SSLS-AA17-LFF (SEQ ID NO: 6605), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):SSLS-AA17-LFF (SEQ ID NO: 6605), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):SSLS-AA17-LFF (SEQ ID NO: 6605), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):SSLS-AA17-LFF (SEQ ID NO: 6605), KIPKAXX (SEQ ID NO: 6445):APTEL (SEQ ID NO: 6368):NAIS-AA17-LYF (SEQ ID NO: 6595), GIPEPXX (SEQ ID NO: 6440):APTKM (SEQ ID NO: 6370):NAIS-AA17-LYF (SEQ ID NO: 6595), SIPKAXX (SEQ ID NO: 6450):APTEL (SEQ ID NO: 6368):NAIS-AA17-LYF (SEQ ID NO: 6595), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):NAIS-AA17-LYF (SEQ ID NO: 6595), KVGKAXX (SEQ ID NO: 6446):APTKL (SEQ ID NO: 6369):NAIS-AA17-LYF (SEQ ID NO: 6595), KASKAXX (SEQ ID NO: 6444):APTKL (SEQ ID NO: 6369):NAIS-AA17-LYF (SEQ ID NO: 6595), GSAGPXX (SEQ ID NO: 6441):APTKM (SEQ ID NO: 6370):NAIS-AA17-LYF (SEQ ID NO: 6595), AAPASXX (SEQ ID NO: 6436):APTRL (SEQ ID NO: 6373):NAIS-AA17-LYF (SEQ ID NO: 6595), STPPTXX (SEQ ID NO: 6452):APTRL (SEQ ID NO: 6373):NAIS-AA17-LYF (SEQ ID NO: 6595), RVPSTXX (SEQ ID NO: 6449):APTKT (SEQ ID NO: 6371):NAIS-AA17-LYF (SEQ ID NO: 6595), ASAAPXX (SEQ ID NO: 6437):APTAL (SEQ ID NO: 6366):NAIS-AA17-LYF (SEQ ID NO: 6595), ASASPXX (SEQ ID NO: 6438):APTDL (SEQ ID NO: 6367):NAIS-AA17-LYF (SEQ ID NO: 6595), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):NAIS-AA17-LYF (SEQ ID NO: 6595), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):NAIS-AA17-LYF (SEQ ID NO: 6595), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):NAIS-AA17-LYF (SEQ ID NO: 6595), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):NAIS-AA17-LYF (SEQ ID NO: 6595), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):NAIS-AA17-LYF (SEQ ID NO: 6595), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):NAIS-AA17-LYF (SEQ ID NO: 6595), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):NAIS-AA17-LYF (SEQ ID NO: 6595), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):NAIS-AA17-LYF (SEQ ID NO: 6595), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):NAIS-AA17-LYF (SEQ ID NO: 6595), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):NAIS-AA17-LYF (SEQ ID NO: 6595), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):NAIS-AA17-LYF (SEQ ID NO: 6595), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):NAIS-AA17-LYF (SEQ ID NO: 6595), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):NAIS-AA17-LYF (SEQ ID NO: 6595), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):NAIS-AA17-LYF (SEQ ID NO: 6595), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):NAIS-AA17-LYF (SEQ ID NO: 6595), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):NAIS-AA17-LYF (SEQ ID NO: 6595), KIPKAXX (SEQ ID NO: 6445):APTEL (SEQ ID NO: 6368):SATS-AA17-LYY (SEQ ID NO: 6599), GIPEPXX (SEQ ID NO: 6440):APTKM (SEQ ID NO: 6370):SATS-AA17-LYY (SEQ ID NO: 6599), SIPKAXX (SEQ ID NO: 6450):APTEL (SEQ ID NO: 6368):SATS-AA17-LYY (SEQ ID NO: 6599), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):SATS-AA17-LYY (SEQ ID NO: 6599), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):SATS-AA17-LYY (SEQ ID NO: 6599), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):SATS-AA17-LYY (SEQ ID NO: 6599), KVGKAXX (SEQ ID NO: 6446):APTKL (SEQ ID NO: 6369):SATS-AA17-LYY (SEQ ID NO: 6599), KASKAXX (SEQ ID NO: 6444):APTKL (SEQ ID NO: 6369):SATS-AA17-LYY (SEQ ID NO: 6599), GSAGPXX (SEQ ID NO: 6441):APTKM (SEQ ID NO: 6370):SATS-AA17-LYY (SEQ ID NO: 6599), AAPASXX (SEQ ID NO: 6436):APTRL (SEQ ID NO: 6373):SATS-AA17-LYY (SEQ ID NO: 6599), STPPTXX (SEQ ID NO: 6452):APTRL (SEQ ID NO: 6373):SATS-AA17-LYY (SEQ ID NO: 6599), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):SATS-AA17-LYY (SEQ ID NO: 6599), RVPSTXX (SEQ ID NO: 6449):APTKT (SEQ ID NO: 6371):SATS-AA17-LYY (SEQ ID NO: 6599), ASAAPXX (SEQ ID NO: 6437):APTAL (SEQ ID NO: 6366):SATS-AA17-LYY (SEQ ID NO: 6599), ASASPXX (SEQ ID NO: 6438):APTDL (SEQ ID NO: 6367):SATS-AA17-LYY (SEQ ID NO: 6599), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):SATS-AA17-LYY (SEQ ID NO: 6599), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):SATS-AA17-LYY (SEQ ID NO: 6599), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):SATS-AA17-LYY (SEQ ID NO: 6599), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):SATS-AA17-LYY (SEQ ID NO: 6599), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):SATS-AA17-LYY (SEQ ID NO: 6599), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):SATS-AA17-LYY (SEQ ID NO: 6599), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):SATS-AA17-LYY (SEQ ID NO: 6599), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):SATS-AA17-LYY (SEQ ID NO: 6599), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):SATS-AA17-LYY (SEQ ID NO: 6599), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):SATS-AA17-LYY (SEQ ID NO: 6599), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):SATS-AA17-LYY (SEQ ID NO: 6599), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):SATS-AA17-LYY (SEQ ID NO: 6599), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):SATS-AA17-LYY (SEQ ID NO: 6599), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):SATS-AA17-LYY (SEQ ID NO: 6599), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):SATS-AA17-LYY (SEQ ID NO: 6599), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):SATS-AA17-LYY (SEQ ID NO: 6599), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):SPIS-AA17-LYK (SEQ ID NO: 6604), GIPEPXX (SEQ ID NO: 6440):VPTKM (SEQ ID NO: 6424):SPIS-AA17-LYK (SEQ ID NO: 6604), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):SPIS-AA17-LYK (SEQ ID NO: 6604), HVTKPTX (SEQ ID NO: 6443):VPTKL (SEQ ID NO: 6423):SPIS-AA17-LYK (SEQ ID NO: 6604), YVPKPXX (SEQ ID NO: 6454):VPTKL (SEQ ID NO: 6423):SPIS-AA17-LYK (SEQ ID NO: 6604), TVPKPXX (SEQ ID NO: 6453):VPTQL (SEQ ID NO: 6426):SPIS-AA17-LYK (SEQ ID NO: 6604), AVPKAXX (SEQ ID NO: 6439):VPTKL (SEQ ID NO: 6423):SPIS-AA17-LYK (SEQ ID NO: 6604), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):SPIS-AA17-LYK (SEQ ID NO: 6604), GSAGPXX (SEQ ID NO: 6441):VPTKM (SEQ ID NO: 6424):SPIS-AA17-LYK (SEQ ID NO: 6604), AAPASXX (SEQ ID NO: 6436):VPTRL (SEQ ID NO: 6427):SPIS-AA17-LYK (SEQ ID NO: 6604), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):SPIS-AA17-LYK (SEQ ID NO: 6604), HVPKPXX (SEQ ID NO: 6442):VPTKL (SEQ ID NO: 6423):SPIS-AA17-LYK (SEQ ID NO: 6604), RVPSTXX (SEQ ID NO: 6449):VPTKT (SEQ ID NO: 6425):SPIS-AA17-LYK (SEQ ID NO: 6604), ASAAPXX (SEQ ID NO: 6437):VPTAL (SEQ ID NO: 6418):SPIS-AA17-LYK (SEQ ID NO: 6604), ASASPXX (SEQ ID NO: 6438):VPTDL (SEQ ID NO: 6419):SPIS-AA17-LYK (SEQ ID NO: 6604), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):SPIS-AA17-LYK (SEQ ID NO: 6604), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):SPIS-AA17-LYK (SEQ ID NO: 6604), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):SPIS-AA17-LYK (SEQ ID NO: 6604), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):SPIS-AA17-LYK (SEQ ID NO: 6604), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):SPIS-AA17-LYK (SEQ ID NO: 6604), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):SPIS-AA17-LYK (SEQ ID NO: 6604), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):SPIS-AA17-LYK (SEQ ID NO: 6604), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):SPIS-AA17-LYK (SEQ ID NO: 6604), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):SPIS-AA17-LYK (SEQ ID NO: 6604), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):SPIS-AA17-LYK (SEQ ID NO: 6604), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):SPIS-AA17-LYK (SEQ ID NO: 6604), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):SPIS-AA17-LYK (SEQ ID NO: 6604), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):SPIS-AA17-LYK (SEQ ID NO: 6604), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):SPIS-AA17-LYK (SEQ ID NO: 6604), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):EPIS-AA17-LYL (SEQ ID NO: 6591), GIPEPXX (SEQ ID NO: 6440):VPTKM (SEQ ID NO: 6424):EPIS-AA17-LYL (SEQ ID NO: 6591), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):EPIS-AA17-LYL (SEQ ID NO: 6591), HVTKPTX (SEQ ID NO: 6443):VPTKL (SEQ ID NO: 6423):EPIS-AA17-LYL (SEQ ID NO: 6591), YVPKPXX (SEQ ID NO: 6454):VPTKL (SEQ ID NO: 6423):EPIS-AA17-LYL (SEQ ID NO: 6591), TVPKPXX (SEQ ID NO: 6453):VPTQL (SEQ ID NO: 6426):EPIS-AA17-LYL (SEQ ID NO: 6591), AVPKAXX (SEQ ID NO: 6439):VPTKL (SEQ ID NO: 6423):EPIS-AA17-LYL (SEQ ID NO: 6591), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):EPIS-AA17-LYL (SEQ ID NO: 6591), GSAGPXX (SEQ ID NO: 6441):VPTKM (SEQ ID NO: 6424):EPIS-AA17-LYL (SEQ ID NO: 6591), AAPASXX (SEQ ID NO: 6436):VPTRL (SEQ ID NO: 6427):EPIS-AA17-LYL (SEQ ID NO: 6591), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):EPIS-AA17-LYL (SEQ ID NO: 6591), HVPKPXX (SEQ ID NO: 6442):VPTKL (SEQ ID NO: 6423):EPIS-AA17-LYL (SEQ ID NO: 6591), RVPSTXX (SEQ ID NO: 6449):VPTKT (SEQ ID NO: 6425):EPIS-AA17-LYL (SEQ ID NO: 6591), ASAAPXX (SEQ ID NO: 6437):VPTAL (SEQ ID NO: 6418):EPIS-AA17-LYL (SEQ ID NO: 6591), ASASPXX (SEQ ID NO: 6438):VPTDL (SEQ ID NO: 6419):EPIS-AA17-LYL (SEQ ID NO: 6591), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):EPIS-AA17-LYL (SEQ ID NO: 6591), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):EPIS-AA17-LYL (SEQ ID NO: 6591), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):EPIS-AA17-LYL (SEQ ID NO: 6591), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):EPIS-AA17-LYL (SEQ ID NO: 6591), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):EPIS-AA17-LYL (SEQ ID NO: 6591), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):EPIS-AA17-LYL (SEQ ID NO: 6591), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):EPIS-AA17-LYL (SEQ ID NO: 6591), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):EPIS-AA17-LYL (SEQ ID NO: 6591), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):EPIS-AA17-LYL (SEQ ID NO: 6591), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):EPIS-AA17-LYL (SEQ ID NO: 6591), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):EPIS-AA17-LYL (SEQ ID NO: 6591), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):EPIS-AA17-LYL (SEQ ID NO: 6591), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):EPIS-AA17-LYL (SEQ ID NO: 6591), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):EPIS-AA17-LYL (SEQ ID NO: 6591), KIPKAXX (SEQ ID NO: 6445):TPTEL (SEQ ID NO: 6386):SPIN-AA17-LYF (SEQ ID NO: 6601), GIPEPXX (SEQ ID NO: 6440):TPTKM (SEQ ID NO: 6388):SPIN-AA17-LYF (SEQ ID NO: 6601), SIPKAXX (SEQ ID NO: 6450):TPTEL (SEQ ID NO: 6386):SPIN-AA17-LYF (SEQ ID NO: 6601), HVTKPTX (SEQ ID NO: 6443):TPTKL (SEQ ID NO: 6387):SPIN-AA17-LYF (SEQ ID NO: 6601), YVPKPXX (SEQ ID NO: 6454):TPTKL (SEQ ID NO: 6387):SPIN-AA17-LYF (SEQ ID NO: 6601), TVPKPXX (SEQ ID NO: 6453):TPTQL (SEQ ID NO: 6390):SPIN-AA17-LYF (SEQ ID NO: 6601), AVPKAXX (SEQ ID NO: 6439):TPTKL (SEQ ID NO: 6387):SPIN-AA17-LYF (SEQ ID NO: 6601), KVGKAXX (SEQ ID NO: 6446):TPTKL (SEQ ID NO: 6387):SPIN-AA17-LYF (SEQ ID NO: 6601), KASKAXX (SEQ ID NO: 6444):TPTKL (SEQ ID NO: 6387):SPIN-AA17-LYF (SEQ ID NO: 6601), AAPASXX (SEQ ID NO: 6436):TPTRL (SEQ ID NO: 6391):SPIN-AA17-LYF (SEQ ID NO: 6601), STPPTXX (SEQ ID NO: 6452):TPTRL (SEQ ID NO: 6391):SPIN-AA17-LYF (SEQ ID NO: 6601), HVPKPXX (SEQ ID NO: 6442):TPTKL (SEQ ID NO: 6387):SPIN-AA17-LYF (SEQ ID NO: 6601), RVPSTXX (SEQ ID NO: 6449):TPTKT (SEQ ID NO: 6389):SPIN-AA17-LYF (SEQ ID NO: 6601), ASAAPXX (SEQ ID NO: 6437):TPTAL (SEQ ID NO: 6384):SPIN-AA17-LYF (SEQ ID NO: 6601), ASASPXX (SEQ ID NO: 6438):TPTDL (SEQ ID NO: 6385):SPIN-AA17-LYF (SEQ ID NO: 6601), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):SPIN-AA17-LYF (SEQ ID NO: 6601), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):SPIN-AA17-LYF (SEQ ID NO: 6601), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):SPIN-AA17-LYF (SEQ ID NO: 6601), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):SPIN-AA17-LYF (SEQ ID NO: 6601), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):SPIN-AA17-LYF (SEQ ID NO: 6601), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):SPIN-AA17-LYF (SEQ ID NO: 6601), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):SPIN-AA17-LYF (SEQ ID NO: 6601), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):SPIN-AA17-LYF (SEQ ID NO: 6601), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):SPIN-AA17-LYF (SEQ ID NO: 6601), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):SPIN-AA17-LYF (SEQ ID NO: 6601), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):SPIN-AA17-LYF (SEQ ID NO: 6601), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):SPIN-AA17-LYF (SEQ ID NO: 6601), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):SPIN-AA17-LYF (SEQ ID NO: 6601), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):SPIN-AA17-LYF (SEQ ID NO: 6601), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):SPIN-AA17-LYF (SEQ ID NO: 6601), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):SPIN-AA17-LYF (SEQ ID NO: 6601), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):SPIN-AA17-LYF (SEQ ID NO: 6601), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):SPIN-AA17-LYF (SEQ ID NO: 6601), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):SPIN-AA17-LYF (SEQ ID NO: 6601), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):SPIN-AA17-LYF (SEQ ID NO: 6601), KIPKAXX (SEQ ID NO: 6445):VPAEL (SEQ ID NO: 6396):SPIS-AA17-LYI (SEQ ID NO: 6603), GIPEPXX (SEQ ID NO: 6440):VPAKM (SEQ ID NO: 6398):SPIS-AA17-LYI (SEQ ID NO: 6603), SIPKAXX (SEQ ID NO: 6450):VPAEL (SEQ ID NO: 6396):SPIS-AA17-LYI (SEQ ID NO: 6603), HVTKPTX (SEQ ID NO: 6443):VPAKL (SEQ ID NO: 6397):SPIS-AA17-LYI (SEQ ID NO: 6603), YVPKPXX (SEQ ID NO: 6454):VPAKL (SEQ ID NO: 6397):SPIS-AA17-LYI (SEQ ID NO: 6603), TVPKPXX (SEQ ID NO: 6453):VPAQL (SEQ ID NO: 6400):SPIS-AA17-LYI (SEQ ID NO: 6603), AVPKAXX (SEQ ID NO: 6439):VPAKL (SEQ ID NO: 6397):SPIS-AA17-LYI (SEQ ID NO: 6603), KVGKAXX (SEQ ID NO: 6446):VPAKL (SEQ ID NO: 6397):SPIS-AA17-LYI (SEQ ID NO: 6603), KASKAXX (SEQ ID NO: 6444):VPAKL (SEQ ID NO: 6397):SPIS-AA17-LYI (SEQ ID NO: 6603), GSAGPXX (SEQ ID NO: 6441):VPAKM (SEQ ID NO: 6398):SPIS-AA17-LYI (SEQ ID NO: 6603), STPPTXX (SEQ ID NO: 6452):VPARL (SEQ ID NO: 6401):SPIS-AA17-LYI (SEQ ID NO: 6603), HVPKPXX (SEQ ID NO: 6442):VPAKL (SEQ ID NO: 6397):SPIS-AA17-LYI (SEQ ID NO: 6603), RVPSTXX (SEQ ID NO: 6449):VPAKT (SEQ ID NO: 6399):SPIS-AA17-LYI (SEQ ID NO: 6603), ASAAPXX (SEQ ID NO: 6437):VPAAL (SEQ ID NO: 6394):SPIS-AA17-LYI (SEQ ID NO: 6603), ASASPXX (SEQ ID NO: 6438):VPADL (SEQ ID NO: 6395):SPIS-AA17-LYI (SEQ ID NO: 6603), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):SPIS-AA17-LYI (SEQ ID NO: 6603), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):SPIS-AA17-LYI (SEQ ID NO: 6603), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):SPIS-AA17-LYI (SEQ ID NO: 6603), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):SPIS-AA17-LYI (SEQ ID NO: 6603), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):SPIS-AA17-LYI (SEQ ID NO: 6603), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):SPIS-AA17-LYI (SEQ ID NO: 6603), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):SPIS-AA17-LYI (SEQ ID NO: 6603), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):SPIS-AA17-LYI (SEQ ID NO: 6603), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):SPIS-AA17-LYI (SEQ ID NO: 6603), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):SPIS-AA17-LYI (SEQ ID NO: 6603), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):SPIS-AA17-LYI (SEQ ID NO: 6603), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):SPIS-AA17-LYI (SEQ ID NO: 6603), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):SPIS-AA17-LYI (SEQ ID NO: 6603), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):SPIS-AA17-LYI (SEQ ID NO: 6603), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):SPIS-AA17-LYI (SEQ ID NO: 6603), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):SPIS-AA17-LYI (SEQ ID NO: 6603), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):SPIS-AA17-LYI (SEQ ID NO: 6603), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):SPIS-AA17-LYI (SEQ ID NO: 6603), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):SPIS-AA17-LYI (SEQ ID NO: 6603), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):SPIS-AA17-LYI (SEQ ID NO: 6603), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):SPIS-AA17-LFI (SEQ ID NO: 6602), GIPEPXX (SEQ ID NO: 6440):VPTKM (SEQ ID NO: 6424):SPIS-AA17-LFI (SEQ ID NO: 6602), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):SPIS-AA17-LFI (SEQ ID NO: 6602), HVTKPTX (SEQ ID NO: 6443):VPTKL (SEQ ID NO: 6423):SPIS-AA17-LFI (SEQ ID NO: 6602), YVPKPXX (SEQ ID NO: 6454):VPTKL (SEQ ID NO: 6423):SPIS-AA17-LFI (SEQ ID NO: 6602), TVPKPXX (SEQ ID NO: 6453):VPTQL (SEQ ID NO: 6426):SPIS-AA17-LFI (SEQ ID NO: 6602), AVPKAXX (SEQ ID NO: 6439):VPTKL (SEQ ID NO: 6423):SPIS-AA17-LFI (SEQ ID NO: 6602), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):SPIS-AA17-LFI (SEQ ID NO: 6602), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):SPIS-AA17-LFI (SEQ ID NO: 6602), GSAGPXX (SEQ ID NO: 6441):VPTKM (SEQ ID NO: 6424):SPIS-AA17-LFI (SEQ ID NO: 6602), AAPASXX (SEQ ID NO: 6436):VPTRL (SEQ ID NO: 6427):SPIS-AA17-LFI (SEQ ID NO: 6602), HVPKPXX (SEQ ID NO: 6442):VPTKL (SEQ ID NO: 6423):SPIS-AA17-LFI (SEQ ID NO: 6602), RVPSTXX (SEQ ID NO: 6449):VPTKT (SEQ ID NO: 6425):SPIS-AA17-LFI (SEQ ID NO: 6602), ASAAPXX (SEQ ID NO: 6437):VPTAL (SEQ ID NO: 6418):SPIS-AA17-LFI (SEQ ID NO: 6602), ASASPXX (SEQ ID NO: 6438):VPTDL (SEQ ID NO: 6419):SPIS-AA17-LFI (SEQ ID NO: 6602), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):SPIS-AA17-LFI (SEQ ID NO: 6602), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):SPIS-AA17-LFI (SEQ ID NO: 6602), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):SPIS-AA17-LFI (SEQ ID NO: 6602), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):SPIS-AA17-LFI (SEQ ID NO: 6602), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):SPIS-AA17-LFI (SEQ ID NO: 6602), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):SPIS-AA17-LFI (SEQ ID NO: 6602), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):SPIS-AA17-LFI (SEQ ID NO: 6602), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):SPIS-AA17-LFI (SEQ ID NO: 6602), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):SPIS-AA17-LFI (SEQ ID NO: 6602), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):SPIS-AA17-LFI (SEQ ID NO: 6602), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):SPIS-AA17-LFI (SEQ ID NO: 6602), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):SPIS-AA17-LFI (SEQ ID NO: 6602), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):SPIS-AA17-LFI (SEQ ID NO: 6602), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):SPIS-AA17-LFI (SEQ ID NO: 6602), KIPKAXX (SEQ ID NO: 6445):APVEL (SEQ ID NO: 6376):KPLS-AA17-LYV (SEQ ID NO: 6594), GIPEPXX (SEQ ID NO: 6440):APVKM (SEQ ID NO: 6378):KPLS-AA17-LYV (SEQ ID NO: 6594), SIPKAXX (SEQ ID NO: 6450):APVEL (SEQ ID NO: 6376):KPLS-AA17-LYV (SEQ ID NO: 6594), HVTKPTX (SEQ ID NO: 6443):APVKL (SEQ ID NO: 6377):KPLS-AA17-LYV (SEQ ID NO: 6594), YVPKPXX (SEQ ID NO: 6454):APVKL (SEQ ID NO: 6377):KPLS-AA17-LYV (SEQ ID NO: 6594), TVPKPXX (SEQ ID NO: 6453):APVQL (SEQ ID NO: 6380):KPLS-AA17-LYV (SEQ ID NO: 6594), AVPKAXX (SEQ ID NO: 6439):APVKL (SEQ ID NO: 6377):KPLS-AA17-LYV (SEQ ID NO: 6594), KVGKAXX (SEQ ID NO: 6446):APVKL (SEQ ID NO: 6377):KPLS-AA17-LYV (SEQ ID NO: 6594), KASKAXX (SEQ ID NO: 6444):APVKL (SEQ ID NO: 6377):KPLS-AA17-LYV (SEQ ID NO: 6594), GSAGPXX (SEQ ID NO: 6441):APVKM (SEQ ID NO: 6378):KPLS-AA17-LYV (SEQ ID NO: 6594), AAPASXX (SEQ ID NO: 6436):APVRL (SEQ ID NO: 6381):KPLS-AA17-LYV (SEQ ID NO: 6594), STPPTXX (SEQ ID NO: 6452):APVRL (SEQ ID NO: 6381):KPLS-AA17-LYV (SEQ ID NO: 6594), HVPKPXX (SEQ ID NO: 6442):APVKL (SEQ ID NO: 6377):KPLS-AA17-LYV (SEQ ID NO: 6594), ASAAPXX (SEQ ID NO: 6437):APVAL (SEQ ID NO: 6374):KPLS-AA17-LYV (SEQ ID NO: 6594), ASASPXX (SEQ ID NO: 6438):APVDL (SEQ ID NO: 6375):KPLS-AA17-LYV (SEQ ID NO: 6594), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):KPLS-AA17-LYV (SEQ ID NO: 6594), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):KPLS-AA17-LYV (SEQ ID NO: 6594), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):KPLS-AA17-LYV (SEQ ID NO: 6594), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):KPLS-AA17-LYV (SEQ ID NO: 6594), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):KPLS-AA17-LYV (SEQ ID NO: 6594), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):KPLS-AA17-LYV (SEQ ID NO: 6594), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):KPLS-AA17-LYV (SEQ ID NO: 6594), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):KPLS-AA17-LYV (SEQ ID NO: 6594), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):KPLS-AA17-LYV (SEQ ID NO: 6594), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):KPLS-AA17-LYV (SEQ ID NO: 6594), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):KPLS-AA17-LYV (SEQ ID NO: 6594), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):KPLS-AA17-LYV (SEQ ID NO: 6594), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):KPLS-AA17-LYV (SEQ ID NO: 6594), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):KPLS-AA17-LYV (SEQ ID NO: 6594), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):KPLS-AA17-LYV (SEQ ID NO: 6594), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):KPLS-AA17-LYV (SEQ ID NO: 6594), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):KPLS-AA17-LYV (SEQ ID NO: 6594), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):KPLS-AA17-LYV (SEQ ID NO: 6594), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):KPLS-AA17-LYV (SEQ ID NO: 6594), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):KPLS-AA17-LYV (SEQ ID NO: 6594), KIPKAXX (SEQ ID NO: 6445):VPQEL (SEQ ID NO: 6412):EPLP-AA17-VYY (SEQ ID NO: 6592), GIPEPXX (SEQ ID NO: 6440):VPQKM (SEQ ID NO: 6414):EPLP-AA17-VYY (SEQ ID NO: 6592), SIPKAXX (SEQ ID NO: 6450):VPQEL (SEQ ID NO: 6412):EPLP-AA17-VYY (SEQ ID NO: 6592), HVTKPTX (SEQ ID NO: 6443):VPQKL (SEQ ID NO: 6413):EPLP-AA17-VYY (SEQ ID NO: 6592), YVPKPXX (SEQ ID NO: 6454):VPQKL (SEQ ID NO: 6413):EPLP-AA17-VYY (SEQ ID NO: 6592), TVPKPXX (SEQ ID NO: 6453):VPQQL (SEQ ID NO: 6416):EPLP-AA17-VYY (SEQ ID NO: 6592), AVPKAXX (SEQ ID NO: 6439):VPQKL (SEQ ID NO: 6413):EPLP-AA17-VYY (SEQ ID NO: 6592), KVGKAXX (SEQ ID NO: 6446):VPQKL (SEQ ID NO: 6413):EPLP-AA17-VYY (SEQ ID NO: 6592), KASKAXX (SEQ ID NO: 6444):VPQKL (SEQ ID NO: 6413):EPLP-AA17-VYY (SEQ ID NO: 6592), GSAGPXX (SEQ ID NO: 6441):VPQKM (SEQ ID NO: 6414):EPLP-AA17-VYY (SEQ ID NO: 6592), AAPASXX (SEQ ID NO: 6436):VPQRL (SEQ ID NO: 6417):EPLP-AA17-VYY (SEQ ID NO: 6592), STPPTXX (SEQ ID NO: 6452):VPQRL (SEQ ID NO: 6417):EPLP-AA17-VYY (SEQ ID NO: 6592), HVPKPXX (SEQ ID NO: 6442):VPQKL (SEQ ID NO: 6413):EPLP-AA17-VYY (SEQ ID NO: 6592), RVPSTXX (SEQ ID NO: 6449):VPQKT (SEQ ID NO: 6415):EPLP-AA17-VYY (SEQ ID NO: 6592), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):EPLP-AA17-VYY (SEQ ID NO: 6592), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):EPLP-AA17-VYY (SEQ ID NO: 6592), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):EPLP-AA17-VYY (SEQ ID NO: 6592), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):EPLP-AA17-VYY (SEQ ID NO: 6592), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):EPLP-AA17-VYY (SEQ ID NO: 6592), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):EPLP-AA17-VYY (SEQ ID NO: 6592), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):EPLP-AA17-VYY (SEQ ID NO: 6592), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):EPLP-AA17-VYY (SEQ ID NO: 6592), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):EPLP-AA17-VYY (SEQ ID NO: 6592), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):EPLP-AA17-VYY (SEQ ID NO: 6592), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):EPLP-AA17-VYY (SEQ ID NO: 6592), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):EPLP-AA17-VYY (SEQ ID NO: 6592), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):EPLP-AA17-VYY (SEQ ID NO: 6592), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):EPLP-AA17-VYY (SEQ ID NO: 6592), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):EPLP-AA17-VYY (SEQ ID NO: 6592), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):EPLP-AA17-VYY (SEQ ID NO: 6592), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):EPLP-AA17-VYY (SEQ ID NO: 6592), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):EPLP-AA17-VYY (SEQ ID NO: 6592), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):EPLP-AA17-VYY (SEQ ID NO: 6592), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):EPLP-AA17-VYY (SEQ ID NO: 6592), KIPKAXX (SEQ ID NO: 6445):VSQEL (SEQ ID NO: 6430):EPLT-AA17-LYY (SEQ ID NO: 6593), GIPEPXX (SEQ ID NO: 6440):VSQKM (SEQ ID NO: 6432):EPLT-AA17-LYY (SEQ ID NO: 6593), SIPKAXX (SEQ ID NO: 6450):VSQEL (SEQ ID NO: 6430):EPLT-AA17-LYY (SEQ ID NO: 6593), HVTKPTX (SEQ ID NO: 6443):VSQKL (SEQ ID NO: 6431):EPLT-AA17-LYY (SEQ ID NO: 6593), YVPKPXX (SEQ ID NO: 6454):VSQKL (SEQ ID NO: 6431):EPLT-AA17-LYY (SEQ ID NO: 6593), TVPKPXX (SEQ ID NO: 6453):VSQQL (SEQ ID NO: 6434):EPLT-AA17-LYY (SEQ ID NO: 6593), AVPKAXX (SEQ ID NO: 6439):VSQKL (SEQ ID NO: 6431):EPLT-AA17-LYY (SEQ ID NO: 6593), KVGKAXX (SEQ ID NO: 6446):VSQKL (SEQ ID NO: 6431):EPLT-AA17-LYY (SEQ ID NO: 6593), KASKAXX (SEQ ID NO: 6444):VSQKL (SEQ ID NO: 6431):EPLT-AA17-LYY (SEQ ID NO: 6593), GSAGPXX (SEQ ID NO: 6441):VSQKM (SEQ ID NO: 6432):EPLT-AA17-LYY (SEQ ID NO: 6593), AAPASXX (SEQ ID NO: 6436):VSQRL (SEQ ID NO: 6435):EPLT-AA17-LYY (SEQ ID NO: 6593), STPPTXX (SEQ ID NO: 6452):VSQRL (SEQ ID NO: 6435):EPLT-AA17-LYY (SEQ ID NO: 6593), HVPKPXX (SEQ ID NO: 6442):VSQKL (SEQ ID NO: 6431):EPLT-AA17-LYY (SEQ ID NO: 6593), RVPSTXX (SEQ ID NO: 6449):VSQKT (SEQ ID NO: 6433):EPLT-AA17-LYY (SEQ ID NO: 6593), ASAAPXX (SEQ ID NO: 6437):VSQAL (SEQ ID NO: 6428):EPLT-AA17-LYY (SEQ ID NO: 6593), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):EPLT-AA17-LYY (SEQ ID NO: 6593), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):EPLT-AA17-LYY (SEQ ID NO: 6593), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):EPLT-AA17-LYY (SEQ ID NO: 6593), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):EPLT-AA17-LYY (SEQ ID NO: 6593), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):EPLT-AA17-LYY (SEQ ID NO: 6593), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):EPLT-AA17-LYY (SEQ ID NO: 6593), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):EPLT-AA17-LYY (SEQ ID NO: 6593), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):EPLT-AA17-LYY (SEQ ID NO: 6593), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):EPLT-AA17-LYY (SEQ ID NO: 6593), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):EPLT-AA17-LYY (SEQ ID NO: 6593), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):EPLT-AA17-LYY (SEQ ID NO: 6593), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):EPLT-AA17-LYY (SEQ ID NO: 6593), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):EPLT-AA17-LYY (SEQ ID NO: 6593), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):EPLT-AA17-LYY (SEQ ID NO: 6593), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):EPLT-AA17-LYY (SEQ ID NO: 6593), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):EPLT-AA17-LYY (SEQ ID NO: 6593), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):EPLT-AA17-LYY (SEQ ID NO: 6593), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):EPLT-AA17-LYY (SEQ ID NO: 6593), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):EPLT-AA17-LYY (SEQ ID NO: 6593), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):EPLT-AA17-LYY (SEQ ID NO: 6593), KIPKAXX (SEQ ID NO: 6445):VPQEL (SEQ ID NO: 6412):EPLT-AA17-LYY (SEQ ID NO: 6593), GIPEPXX (SEQ ID NO: 6440):VPQKM (SEQ ID NO: 6414):EPLT-AA17-LYY (SEQ ID NO: 6593), SIPKAXX (SEQ ID NO: 6450):VPQEL (SEQ ID NO: 6412):EPLT-AA17-LYY (SEQ ID NO: 6593), HVTKPTX (SEQ ID NO: 6443):VPQKL (SEQ ID NO: 6413):EPLT-AA17-LYY (SEQ ID NO: 6593), YVPKPXX (SEQ ID NO: 6454):VPQKL (SEQ ID NO: 6413):EPLT-AA17-LYY (SEQ ID NO: 6593), TVPKPXX (SEQ ID NO: 6453):VPQQL (SEQ ID NO: 6416):EPLT-AA17-LYY (SEQ ID NO: 6593), AVPKAXX (SEQ ID NO: 6439):VPQKL (SEQ ID NO: 6413):EPLT-AA17-LYY (SEQ ID NO: 6593), KVGKAXX (SEQ ID NO: 6446):VPQKL (SEQ ID NO: 6413):EPLT-AA17-LYY (SEQ ID NO: 6593), KASKAXX (SEQ ID NO: 6444):VPQKL (SEQ ID NO: 6413):EPLT-AA17-LYY (SEQ ID NO: 6593), GSAGPXX (SEQ ID NO: 6441):VPQKM (SEQ ID NO: 6414):EPLT-AA17-LYY (SEQ ID NO: 6593), AAPASXX (SEQ ID NO: 6436):VPQRL (SEQ ID NO: 6417):EPLT-AA17-LYY (SEQ ID NO: 6593), STPPTXX (SEQ ID NO: 6452):VPQRL (SEQ ID NO: 6417):EPLT-AA17-LYY (SEQ ID NO: 6593), HVPKPXX (SEQ ID NO: 6442):VPQKL (SEQ ID NO: 6413):EPLT-AA17-LYY (SEQ ID NO: 6593), RVPSTXX (SEQ ID NO: 6449):VPQKT (SEQ ID NO: 6415):EPLT-AA17-LYY (SEQ ID NO: 6593), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):EPLT-AA17-LYY (SEQ ID NO: 6593), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):SNIT-AA17-QIM (SEQ ID NO: 6600), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):SNIT-AA17-QIM (SEQ ID NO: 6600), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):SNIT-AA17-QIM (SEQ ID NO: 6600), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):SNIT-AA17-QIM (SEQ ID NO: 6600), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):SNIT-AA17-QIM (SEQ ID NO: 6600), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):SNIT-AA17-QIM (SEQ ID NO: 6600), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):SNIT-AA17-QIM (SEQ ID NO: 6600), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):SNIT-AA17-QIM (SEQ ID NO: 6600), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):SNIT-AA17-QIM (SEQ ID NO: 6600), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):SNIT-AA17-QIM (SEQ ID NO: 6600), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):SNIT-AA17-QIM (SEQ ID NO: 6600), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):SNIT-AA17-QIM (SEQ ID NO: 6600), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):SNIT-AA17-QIM (SEQ ID NO: 6600), SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):SNIT-AA17-QIM (SEQ ID NO: 6600), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):SNIT-AA17-QIM (SEQ ID NO: 6600), RNVQXRP (SEQ ID NO: 6448):SRVQL (SEQ ID NO: 6383):RSVK-AA17-AKV (SEQ ID NO: 6597), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):RSVK-AA17-AKV (SEQ ID NO: 6597), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):RSVK-AA17-AKV (SEQ ID NO: 6597), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):RSVK-AA17-AKV (SEQ ID NO: 6597), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):RSVK-AA17-AKV (SEQ ID NO: 6597), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):RSVK-AA17-AKV (SEQ ID NO: 6597), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):RSVK-AA17-AKV (SEQ ID NO: 6597), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):RSVK-AA17-AKV (SEQ ID NO: 6597), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):RSVK-AA17-AKV (SEQ ID NO: 6597), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):RSVK-AA17-AKV (SEQ ID NO: 6597), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):RSVK-AA17-AKV (SEQ ID NO: 6597), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):RSVK-AA17-AKV (SEQ ID NO: 6597), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):RSVK-AA17-AKV (SEQ ID NO: 6597), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):RSVK-AA17-AKV (SEQ ID NO: 6597), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):RSVK-AA17-AKV (SEQ ID NO: 6597), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):RSVK-AA17-AKV (SEQ ID NO: 6597), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):RSVK-AA17-AKV (SEQ ID NO: 6597), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):RSVK-AA17-AKV (SEQ ID NO: 6597), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):RSVK-AA17-AKV (SEQ ID NO: 6597), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):RSVK-AA17-AKV (SEQ ID NO: 6597), RNVQXRP (SEQ ID NO: 6448):TQVQL (SEQ ID NO: 6393):RSVK-AA17-AKV (SEQ ID NO: 6597), SSVKXQP (SEQ ID NO: 6451):TQVHH (SEQ ID NO: 6392):RPVQ-AA17-RKI (SEQ ID NO: 6596), KIPKAXX (SEQ ID NO: 6445):VPTEL (SEQ ID NO: 6421):RPVQ-AA17-RKI (SEQ ID NO: 6596), GIPEPXX (SEQ ID NO: 6440):VPEKM (SEQ ID NO: 6406):RPVQ-AA17-RKI (SEQ ID NO: 6596), SIPKAXX (SEQ ID NO: 6450):VPTEL (SEQ ID NO: 6421):RPVQ-AA17-RKI (SEQ ID NO: 6596), HVTKPTX (SEQ ID NO: 6443):APTKL (SEQ ID NO: 6369):RPVQ-AA17-RKI (SEQ ID NO: 6596), YVPKPXX (SEQ ID NO: 6454):APTKL (SEQ ID NO: 6369):RPVQ-AA17-RKI (SEQ ID NO: 6596), TVPKPXX (SEQ ID NO: 6453):APTQL (SEQ ID NO: 6372):RPVQ-AA17-RKI (SEQ ID NO: 6596), AVPKAXX (SEQ ID NO: 6439):APTKL (SEQ ID NO: 6369):RPVQ-AA17-RKI (SEQ ID NO: 6596), KVGKAXX (SEQ ID NO: 6446):VPTKL (SEQ ID NO: 6423):RPVQ-AA17-RKI (SEQ ID NO: 6596), KASKAXX (SEQ ID NO: 6444):VPTKL (SEQ ID NO: 6423):RPVQ-AA17-RKI (SEQ ID NO: 6596), GSAGPXX (SEQ ID NO: 6441):TPTKM (SEQ ID NO: 6388):RPVQ-AA17-RKI (SEQ ID NO: 6596), AAPASXX (SEQ ID NO: 6436):VPARL (SEQ ID NO: 6401):RPVQ-AA17-RKI (SEQ ID NO: 6596), STPPTXX (SEQ ID NO: 6452):VPTRL (SEQ ID NO: 6427):RPVQ-AA17-RKI (SEQ ID NO: 6596), HVPKPXX (SEQ ID NO: 6442):APTKL (SEQ ID NO: 6369):RPVQ-AA17-RKI (SEQ ID NO: 6596), RVPSTXX (SEQ ID NO: 6449):APVKT (SEQ ID NO: 6379):RPVQ-AA17-RKI (SEQ ID NO: 6596), ASAAPXX (SEQ ID NO: 6437):VPQAL (SEQ ID NO: 6410):RPVQ-AA17-RKI (SEQ ID NO: 6596), ASASPXX (SEQ ID NO: 6438):VSODL (SEQ ID NO: 6429):RPVQ-AA17-RKI (SEQ ID NO: 6596), ASASPXX (SEQ ID NO: 6438):VPQDL (SEQ ID NO: 6411):RPVQ-AA17-RKI (SEQ ID NO: 6596), NDEGLEX (SEQ ID NO: 6447):VPTEE (SEQ ID NO: 6420):RPVQ-AA17-RKI (SEQ ID NO: 6596), NDEGLEX (SEQ ID NO: 6447):VPTGQ (SEQ ID NO: 6422):RPVQ-AA17-RKI (SEQ ID NO: 6596) and SSVKXQP (SEQ ID NO: 6451):SRVHH (SEQ ID NO: 6382):RPVQ-AA17-RKI (SEQ ID NO: 6596); and wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T).
In certain embodiments, PEP11 is a peptide with 3 amino acids of general formula AA18-AA19-AA20; wherein AA18 is selected from the group consisting of L, V, Q, A and R; wherein AA19 is selected from the group consisting of F, W, H, Y, I and K; wherein AA20 is selected from the group consisting of L, F, Y, K, I, V and M. In one particular example, PEP11 is selected from the group consisting of LYL, LFF, LYF, LYY, LYK, LYI, LFI, LYV, VYY, QIM, AKV and RKI.
In certain embodiments, PEP1 is selected from the group consisting of SAIS (SEQ ID NO: 6360), SSLS (SEQ ID NO: 6365), NAIS (SEQ ID NO: 6357), SATS (SEQ ID NO: 6361), SPIS (SEQ ID NO: 6364), EPIS (SEQ ID NO: 6353), SPIN (SEQ ID NO: 6363), KPLS (SEQ ID NO: 6356), EPLP (SEQ ID NO: 6354), EPLT (SEQ ID NO: 6355), SNIT (SEQ ID NO: 6362), RSVK (SEQ ID NO: 6359) and RPVQ (SEQ ID NO: 6358); PEP11 is selected from the group consisting of LYL, LFF, LYF, LYY, LYK, LYI, LFI, LYV, VYY, QIM, AKV and RKI; and the pair PEP1:PEP11 is selected from the group consisting of SAIS (SEQ ID NO: 6360):LYL, SSLS (SEQ ID NO: 6365):LFF, NAIS (SEQ ID NO: 6357):LYF, SATS (SEQ ID NO: 6361):LYY, SPIS (SEQ ID NO: 6364):LYK, SPIS (SEQ ID NO: 6364):LYI, SPIS (SEQ ID NO: 6364):LFI, EPIS (SEQ ID NO: 6353):LYL, SPIN (SEQ ID NO: 6363):LYF, KPLS (SEQ ID NO: 6356):LYV, EPLP (SEQ ID NO: 6354):VYY, EPLT (SEQ ID NO: 6355):LYY, SNIT (SEQ ID NO: 6362):QIM, RSVK (SEQ ID NO: 6359):AKV and RPVQ (SEQ ID NO: 6358):RKI.
In one aspect, the present disclosure provides a GFR-binding compound, wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, having the following general formula (III) (hereinafter may also be referred to as compound (III) or peptide (III)):
AA
1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-AA9-AA10-AA11-AA12-AA13-AA14-AA15-AA16-AA17-AA18-AA19-AA20 (III)
wherein AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606) is PEP7 as defined herein; wherein AA13-AA14-AA15-AA16-AA17-AA18-AA19-AA20 is PEP12 as defined herein; wherein AA8-AA9-AA10 is PEP3 as defined herein; wherein AA11 and AA12 are as defined herein; wherein AA1 may be an N-terminal amino acid or a C-terminal amino acid; wherein AA20 may be an N-terminal amino acid or a C-terminal amino acid; and wherein the RMSD is 2.45 Å or less.
In one example, said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
In one particular example, said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
In one most particular example, said GFR-binding compound is a synthetic peptide.
In one example, length of said GFR-binding compound, in solution, such as in a physiologically acceptable solvent such as water or PBS, is comprised between about 6 and about 20 nm, preferably between about 6 and about 16 nm, as determined using the standard «3D» procedure described above.
In one particular example, said GFR-binding compounds may be any one or a plurality of of peptides of SEQ ID NO: 1 to 1085 and 1143 to 6352.
Bone
Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the bone cell lineage, regenerating bone tissues, repairing bone and protecting from osteoporosis.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the bone cell lineage, regenerating bone tissues, repairing bone and protecting from osteoporosis, PEP1 is selected from the group consisting of SAIS (SEQ ID NO: 6360), NAIS (SEQ ID NO: 6357), SATS (SEQ ID NO: 6361) and SPIS (SEQ ID NO: 6364).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the bone cell lineage, regenerating bone tissues, repairing bone and protecting from osteoporosis, PEP3 is selected from the group consisting of VPT, APT, VPQ, VSO and TQV.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the bone cell lineage, regenerating bone tissues, repairing bone and protecting from osteoporosis, PEP5 is a peptide of general formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, APT, VPQ, VSO and TQV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular E, K, Q, A and D; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular L. In one particular example, PEP5 is selected from the group consisting of VPTEL (SEQ ID NO: 6421), APTKL (SEQ ID NO: 6369), APTQL (SEQ ID NO: 6372), VPTKL (SEQ ID NO: 6423), VPQAL (SEQ ID NO: 6410), VSODL (SEQ ID NO: 6429), VPQDL (SEQ ID NO: 6411) and TQVQL (SEQ ID NO: 6393).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the bone cell lineage, regenerating bone tissues, repairing bone and protecting from osteoporosis, PEP7 is an amino acid or a peptide with between two and seven amino acids of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606); wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably C, S, T or R; wherein AA7 is absent or is selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of C, S and P; and wherein at least one of AA1, AA2, AA3, AA4, AA5, AA6 or AA7 is not absent. In one particular example, PEP7 is selected from the group consisting of KIPKAXX (SEQ ID NO: 6445), SIPKAXX (SEQ ID NO: 6450), HVTKPTX (SEQ ID NO: 6443), YVPKPXX (SEQ ID NO: 6454), TVPKPXX (SEQ ID NO: 6453), AVPKAXX (SEQ ID NO: 6439), KVGKAXX (SEQ ID NO: 6446), ASAAPXX (SEQ ID NO: 6437), ASASPXX (SEQ ID NO: 6438) and RNVQXRP (SEQ ID NO: 6448).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the bone cell lineage, regenerating bone tissues, repairing bone and protecting from osteoporosis, PEP9 is a peptide of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7-PEP5; wherein PEP5 is a peptide of formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, APT, VPQ, VSO and TQV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular E, K, Q, A and D; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular L; wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably C, S, T or R; wherein AA7 is selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of C, S and P. In one particular example, PEP9 is selected from the group consisting of KIPKAXXVPTEL (SEQ ID NO: 6535), SIPKAXXVPTEL (SEQ ID NO: 6563), HVTKPTXAPTKL (SEQ ID NO: 6511), YVPKPXXAPTKL (SEQ ID NO: 6583), TVPKPXXAPTQL (SEQ ID NO: 6575), AVPKAXXAPTKL (SEQ ID NO: 6479), KVGKAXXVPTKL (SEQ ID NO: 6543), ASAAPXXVPQAL (SEQ ID NO: 6468), ASASPXXVSQDL (SEQ ID NO: 6478), ASASPXXVPQDL (SEQ ID NO: 6476) and RNVQXRPTQVQL (SEQ ID NO: 6548).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the bone cell lineage, regenerating bone tissues, repairing bone and protecting from osteoporosis, PEP12 is a peptide of general formula PEP1-AA17-PEP11; wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T); wherein PEP1 is selected from the group consisting of SAIS (SEQ ID NO: 6360), NAIS (SEQ ID NO: 6357), SATS (SEQ ID NO: 6361) and SPIS (SEQ ID NO: 6364).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the bone cell lineage, regenerating bone tissues, repairing bone and protecting from osteoporosis, PEP11 is a peptide with 3 amino acids of general formula AA18-AA19-AA20; wherein AA18 is selected from the group consisting of L, V, Q, A and R, in particular is L; wherein AA19 is selected from the group consisting of F, W, H and Y (in particular is an aromatic, polar amino acid such as Y); wherein AA2 is selected from the group consisting of L, F, Y, K, I, V and M, in particular is selected from the group consisting of L, F, Y, and K. In one particular example, PEP11 is selected from the group consisting of LYL, LYF, LYY and LYK.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the bone cell lineage, regenerating bone tissues, repairing bone and protecting from osteoporosis, PEP1 is selected from the group consisting of SAIS (SEQ ID NO: 6360), NAIS (SEQ ID NO: 6357), SATS (SEQ ID NO: 6361) and SPIS (SEQ ID NO: 6364); PEP11 is selected from the group consisting of LYL, LFF, LYF, LYY, LYK, LYI, LFI, LYV, VYY, QIM, AKV and RKI; and the pair PEP1:PEP11 is selected from the group consisting of SAIS (SEQ ID NO: 6360):LYL, NAIS (SEQ ID NO: 6357):LYF, SATS (SEQ ID NO: 6361):LYY and SPIS (SEQ ID NO: 6364):LYK.
The definitions of “PEP” pairs and triplets e.g. PEP3:PEP1, PEP5:PEP12, or PEP7:PEP5:PEP1, most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the bone cell lineage, regenerating bone tissues, repairing bone and protecting from osteoporosis, are as already defined herein to the extent that PEP1, PEP3, PEP5, PEP7, PEP9, PEP11 and PEP12 are particularly useful for these applications as defined in the present bone section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the bone cell lineage, regenerating bone tissues, repairing bone and protecting from osteoporosis, said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the bone cell lineage, regenerating bone tissues, repairing bone and protecting from osteoporosis, said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
Cartilage
Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the cartilage cell lineage, regenerating cartilage tissues, repairing cartilage and protecting from, for instance, osteoarthritis, costochondritis, Herniation, achondroplasia or relapsing polychondritis.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the cartilage cell lineage, regenerating cartilage tissues, repairing cartilage and protecting from, for instance, osteoarthritis, costochondritis, Herniation, achondroplasia or relapsing polychondritis, PEP1 is selected from the group consisting of SAIS (SEQ ID NO: 6360), NAIS (SEQ ID NO: 6357), SPIS (SEQ ID NO: 6364), EPLP (SEQ ID NO: 6354) and EPLT (SEQ ID NO: 6355).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the cartilage cell lineage, regenerating cartilage tissues, repairing cartilage and protecting from, for instance, osteoarthritis, costochondritis, Herniation, achondroplasia or relapsing polychondritis, PEP3 is selected from the group consisting of VPT, APT, VPQ and VSO.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the cartilage cell lineage, regenerating cartilage tissues, repairing cartilage and protecting from, for instance, osteoarthritis, costochondritis, Herniation, achondroplasia or relapsing polychondritis, PEP5 is a peptide of general formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, APT, VPQ and VSQ; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular E, K, Q, R, A and D; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is L In one particular example, PEP5 is selected from the group consisting of VPTEL (SEQ ID NO: 6421), APTKL (SEQ ID NO: 6369), APTQL (SEQ ID NO: 6372), VPTRL (SEQ ID NO: 6427), VPQAL (SEQ ID NO: 6410), VSODL (SEQ ID NO: 6429) and VPQDL (SEQ ID NO: 6411).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the cartilage cell lineage, regenerating cartilage tissues, repairing cartilage and protecting from, for instance, osteoarthritis, costochondritis, Herniation, achondroplasia or relapsing polychondritis, PEP7 is an amino acid or a peptide with between two and seven amino acids of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606); wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is S, C or T; wherein AA7 is absent or is selected from the group consisting of S, T, C, E, Q, P and R, preferably is S or C; and wherein at least one of AA, AA2, AA3, AA4, AA5, AA6 or AA7 is not absent. In one particular example, PEP7 is selected from the group consisting of KIPKAXX (SEQ ID NO: 6445), SIPKAXX (SEQ ID NO: 6450), HVTKPTX (SEQ ID NO: 6443), YVPKPXX (SEQ ID NO: 6454), TVPKPXX (SEQ ID NO: 6453), STPPTXX (SEQ ID NO: 6452), ASAAPXX (SEQ ID NO: 6437) and ASASPXX (SEQ ID NO: 6438).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the cartilage cell lineage, regenerating cartilage tissues, repairing cartilage and protecting from, for instance, osteoarthritis, costochondritis, Herniation, achondroplasia or relapsing polychondritis, PEP9 is a peptide of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7-PEP5; wherein PEP5 is a peptide of formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, APT, VPQ and VSO; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular E, K, Q, R, A and D; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is L; wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is S, C or T; wherein AA7 is selected from the group consisting of S, T, C, E, Q, P and R, preferably is S or C. In one particular example, PEP9 is selected from the group consisting of KIPKAXXVPTEL (SEQ ID NO: 6535), SIPKAXXVPTEL (SEQ ID NO: 6563), HVTKPTXAPTKL (SEQ ID NO: 6511), YVPKPXXAPTKL (SEQ ID NO: 6583), TVPKPXXAPTQL (SEQ ID NO: 6575), STPPTXXVPTRL (SEQ ID NO: 6573), ASAAPXXVPQAL (SEQ ID NO: 6468), ASASPXXVSQDL (SEQ ID NO: 6478) and ASASPXXVPQDL (SEQ ID NO: 6476).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the cartilage cell lineage, regenerating cartilage tissues, repairing cartilage and protecting from, for instance, osteoarthritis, costochondritis, Herniation, achondroplasia or relapsing polychondritis, PEP12 is a peptide of general formula PEP1-AA17-PEP11; wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T); wherein PEP1 is selected from the group consisting of SAIS (SEQ ID NO: 6360), NAIS (SEQ ID NO: 6357), SPIS (SEQ ID NO: 6364), EPLP (SEQ ID NO: 6354) and EPLT (SEQ ID NO: 6355).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the cartilage cell lineage, regenerating cartilage tissues, repairing cartilage and protecting from, for instance, osteoarthritis, costochondritis, Herniation, achondroplasia or relapsing polychondritis, PEP11 is a peptide with 3 amino acids of general formula AA18-AA19-AA20; wherein AA18 is selected from the group consisting of L, V, Q, A and R, in particular is L or V; wherein AA19 is selected from the group consisting of F, W, H and Y, in particular is Y or F; wherein AA2 is selected from the group consisting of L, F, Y and I. In one particular example, PEP11 is selected from the group consisting of LYL, LYF, LFI, VYY and LYY.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the cartilage cell lineage, regenerating cartilage tissues, repairing cartilage and protecting from, for instance, osteoarthritis, costochondritis, Herniation, achondroplasia or relapsing polychondritis, PEP1 is selected from the group consisting of SAIS (SEQ ID NO: 6360), NAIS (SEQ ID NO: 6357), SPIS (SEQ ID NO: 6364), EPLP (SEQ ID NO: 6354) and EPLT (SEQ ID NO: 6355); PEP11 is selected from the group consisting of LYL, LYF, LFI, VYY and LYY; and the pair PEP1:PEP11 is selected from the group consisting of SAIS (SEQ ID NO: 6360):LYL, NAIS (SEQ ID NO: 6357):LYF, SPIS (SEQ ID NO: 6364):LFI, EPLP (SEQ ID NO: 6354):VYY and EPLT (SEQ ID NO: 6355):LYY.
The definitions of “PEP” pairs and triplets e.g. PEP3:PEP1, PEP5:PEP12, or PEP7:PEP5:PEP1, most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the cartilage cell lineage, regenerating cartilage tissues, repairing cartilage and protecting from, for instance, osteoarthritis, costochondritis, Herniation, achondroplasia or relapsing polychondritis, are as already defined herein to the extent that PEP1, PEP3, PEP5, PEP7, PEP9, PEP11 and PEP12 are particularly useful for these applications as defined in the present cartilage section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the cartilage cell lineage, regenerating cartilage tissues, repairing cartilage and protecting from, for instance, osteoarthritis, costochondritis, Herniation, achondroplasia or relapsing polychondritis, said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the cartilage cell lineage, regenerating cartilage tissues, repairing cartilage and protecting from, for instance, osteoarthritis, costochondritis, Herniation, achondroplasia or relapsing polychondritis, said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
Vascular Tissues
Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the vascular cell lineage, enhancing of endothelization, vascularization/angiogenesis, protecting a subject from heart tissue degeneration-related diseases, disorders, conditions or pathologies.
In other embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the vascular cell lineage, enhancing of endothelization, vascularization/angiogenesis, protecting a subject from heart tissue degeneration-related diseases, disorders, conditions or pathologies, PEP1 is selected from the group consisting of SNIT (SEQ ID NO: 6362), RPVQ (SEQ ID NO: 6358) and RSVK (SEQ ID NO: 6359).
In other embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the vascular cell lineage, enhancing of endothelization, vascularization/angiogenesis, protecting a subject from heart tissue degeneration-related diseases, disorders, conditions or pathologies, PEP3 is selected from the group consisting of VPT, SRV and TQV.
In other embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the vascular cell lineage, enhancing of endothelization, vascularization/angiogenesis, protecting a subject from heart tissue degeneration-related diseases, disorders, conditions or pathologies, PEP5 is a peptide of general formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, SRV and TQV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is E, G, H and Q; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is selected from the group consisting of E, Q, H and L. In one particular example, PEP5 is selected from the group consisting of VPTGQ (SEQ ID NO: 6422), VPTEE (SEQ ID NO: 6420), SRVHH (SEQ ID NO: 6382) and TQVQL (SEQ ID NO: 6393).
In other embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the vascular cell lineage, enhancing of endothelization, vascularization/angiogenesis, protecting a subject from heart tissue degeneration-related diseases, disorders, conditions or pathologies, PEP7 is an amino acid or a peptide with between two and seven amino acids of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606); wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of E, Q and R; wherein AA7 is absent or is selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of S, C and P; and wherein at least one of AA1, AA2, AA3, AA4, AA5, AA or AA7 is not absent. In one particular example, PEP7 is selected from the group consisting of NDEGLEX (SEQ ID NO: 6447), SSVKXQP (SEQ ID NO: 6451) and RNVQXRP (SEQ ID NO: 6448).
In other embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the vascular cell lineage, enhancing of endothelization, vascularization/angiogenesis, protecting a subject from heart tissue degeneration-related diseases, disorders, conditions or pathologies, PEP9 is a peptide of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7-PEP5; wherein PEP5 is a peptide of formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, SRV and TQV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is E, G, H and Q; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is selected from the group consisting of E, Q, H and L; wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of E, Q and R; wherein AA7 is selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of S, C and P. In one particular example, PEP9 is selected from the group consisting of NDEGLEXVPTEE (SEQ ID NO: 6545), NDEGLEXVPTGQ (SEQ ID NO: 6546), SSVKXQPSRVHH (SEQ ID NO: 6565) and RNVQXRPTQVQL (SEQ ID NO: 6548).
In other embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the vascular cell lineage, enhancing of endothelization, vascularization/angiogenesis, protecting a subject from heart tissue degeneration-related diseases, disorders, conditions or pathologies, PEP12 is a peptide of general formula PEP1-AA17-PEP11; wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T); wherein PEP1 is selected from the group consisting of SNIT (SEQ ID NO: 6362), RPVQ (SEQ ID NO: 6358) and RSVK (SEQ ID NO: 6359).
In other embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the vascular cell lineage, enhancing of endothelization, vascularization/angiogenesis, protecting a subject from heart tissue degeneration-related diseases, disorders, conditions or pathologies, PEP11 is a peptide with 3 amino acids of general formula AA18-AA19-AA20; wherein AA18 is selected from the group consisting of L, V, Q, A and R, in particular is selected from the group consisting of Q, A and R; wherein AA19 is selected from the group consisting of F, W, H, Y, I and K, in particular is I or K; wherein AA20 is selected from the group consisting of L, F, Y, K, I, V and M, in particular is selected from the group consisting of M, V and I. In one particular example, PEP11 is selected from the group consisting of QIM, AKV and RKI.
In other embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the vascular cell lineage, enhancing of endothelization, vascularization/angiogenesis, protecting a subject from heart tissue degeneration-related diseases, disorders, conditions or pathologies, PEP1 is selected from the group consisting of SNIT (SEQ ID NO: 6362), RPVQ (SEQ ID NO: 6358) and RSVK (SEQ ID NO: 6359); PEP11 is selected from the group consisting of QIM, AKV and RKI; and the pair PEP1:PEP11 is selected from the group consisting of SNIT (SEQ ID NO: 6362):QIM, RSVK (SEQ ID NO: 6359):KEVQV and RPVQ (SEQ ID NO: 6358):KKATV.
The definitions of “PEP” pairs and triplets e.g. PEP3:PEP1, PEP5:PEP12, or PEP7:PEP5:PEP1, most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the vascular cell lineage, enhancing of endothelization, vascularization/angiogenesis, protecting a subject from heart tissue degeneration-related diseases, disorders, conditions or pathologies, are as already defined herein to the extent that PEP1, PEP3, PEP5, PEP7, PEP9, PEP11 and PEP12 are particularly useful for these applications as defined in the present vascular tissue section.
In other embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the vascular cell lineage, enhancing of endothelization, vascularization/angiogenesis, protecting a subject from heart tissue degeneration-related diseases, disorders, conditions or pathologies, said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
In other embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the vascular cell lineage, enhancing of endothelization, vascularization/angiogenesis, protecting a subject from heart tissue degeneration-related diseases, disorders, conditions or pathologies, said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
Neuroregeneration
Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the neuronal cell lineage, promoting neuron-regeneration, and protecting from neuron degeneration-related conditions and diseases.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the neuronal cell lineage, promoting neuron-regeneration, and protecting from neuron degeneration-related conditions and diseases, PEP1 is selected from the group consisting of NAIS (SEQ ID NO: 6357), SPIS (SEQ ID NO: 6364) and EPIS (SEQ ID NO: 6353).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the neuronal cell lineage, promoting neuron-regeneration, and protecting from neuron degeneration-related conditions and diseases, PEP3 is selected from the group consisting of VPT, APT, VPA, VPQ and VSQ.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the neuronal cell lineage, promoting neuron-regeneration, and protecting from neuron degeneration-related conditions and diseases, PEP5 is a peptide of general formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, APT, VPA, VPQ and VSQ; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular E, K, Q, R, A and D; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular L. In one particular example, PEP5 is selected from the group consisting of VPTEL (SEQ ID NO: 6421), APTKL (SEQ ID NO: 6369), APTQL (SEQ ID NO: 6372), VPTKL (SEQ ID NO: 6423), VPARL (SEQ ID NO: 6401), VPQAL (SEQ ID NO: 6410), VSQDL (SEQ ID NO: 6429) and VPQDL (SEQ ID NO: 6411).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the neuronal cell lineage, promoting neuron-regeneration, and protecting from neuron degeneration-related conditions and diseases, PEP7 is an amino acid or a peptide with between two and seven amino acids of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606); wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA1 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably S or C; wherein AA7 is absent or is selected from the group consisting of S, T, C, E, Q, P and R, preferably is S or C; and wherein at least one of AA1, AA2, AA3, AA4, AA5, AA6 or AA7 is not absent. In one particular example, PEP7 is selected from the group consisting of KIPKAXX (SEQ ID NO: 6445), SIPKAXX (SEQ ID NO: 6450), HVTKPTX (SEQ ID NO: 6443), YVPKPXX (SEQ ID NO: 6454), TVPKPXX (SEQ ID NO: 6453), AVPKAXX (SEQ ID NO: 6439), KVGKAXX (SEQ ID NO: 6446), ASAAPXX (SEQ ID NO: 6437), ASASPXX (SEQ ID NO: 6438) and RNVQXRP (SEQ ID NO: 6448).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the neuronal cell lineage, promoting neuron-regeneration, and protecting from neuron degeneration-related conditions and diseases, PEP9 is a peptide of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7-PEP5; wherein PEP5 is a peptide of formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, APT, VPA, VPQ and VSO; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular E, K, Q, R, A and D; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular L; wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably S or C; wherein AA7 is selected from the group consisting of S, T, C, E, Q, P and R, preferably is S or C. In one particular example, PEP9 is selected from the group consisting of KIPKAXXVPTEL (SEQ ID NO: 6535), SIPKAXXVPTEL (SEQ ID NO: 6563), HVTKPTXAPTKL (SEQ ID NO: 6511), YVPKPXXAPTKL (SEQ ID NO: 6583), TVPKPXXAPTQL (SEQ ID NO: 6575), AVPKAXXAPTKL (SEQ ID NO: 6479), KVGKAXXVPTKL (SEQ ID NO: 6543), ASAAPXXVPQAL (SEQ ID NO: 6468), ASASPXXVSQDL (SEQ ID NO: 6478), ASASPXXVPQDL (SEQ ID NO: 6476) and RNVQXRPTQVQL (SEQ ID NO: 6548).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the neuronal cell lineage, promoting neuron-regeneration, and protecting from neuron degeneration-related conditions and diseases, PEP12 is a peptide of general formula PEP1-AA17-PEP11; wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T); wherein PEP1 is selected from the group consisting of NAIS (SEQ ID NO: 6357), SPIS (SEQ ID NO: 6364) and EPIS (SEQ ID NO: 6353).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the neuronal cell lineage, promoting neuron-regeneration, and protecting from neuron degeneration-related conditions and diseases, PEP11 is a peptide with 3 amino acids of general formula AA18-AA19-AA20; wherein AA18 is selected from the group consisting of L, V, Q, A and R, in particular is L; wherein AA19 is selected from the group consisting of F, W, H and Y (in particular is an aromatic, polar amino acid such as Y); wherein AA2 is selected from the group consisting of L, F, Y, K, I, V and M, in particular is selected from the group consisting of L, F, I, and K. In one particular example, PEP11 is selected from the group consisting of LYL, LYF, LYI and LYK.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the neuronal cell lineage, promoting neuron-regeneration, and protecting from neuron degeneration-related conditions and diseases, PEP1 is selected from the group consisting of NAIS (SEQ ID NO: 6357), SPIS (SEQ ID NO: 6364) and EPIS (SEQ ID NO: 6353); PEP11 is selected from the group consisting of LYF, LYK, LYL and LYI; and the pair PEP1:PEP11 is selected from the group consisting of NAIS (SEQ ID NO: 6357):LYF, SPIS (SEQ ID NO: 6364):LYK, EPIS (SEQ ID NO: 6353):LYL and SPIS (SEQ ID NO: 6364):LYI.
The definitions of “PEP” pairs and triplets e.g. PEP3:PEP1, PEP5:PEP12, or PEP7:PEP5:PEP1, most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the neuronal cell lineage, promoting neuron-regeneration, and protecting from neuron degeneration-related conditions and diseases, are as already defined herein to the extent that PEP1, PEP3, PEP5, PEP7, PEP9, PEP11 and PEP12 are particularly useful for these applications as defined in the present neuroregeneration section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the neuronal cell lineage, promoting neuron-regeneration, and protecting from neuron degeneration-related conditions and diseases, said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the neuronal cell lineage, promoting neuron-regeneration, and protecting from neuron degeneration-related conditions and diseases, said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
Eye Retina
Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the retinal cell lineage, promoting eye retina cell regeneration and protecting from eye retina cell degeneration-related conditions or diseases such as macular degeneration.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the retinal cell lineage, promoting eye retina cell regeneration and protecting from eye retina cell degeneration-related conditions or diseases, PEP1 is SPIN (SEQ ID NO: 6363).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the retinal cell lineage, promoting eye retina cell regeneration and protecting from eye retina cell degeneration-related conditions or diseases, PEP3 is selected from the group consisting of VPT, APT, TPT, VPA and APV.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the retinal cell lineage, promoting eye retina cell regeneration and protecting from eye retina cell degeneration-related conditions or diseases, PEP5 is a peptide of general formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, APT, TPT, VPA and APV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is E, K, Q and R; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is L, M or T. In one particular example, PEP5 is selected from the group consisting of VPTEL (SEQ ID NO: 6421), APTKL (SEQ ID NO: 6369), APTQL (SEQ ID NO: 6372), VPTKL (SEQ ID NO: 6423), TPTKM (SEQ ID NO: 6388), VPARL (SEQ ID NO: 6401), VPTRL (SEQ ID NO: 6427) and APVKT (SEQ ID NO: 6379).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the retinal cell lineage, promoting eye retina cell regeneration and protecting from eye retina cell degeneration-related conditions or diseases, PEP7 is an amino acid or a peptide with between two and seven amino acids of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606); wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA1 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is S or C; wherein AA7 is absent or is selected from the group consisting of S, T, C, E, Q, P and R, preferably is S or C; and wherein at least one of AA1, AA2, AA3, AA4, AA5, AA6 or AA7 is not absent. In one particular example, PEP7 is selected from the group consisting of KIPKAXX (SEQ ID NO: 6445), SIPKAXX (SEQ ID NO: 6450), HVTKPTX (SEQ ID NO: 6443), YVPKPXX (SEQ ID NO: 6454), TVPKPXX (SEQ ID NO: 6453), AVPKAXX (SEQ ID NO: 6439), KVGKAXX (SEQ ID NO: 6446), KASKAXX (SEQ ID NO: 6444), GSAGPXX (SEQ ID NO: 6441), AAPAXXS, STPPTXX (SEQ ID NO: 6452), HVPKPXX (SEQ ID NO: 6442) and RVPSTXX (SEQ ID NO: 6449).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the retinal cell lineage, promoting eye retina cell regeneration and protecting from eye retina cell degeneration-related conditions or diseases, PEP9 is a peptide of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7-PEP5; wherein PEP5 is a peptide of formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, APT, TPT, VPA and APV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is E, K, Q and R; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is L, M or T; wherein AA, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is S or C; wherein AA7 is selected from the group consisting of S, T, C, E, Q, P and R, preferably is S or C. In one particular example, PEP9 is selected from the group consisting of KIPKAXXVPTEL (SEQ ID NO: 6535), SIPKAXXVPTEL (SEQ ID NO: 6563), HVTKPTXAPTKL (SEQ ID NO: 6511), YVPKPXXAPTKL (SEQ ID NO: 6583), TVPKPXXAPTQL (SEQ ID NO: 6575), AVPKAXXAPTKL (SEQ ID NO: 6479), KVGKAXXVPTKL (SEQ ID NO: 6543), KASKAXXVPTKL (SEQ ID NO: 6527), GSAGPXX (SEQ ID NO: 6441)TPTKL (SEQ ID NO: 6387), AAPASXXVPARL (SEQ ID NO: 6458), STPPTXXVPTRL (SEQ ID NO: 6573), HVPKPXXAPTKL (SEQ ID NO: 6503) and RVPSTXXAPVKT (SEQ ID NO: 6550).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the retinal cell lineage, promoting eye retina cell regeneration and protecting from eye retina cell degeneration-related conditions or diseases, PEP12 is a peptide of general formula PEP1-AA17-PEP11; wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T); wherein PEP1 is SPIN (SEQ ID NO: 6363).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the retinal cell lineage, promoting eye retina cell regeneration and protecting from eye retina cell degeneration-related conditions or diseases, PEP11 is a peptide with 3 amino acids of general formula AA18-AA19-AA20; wherein AA18 is selected from the group consisting of L, V, Q, A and R, in particular is L; wherein AA19 is selected from the group consisting of F, W, H and Y, in particular is Y or F; wherein AA20 is selected from the group consisting of L, F, Y, K, I, V and M, in particular is selected from the group consisting of L, F, Y, K, I and V. In one particular example, PEP11 is LYF.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the retinal cell lineage, promoting eye retina cell regeneration and protecting from eye retina cell degeneration-related conditions or diseases, PEP1 is SPIN (SEQ ID NO: 6363) and PEP11 is LYF.
The definitions of “PEP” pairs and triplets e.g. PEP3:PEP1, PEP5:PEP12, or PEP7:PEP5:PEP1, most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the retinal cell lineage, promoting eye retina cell regeneration and protecting from eye retina cell degeneration-related conditions or diseases, are as already defined herein to the extent that PEP1, PEP3, PEP5, PEP7, PEP9, PEP11 and PEP12 are particularly useful for these applications as defined in the present eye retina section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the retinal cell lineage, promoting eye retina cell regeneration and protecting from eye retina cell degeneration-related conditions or diseases, said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the retinal cell lineage, promoting eye retina cell regeneration and protecting from eye retina cell degeneration-related conditions or diseases, said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
Renal Tissues
Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the renal cell lineage, promoting renal cell regeneration and/or renal functions and protecting from renal cell degeneration-related conditions or diseases such as chronic kidney disease or renal fibrosis.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the renal cell lineage, promoting renal cell regeneration and/or renal functions and protecting from renal cell degeneration-related conditions or diseases, PEP1 is SPIN (SEQ ID NO: 6363).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the renal cell lineage, promoting renal cell regeneration and/or renal functions and protecting from renal cell degeneration-related conditions or diseases, PEP3 is selected from the group consisting of VPT, APT, TPT, VPA and APV.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the renal cell lineage, promoting renal cell regeneration and/or renal functions and protecting from renal cell degeneration-related conditions or diseases, PEP5 is a peptide of general formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, APT, TPT, VPA and APV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is E, K, Q and R; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is L, M or T. In one particular example, PEP5 is selected from the group consisting of VPTEL (SEQ ID NO: 6421), APTKL (SEQ ID NO: 6369), APTQL (SEQ ID NO: 6372), VPTKL (SEQ ID NO: 6423), TPTKM (SEQ ID NO: 6388), VPARL (SEQ ID NO: 6401), VPTRL (SEQ ID NO: 6427) and APVKT (SEQ ID NO: 6379).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the renal cell lineage, promoting renal cell regeneration and/or renal functions and protecting from renal cell degeneration-related conditions or diseases, PEP7 is an amino acid or a peptide with between two and seven amino acids of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606); wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA7 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is S or C; wherein AA7 is absent or is selected from the group consisting of S, T, C, E, Q, P and R, preferably is S or C; and wherein at least one of AA, AA2, AA3, AA4, AA5, AA or AA7 is not absent. In one particular example, PEP7 is selected from the group consisting of KIPKAXX (SEQ ID NO: 6445), SIPKAXX (SEQ ID NO: 6450), HVTKPTX (SEQ ID NO: 6443), YVPKPXX (SEQ ID NO: 6454), TVPKPXX (SEQ ID NO: 6453), AVPKAXX (SEQ ID NO: 6439), KVGKAXX (SEQ ID NO: 6446), KASKAXX (SEQ ID NO: 6444), GSAGPXX (SEQ ID NO: 6441), AAPAXXS, STPPTXX (SEQ ID NO: 6452), HVPKPXX (SEQ ID NO: 6442) and RVPSTXX (SEQ ID NO: 6449).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the renal cell lineage, promoting renal cell regeneration and/or renal functions and protecting from renal cell degeneration-related conditions or diseases, PEP9 is a peptide of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7-PEP5; wherein PEP5 is a peptide of formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, APT, TPT, VPA and APV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is E, K, Q and R; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is L, M or T; wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AAe is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is S or C; wherein AA7 is selected from the group consisting of S, T, C, E, Q, P and R, preferably is S or C. In one particular example, PEP9 is selected from the group consisting of KIPKAXXVPTEL (SEQ ID NO: 6535), SIPKAXXVPTEL (SEQ ID NO: 6563), HVTKPTXAPTKL (SEQ ID NO: 6511), YVPKPXXAPTKL (SEQ ID NO: 6583), TVPKPXXAPTQL (SEQ ID NO: 6575), AVPKAXXAPTKL (SEQ ID NO: 6479), KVGKAXXVPTKL (SEQ ID NO: 6543), KASKAXXVPTKL (SEQ ID NO: 6527), GSAGPXX (SEQ ID NO: 6441)TPTKL (SEQ ID NO: 6387), AAPASXXVPARL (SEQ ID NO: 6458), STPPTXXVPTRL (SEQ ID NO: 6573), HVPKPXXAPTKL (SEQ ID NO: 6503) and RVPSTXXAPVKT (SEQ ID NO: 6550).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the renal cell lineage, promoting renal cell regeneration and/or renal functions and protecting from renal cell degeneration-related conditions or diseases, PEP12 is a peptide of general formula PEP1-AA17-PEP11; wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T); wherein PEP1 is SPIN (SEQ ID NO: 6363).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the renal cell lineage, promoting renal cell regeneration and/or renal functions and protecting from renal cell degeneration-related conditions or diseases, PEP11 is a peptide with 3 amino acids of general formula AA18-AA19-AA20; wherein AA18 is selected from the group consisting of L, V, Q, A and R, in particular is L; wherein AA19 is selected from the group consisting of F, W, H and Y, in particular is Y or F; wherein AA20 is selected from the group consisting of L, F, Y, K, I, V and M, in particular is selected from the group consisting of L, F, Y, K, I and V. In one particular example, PEP11 is LYF.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the renal cell lineage, promoting renal cell regeneration and/or renal functions and protecting from renal cell degeneration-related conditions or diseases, PEP1 is SPIN (SEQ ID NO: 6363) and PEP11 is LYF.
The definitions of “PEP” pairs and triplets e.g. PEP3:PEP1, PEP5:PEP12, or PEP7:PEP5:PEP1, most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the renal cell lineage, promoting renal cell regeneration and/or renal functions and protecting from renal cell degeneration-related conditions or diseases, are as already defined herein to the extent that PEP1, PEP3, PEP5, PEP7, PEP9, PEP11 and PEP12 are particularly useful for these applications as defined in the present renal tissue section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the renal cell lineage, promoting renal cell regeneration and/or renal functions and protecting from renal cell degeneration-related conditions or diseases, said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the renal cell lineage, promoting renal cell regeneration and/or renal functions and protecting from renal cell degeneration-related conditions or diseases, said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
Ligaments and Tendons
Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from LT cell degeneration and LT cell degeneration-related diseases, conditions, disorders or pathologies.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, PEP1 is selected from the group consisting of NAIS (SEQ ID NO: 6357), SPIS (SEQ ID NO: 6364), EPLP (SEQ ID NO: 6354) and EPLT (SEQ ID NO: 6355).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, PEP3 is selected from the group consisting of VPT, APT, VPQ and VSO.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, PEP5 is a peptide of general formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, APT, VPQ and VSO; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is E, K, Q, R, A and D; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is L In one particular example, PEP5 is selected from the group consisting of VPTEL (SEQ ID NO: 6421), APTKL (SEQ ID NO: 6369), APTQL (SEQ ID NO: 6372), VPTRL (SEQ ID NO: 6427), VPQAL (SEQ ID NO: 6410), VSODL (SEQ ID NO: 6429) and VPQDL (SEQ ID NO: 6411).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, PEP7 is an amino acid or a peptide with between two and seven amino acids of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606); wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of T, S and C; wherein AA7 is absent or is selected from the group consisting of S, T, C, E, Q, P and R, preferably S or C; and wherein at least one of AA1, AA2, AA3, AA4, AA5, AA6 or AA7 is not absent. In one particular example, PEP7 is selected from the group consisting of KIPKAXX (SEQ ID NO: 6445), SIPKAXX (SEQ ID NO: 6450), HVTKPTX (SEQ ID NO: 6443), YVPKPXX (SEQ ID NO: 6454), TVPKPXX (SEQ ID NO: 6453), STPPTXX (SEQ ID NO: 6452), ASAAPXX (SEQ ID NO: 6437) and ASASPXX (SEQ ID NO: 6438).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, PEP9 is a peptide of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7-PEP5; wherein PEP5 is a peptide of formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, APT, VPQ and VSO; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is E, K, Q, R, A and D; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is L; wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of T, S and C; wherein AA7 is selected from the group consisting of S, T, C, E, Q, P and R, preferably S or C. In one particular example, PEP9 is selected from the group consisting of KIPKAXXVPTEL (SEQ ID NO: 6535), SIPKAXXVPTEL (SEQ ID NO: 6563), HVTKPTXAPTKL (SEQ ID NO: 6511), YVPKPXXAPTKL (SEQ ID NO: 6583), TVPKPXXAPTQL (SEQ ID NO: 6575), STPPTXXVPTRL (SEQ ID NO: 6573), ASAAPXXVPQAL (SEQ ID NO: 6468), ASASPXXVSQDL (SEQ ID NO: 6478) and ASASPXXVPQDL (SEQ ID NO: 6476).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, PEP12 is a peptide of general formula PEP1-AA17-PEP11; wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T); wherein PEP1 is selected from the group consisting of NAIS (SEQ ID NO: 6357), SPIS (SEQ ID NO: 6364), EPLP (SEQ ID NO: 6354) and EPLT (SEQ ID NO: 6355).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, PEP11 is a peptide with 3 amino acids of general formula AA18-AA19-AA20; wherein AA18 is selected from the group consisting of L, V, Q, A and R, in particular is L or V; wherein AA19 is selected from the group consisting of F, W, H and Y, in particular is Y or F; wherein AA20 is selected from the group consisting of L, F, Y, K, I, V and M, in particular is selected from the group consisting of F, I and Y. In one particular example, PEP11 is selected from the group consisting of LYF, LFI, VYY and LYY.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, PEP1 is selected from the group consisting of NAIS (SEQ ID NO: 6357), SPIS (SEQ ID NO: 6364), EPLP (SEQ ID NO: 6354) and EPLT (SEQ ID NO: 6355); PEP11 is selected from the group consisting of LYF, LFI, VYY and LYY; and the pair PEP1:PEP11 is selected from the group consisting of NAIS (SEQ ID NO: 6357):LYF, SPIS (SEQ ID NO: 6364):LFI, EPLP (SEQ ID NO: 6354):VYY and EPLT (SEQ ID NO: 6355):LYY.
The definitions of “PEP” pairs and triplets e.g. PEP3:PEP1, PEP5:PEP12, or PEP7:PEP5:PEP1, most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from LT cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, are as already defined herein to the extent that PEP1, PEP3, PEP5, PEP7, PEP9, PEP11 and PEP12 are particularly useful for these applications as defined in the present L/T section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
In other embodiments also useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, PEP1 is SPIS (SEQ ID NO: 6364).
In other embodiments also useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, PEP3 is selected from the group consisting of VPT, APT, TPT, VPA and APV.
In other embodiments also useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, PEP5 is a peptide of general formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, APT, TPT, VPA and APV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is selected from the group consisting of E, K, Q and R; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is selected from the group consisting of L, M and T. In one particular example, PEP5 is selected from the group consisting of VPTEL (SEQ ID NO: 6421), APTKL (SEQ ID NO: 6369), APTQL (SEQ ID NO: 6372), VPTKL (SEQ ID NO: 6423), TPTKM (SEQ ID NO: 6388), VPARL (SEQ ID NO: 6401), VPTRL (SEQ ID NO: 6427) and APVKT (SEQ ID NO: 6379).
In other embodiments also useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, PEP7 is an amino acid or a peptide with between two and seven amino acids of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606); wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is S or C; wherein AA6 is absent or is selected from the group consisting of S, T, C, E, Q, P and R, preferably is S or C; and wherein at least one of AA1, AA2, AA3, AA4, AA5, AA6 or AA7 is not absent. In one particular example, PEP7 is selected from the group consisting of KIPKAXX (SEQ ID NO: 6445), SIPKAXX (SEQ ID NO: 6450), HVTKPTX (SEQ ID NO: 6443), YVPKPXX (SEQ ID NO: 6454), TVPKPXX (SEQ ID NO: 6453), AVPKAXX (SEQ ID NO: 6439), KVGKAXX (SEQ ID NO: 6446), KASKAXX (SEQ ID NO: 6444), GSAGPXX (SEQ ID NO: 6441), AAPAXXS, STPPTXX (SEQ ID NO: 6452), HVPKPXX (SEQ ID NO: 6442) and RVPSTXX (SEQ ID NO: 6449).
In other embodiments also useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, PEP9 is a peptide of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7-PEP5; wherein PEP5 is a peptide of formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, APT, TPT, VPA and APV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is E, K, Q and R; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is L, M or T; wherein AA, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AAe is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is S or C; wherein AA7 is selected from the group consisting of S, T, C, E, Q, P and R, preferably is S or C. In one particular example, PEP9 is selected from the group consisting of KIPKAXXVPTEL (SEQ ID NO: 6535), SIPKAXXVPTEL (SEQ ID NO: 6563), HVTKPTXAPTKL (SEQ ID NO: 6511), YVPKPXXAPTKL (SEQ ID NO: 6583), TVPKPXXAPTQL (SEQ ID NO: 6575), AVPKAXXAPTKL (SEQ ID NO: 6479), KVGKAXXVPTKL (SEQ ID NO: 6543), KASKAXXVPTKL (SEQ ID NO: 6527), GSAGPXX (SEQ ID NO: 6441)TPTKL (SEQ ID NO: 6387), AAPASXXVPARL (SEQ ID NO: 6458), STPPTXXVPTRL (SEQ ID NO: 6573), HVPKPXXAPTKL (SEQ ID NO: 6503) and RVPSTXXAPVKT (SEQ ID NO: 6550).
In other embodiments also useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, PEP12 is a peptide of general formula PEP1-AA17-PEP11; wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T); wherein PEP1 is SPIS (SEQ ID NO: 6364).
In other embodiments also useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, PEP11 is a peptide with 3 amino acids of general formula AA18-AA19-AA20; wherein AA18 is selected from the group consisting of L, V, Q, A and R, in particular is L; wherein AA19 is selected from the group consisting of F, W, H and Y, in particular is a polar aromatic amino acid such as Y; wherein AA0 is selected from the group consisting of L, F, Y, K, I, V and M, in particular is I. In one particular example, PEP11 is LYI.
In other embodiments also useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, PEP1 is SPIS (SEQ ID NO: 6364) and PEP11 is LYI.
The definitions of “PEP” pairs and triplets e.g. PEP3:PEP1, PEP5:PEP12, or PEP7:PEP5:PEP1, also most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, are as already defined herein to the extent that PEP1, PEP3, PEP5, PEP7, PEP9, PEP11 and PEP12 are particularly useful for these applications as defined in the present L/T section.
In other embodiments also useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
In other embodiments also useful for inducing differentiation of mensenchymal or progenitor stem cells from the ligament and tendon (L/T) cell lineage, promoting fibrous tissue formation and T/L regeneration and protecting from L/T cell degeneration and L/T cell degeneration-related diseases, conditions, disorders or pathologies, said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
Wound Healing
Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells involved in the process of wound healing as defined herein, promoting wound healing, skin repair and cellular migration.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells involved in the process of wound healing as defined herein, promoting wound healing, skin repair and cellular migration, PEP1 is selected from the group consisting of SNIT (SEQ ID NO: 6362), RPVQ (SEQ ID NO: 6358) and RSVK (SEQ ID NO: 6359).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells involved in the process of wound healing as defined herein, promoting wound healing, skin repair and cellular migration, PEP3 is selected from the group consisting of VPT, SRV and TQV.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells involved in the process of wound healing as defined herein, promoting wound healing, skin repair and cellular migration, PEP5 is a peptide of general formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, SRV and TQV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is selected from the group consisting of E, G, H and Q; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is selected from the group consisting of E, Q, H and L In one particular example, PEP5 is selected from the group consisting of VPTGQ (SEQ ID NO: 6422), VPTEE (SEQ ID NO: 6420), SRVHH (SEQ ID NO: 6382) and TQVQL (SEQ ID NO: 6393).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells involved in the process of wound healing as defined herein, promoting wound healing, skin repair and cellular migration, PEP7 is an amino acid or a peptide with between two and seven amino acids of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606); wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of E, Q and R; wherein AA7 is absent or is selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of S, C and P; and wherein at least one of AA1, AA2, AA3, AA4, AA5, AA6 or AA7 is not absent. In one particular example, PEP7 is selected from the group consisting of NDEGLEX (SEQ ID NO: 6447), SSVKXQP (SEQ ID NO: 6451) and RNVQXRP (SEQ ID NO: 6448).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells involved in the process of wound healing as defined herein, promoting wound healing, skin repair and cellular migration, PEP9 is a peptide of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7-PEP5; wherein PEP5 is a peptide of formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, SRV and TQV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is E, G, H and Q; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is selected from the group consisting of E, Q, H and L; wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of E, Q and R; wherein AA7 is selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of S, C and P. In one particular example, PEP9 is selected from the group consisting of NDEGLEXVPTEE (SEQ ID NO: 6545), NDEGLEXVPTGQ (SEQ ID NO: 6546), SSVKXQPSRVHH (SEQ ID NO: 6565) and RNVQXRPTQVQL (SEQ ID NO: 6548).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells involved in the process of wound healing as defined herein, promoting wound healing, skin repair and cellular migration, PEP12 is a peptide of general formula PEP1-AA17-PEP11; wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T); wherein PEP1 is selected from the group consisting of SNIT (SEQ ID NO: 6362), RPVQ (SEQ ID NO: 6358) and RSVK (SEQ ID NO: 6359).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells involved in the process of wound healing as defined herein, promoting wound healing, skin repair and cellular migration, PEP11 is a peptide with 3 amino acids of general formula AA18-AA19-AA20; wherein AA1S is selected from the group consisting of L, V, Q, A and R, in particular is selected from the group consisting of Q, A and R; wherein AA1 is selected from the group consisting of F, W, H, Y, I and K, in particular is I or K; wherein AA2 is selected from the group consisting of L, F, Y, K, I, V and M, in particular is selected from the group consisting of M, V and I. In one particular example, PEP11 is selected from the group consisting of QIM, AKV and RKI.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells involved in the process of wound healing as defined herein, promoting wound healing, skin repair and cellular migration, PEP1 is selected from the group consisting of SNIT (SEQ ID NO: 6362), RPVQ (SEQ ID NO: 6358) and RSVK (SEQ ID NO: 6359); PEP11 is selected from the group consisting of QIM, AKV and RKI; and the pair PEP1:PEP11 is selected from the group consisting of SNIT (SEQ ID NO: 6362):QIM, RSVK (SEQ ID NO: 6359):KEVQV and RPVQ (SEQ ID NO: 6358):KKATV.
The definitions of “PEP” pairs and triplets e.g. PEP3:PEP1, PEP5:PEP12, or PEP7:PEP5:PEP1, also most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells involved in the process of wound healing as defined herein, promoting wound healing, skin repair and cellular migration, are as already defined herein to the extent that PEP1, PEP3, PEP5, PEP7, PEP9, PEP11 and PEP12 are particularly useful for these applications as defined in the present wound healing section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells involved in the process of wound healing as defined herein, promoting wound healing, skin repair and cellular migration, said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells involved in the process of wound healing as defined herein, promoting wound healing, skin repair and cellular migration, said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
Skin Regeneration and Anti-Aging
Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the fibroblast lineage, inducing skin tissue regeneration and tubular formation, preventing, attenuating, masking or removing wrinkles, firming the skin, preventing, decreasing or suppressing skin pigmentation, and protecting patients from skin tissue degeneration-related diseases, disorders, conditions or pathologies.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the fibroblast lineage, inducing skin tissue regeneration and tubular formation, preventing, attenuating, masking or removing wrinkles, firming the skin, preventing, decreasing or suppressing skin pigmentation, and protecting patients from skin tissue degeneration-related diseases, disorders, conditions or pathologies, PEP1 is selected from the group consisting of EPLP (SEQ ID NO: 6354), EPLT (SEQ ID NO: 6355), SNIT (SEQ ID NO: 6362), RSVK (SEQ ID NO: 6359) and RPVQ (SEQ ID NO: 6358).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the fibroblast lineage, inducing skin tissue regeneration and tubular formation, preventing, attenuating, masking or removing wrinkles, firming the skin, preventing, decreasing or suppressing skin pigmentation, and protecting patients from skin tissue degeneration-related diseases, disorders, conditions or pathologies, PEP3 is selected from the group consisting of VPT, APT, VPQ, VSO, SRV and TQV.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the fibroblast lineage, inducing skin tissue regeneration and tubular formation, preventing, attenuating, masking or removing wrinkles, firming the skin, preventing, decreasing or suppressing skin pigmentation, and protecting patients from skin tissue degeneration-related diseases, disorders, conditions or pathologies, PEP5 is a peptide of general formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, APT, VPQ, VSO, SRV and TQV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is selected from the group consisting of E, K, Q, A, D and H; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is selected from the group consisting of L, E and H. In one particular example, PEP5 is selected from the group consisting of VPTEL (SEQ ID NO: 6421), APTKL (SEQ ID NO: 6369), APTQL (SEQ ID NO: 6372), VPQAL (SEQ ID NO: 6410), VSQDL (SEQ ID NO: 6429), VPQDL (SEQ ID NO: 6411), VPTEE (SEQ ID NO: 6420), SRVHH (SEQ ID NO: 6382) and TQVQL (SEQ ID NO: 6393).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the fibroblast lineage, inducing skin tissue regeneration and tubular formation, preventing, attenuating, masking or removing wrinkles, firming the skin, preventing, decreasing or suppressing skin pigmentation, and protecting patients from skin tissue degeneration-related diseases, disorders, conditions or pathologies, PEP7 is an amino acid or a peptide with between two and seven amino acids of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606); wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of C, S, T, E, R and Q; wherein AA7 is absent or is selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of S, C and P; and wherein at least one of AA1, AA2, AA3, AA4, AA5, AA6 or AA7 is not absent. In one particular example, PEP7 is selected from the group consisting of KIPKAXX (SEQ ID NO: 6445), SIPKAXX (SEQ ID NO: 6450), HVTKPTX (SEQ ID NO: 6443), YVPKPXX (SEQ ID NO: 6454), TVPKPXX (SEQ ID NO: 6453), ASAAPXX (SEQ ID NO: 6437), ASASPXX (SEQ ID NO: 6438), NDEGLEX (SEQ ID NO: 6447), SSVKXQP (SEQ ID NO: 6451) and RNVQXRP (SEQ ID NO: 6448).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the fibroblast lineage, inducing skin tissue regeneration and tubular formation, preventing, attenuating, masking or removing wrinkles, firming the skin, preventing, decreasing or suppressing skin pigmentation, and protecting patients from skin tissue degeneration-related diseases, disorders, conditions or pathologies, PEP9 is a peptide of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7-PEP5; wherein PEP5 is a peptide of formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, APT, VPQ, VSO, SRV and TQV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is selected from the group consisting of E, K, Q, A, D and H; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is selected from the group consisting of L, E and H; wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of C, S, T, E, R and Q; wherein AA7 is selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of S, C and P. In one particular example, PEP9 is selected from the group consisting of KIPKAXXVPTEL (SEQ ID NO: 6535), SIPKAXXVPTEL (SEQ ID NO: 6563), HVTKPTXAPTKL (SEQ ID NO: 6511), YVPKPXXAPTKL (SEQ ID NO: 6583), TVPKPXXAPTQL (SEQ ID NO: 6575), ASAAPXXVPQAL (SEQ ID NO: 6468), ASASPXXVSQDL (SEQ ID NO: 6478), ASASPXXVPQDL (SEQ ID NO: 6476), NDEGLEXVPTEE (SEQ ID NO: 6545), SSVKXQPSRVHH (SEQ ID NO: 6565) and RNVQXRPTQVQL (SEQ ID NO: 6548).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the fibroblast lineage, inducing skin tissue regeneration and tubular formation, preventing, attenuating, masking or removing wrinkles, firming the skin, preventing, decreasing or suppressing skin pigmentation, and protecting patients from skin tissue degeneration-related diseases, disorders, conditions or pathologies, PEP12 is a peptide of general formula PEP1-AA17-PEP11; wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T); wherein PEP1 is selected from the group consisting of EPLP (SEQ ID NO: 6354), EPLT (SEQ ID NO: 6355), SNIT (SEQ ID NO: 6362), RSVK (SEQ ID NO: 6359) and RPVQ (SEQ ID NO: 6358).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the fibroblast lineage, inducing skin tissue regeneration and tubular formation, preventing, attenuating, masking or removing wrinkles, firming the skin, preventing, decreasing or suppressing skin pigmentation, and protecting patients from skin tissue degeneration-related diseases, disorders, conditions or pathologies, PEP11 is a peptide with 3 amino acids of general formula AA18-AA19-AA20; wherein AA18 is selected from the group consisting of L, V, Q, A and R; wherein AA19 is selected from the group consisting of F, W, H, Y, I and K, in particular is selected from the group consisting of Y, I and K; wherein AA0 is selected from the group consisting of L, F, Y, K, I, V and M, in particular is selected from the group consisting of Y, M, V and I. In one particular example, PEP11 is selected from the group consisting of VYY, LYY, QIM, AKV and RKI.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the fibroblast lineage, inducing skin tissue regeneration and tubular formation, preventing, attenuating, masking or removing wrinkles, firming the skin, preventing, decreasing or suppressing skin pigmentation, and protecting patients from skin tissue degeneration-related diseases, disorders, conditions or pathologies, PEP1 is selected from the group consisting of EPLP (SEQ ID NO: 6354), EPLT (SEQ ID NO: 6355), SNIT (SEQ ID NO: 6362), RSVK (SEQ ID NO: 6359) and RPVQ (SEQ ID NO: 6358); PEP11 is selected from the group consisting of VYY, LYY, QIM, AKV and RKI; and the pair PEP1:PEP11 is selected from the group consisting of EPLP (SEQ ID NO: 6354):VYY, EPLT (SEQ ID NO: 6355):LYY, SNIT (SEQ ID NO: 6362):QIM, RSVK (SEQ ID NO: 6359):KEVQV and RPVQ (SEQ ID NO: 6358):KKATV.
The definitions of “PEP” pairs and triplets e.g. PEP3:PEP1, PEP5:PEP12, or PEP7:PEP5:PEP1, also most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the fibroblast lineage, inducing skin tissue regeneration and tubular formation, preventing, attenuating, masking or removing wrinkles, firming the skin, preventing, decreasing or suppressing skin pigmentation, and protecting patients from skin tissue degeneration-related diseases, disorders, conditions or pathologies, are as already defined herein to the extent that PEP1, PEP3, PEP5, PEP7, PEP9, PEP11 and PEP12 are particularly useful for these applications as defined in the present skin regeneration section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the fibroblast lineage, inducing skin tissue regeneration and tubular formation, preventing, attenuating, masking or removing wrinkles, firming the skin, preventing, decreasing or suppressing skin pigmentation, and protecting patients from skin tissue degeneration-related diseases, disorders, conditions or pathologies, said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the fibroblast lineage, inducing skin tissue regeneration and tubular formation, preventing, attenuating, masking or removing wrinkles, firming the skin, preventing, decreasing or suppressing skin pigmentation, and protecting patients from skin tissue degeneration-related diseases, disorders, conditions or pathologies, said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
Hair
Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the hair follicle cell lineage, hair follicle tissue regeneration and formation (hair growth), and for protecting from hair follicle-related diseases, disorders, conditions or pathologies.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the hair follicle cell lineage, hair follicle tissue regeneration and formation (hair growth), and for protecting from hair follicle-related diseases, disorders, conditions or pathologies, PEP1 is SSLS (SEQ ID NO: 6365).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the hair follicle cell lineage, hair follicle tissue regeneration and formation (hair growth), and for protecting from hair follicle-related diseases, disorders, conditions or pathologies, PEP3 is selected from the group consisting of VPT, VPE, APT, TPT, VPA, APV, VPQ, VSO and SRV.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the hair follicle cell lineage, hair follicle tissue regeneration and formation (hair growth), and for protecting from hair follicle-related diseases, disorders, conditions or pathologies, PEP5 is a peptide of general formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, VPE, APT, TPT, VPA, APV, VPQ, VSO and SRV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is selected from the group consisting of E, K, Q, R, A, D and H; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is selected from the group consisting of L, M, T, E and H. In one particular example, PEP5 is selected from the group consisting of VPTEL (SEQ ID NO: 6421), VPEKM (SEQ ID NO: 6406), APTKL (SEQ ID NO: 6369), APTQL (SEQ ID NO: 6372), VPTKL (SEQ ID NO: 6423), TPTKM (SEQ ID NO: 6388), VPARL (SEQ ID NO: 6401), VPTRL (SEQ ID NO: 6427), APVKT (SEQ ID NO: 6379), VPQAL (SEQ ID NO: 6410), VSODL (SEQ ID NO: 6429), VPQDL (SEQ ID NO: 6411), VPTEE (SEQ ID NO: 6420) and SRVHH (SEQ ID NO: 6382).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the hair follicle cell lineage, hair follicle tissue regeneration and formation (hair growth), and for protecting from hair follicle-related diseases, disorders, conditions or pathologies, PEP7 is an amino acid or a peptide with between two and seven amino acids of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606); wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of C, S, T, E and Q; wherein AA7 is absent or is selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of S, C and P; and wherein at least one of AA1, AA2, AA3, AA4, AA5, AA or AA7 is not absent. In one particular example, PEP7 is selected from the group consisting of KIPKAXX (SEQ ID NO: 6445), GIPEPXX (SEQ ID NO: 6440), SIPKAXX (SEQ ID NO: 6450), HVTKPTX (SEQ ID NO: 6443), YVPKPXX (SEQ ID NO: 6454), TVPKPXX (SEQ ID NO: 6453), AVPKAXX (SEQ ID NO: 6439), KVGKAXX (SEQ ID NO: 6446), KASKAXX (SEQ ID NO: 6444), GSAGPXX (SEQ ID NO: 6441), AAPASXX (SEQ ID NO: 6436), STPPTXX (SEQ ID NO: 6452), HVPKPXX (SEQ ID NO: 6442), RVPSTXX (SEQ ID NO: 6449), ASAAPXX (SEQ ID NO: 6437), ASASPXX (SEQ ID NO: 6438), NDEGLEX (SEQ ID NO: 6447) and SSVKXQP (SEQ ID NO: 6451).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the hair follicle cell lineage, hair follicle tissue regeneration and formation (hair growth), and for protecting from hair follicle-related diseases, disorders, conditions or pathologies, PEP9 is a peptide of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7-PEP5; wherein PEP5 is a peptide of formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, VPE, APT, TPT, VPA, APV, VPQ, VSO and SRV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is selected from the group consisting of E, K, Q, R, A, D and H; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is selected from the group consisting of L, M, T, E and H; wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of C, S, T, E and Q; wherein AA7 is selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of S, C and P. In one particular example, PEP9 is selected from the group consisting of KIPKAXXVPTEL (SEQ ID NO: 6535), GIPEPXXVPEKM (SEQ ID NO: 6491), SIPKAXXVPTEL (SEQ ID NO: 6563), HVTKPTXAPTKL (SEQ ID NO: 6511), YVPKPXXAPTKL (SEQ ID NO: 6583), TVPKPXXAPTQL (SEQ ID NO: 6575), AVPKAXXAPTKL (SEQ ID NO: 6479), KVGKAXXVPTKL (SEQ ID NO: 6543), KASKAXXVPTKL (SEQ ID NO: 6527), GSAGPXXTPTKM (SEQ ID NO: 6497), AAPASXXVPARL (SEQ ID NO: 6458), STPPTXXVPTRL (SEQ ID NO: 6573), HVPKPXXAPTKL (SEQ ID NO: 6503), RVPSTXXAPVKT (SEQ ID NO: 6550), ASAAPXXVPQAL (SEQ ID NO: 6468), ASASPXXVSQDL (SEQ ID NO: 6478), ASASPXXVPQDL (SEQ ID NO: 6476), NDEGLEXVPTEE (SEQ ID NO: 6545) and SSVKXQPSRVHH (SEQ ID NO: 6565).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the hair follicle cell lineage, hair follicle tissue regeneration and formation (hair growth), and for protecting from hair follicle-related diseases, disorders, conditions or pathologies, PEP12 is a peptide of general formula PEP1-AA17-PEP11; wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T); wherein PEP1 is SSLS (SEQ ID NO: 6365).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the hair follicle cell lineage, hair follicle tissue regeneration and formation (hair growth), and for protecting from hair follicle-related diseases, disorders, conditions or pathologies, PEP11 is a peptide with 3 amino acids of general formula AA18-AA19-AA20; wherein AA19 is selected from the group consisting of L, V, Q, A and R, in particular is L; wherein AA19 is selected from the group consisting of F, W, H, Y, I and K, in particular is F; wherein AA2 is selected from the group consisting of L, F, Y, K, I, V and M, in particular is F. In one particular example, PEP11 is LFF.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the hair follicle cell lineage, hair follicle tissue regeneration and formation (hair growth), and for protecting from hair follicle-related diseases, disorders, conditions or pathologies, PEP1 is SSLS (SEQ ID NO: 6365) and PEP11 is LFF.
The definitions of “PEP” pairs and triplets e.g. PEP3:PEP1, PEP5:PEP12, or PEP7:PEP5:PEP1, also most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the hair follicle cell lineage, hair follicle tissue regeneration and formation (hair growth), and for protecting from hair follicle-related diseases, disorders, conditions or pathologies, are as already defined herein to the extent that PEP1, PEP3, PEP5, PEP7, PEP9, PEP11 and PEP12 are particularly useful for these applications as defined in the present fertility and reproduction section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the hair follicle cell lineage, hair follicle tissue regeneration and formation (hair growth), and for protecting from hair follicle-related diseases, disorders, conditions or pathologies, said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the hair follicle cell lineage, hair follicle tissue regeneration and formation (hair growth), and for protecting from hair follicle-related diseases, disorders, conditions or pathologies, said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
Fertility and Reproduction
Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the reproduction system lineage, enhancing female fertility, treating, preventing, decreasing or suppressing female infertility or any diseases, conditions, disorders or pathologies related thereof.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the reproduction system lineage, enhancing female fertility, treating, preventing, decreasing or suppressing female infertility or any diseases, conditions, disorders or pathologies related thereof, PEP1 is NAIS (SEQ ID NO: 6357).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the reproduction system lineage, enhancing female fertility, treating, preventing, decreasing or suppressing female infertility or any diseases, conditions, disorders or pathologies related thereof, PEP3 is selected from the group consisting of VPT, APT, TPT, VPA and APV.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the reproduction system lineage, enhancing female fertility, treating, preventing, decreasing or suppressing female infertility or any diseases, conditions, disorders or pathologies related thereof, PEP5 is a peptide of general formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, APT, TPT, VPA and APV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is selected from the group consisting of E, K, Q and R; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is selected from the group consisting of L, M and T. In one particular example, PEP5 is selected from the group consisting of VPTEL (SEQ ID NO: 6421), APTKL (SEQ ID NO: 6369), APTQL (SEQ ID NO: 6372), VPTKL (SEQ ID NO: 6423), TPTKM (SEQ ID NO: 6388), VPARL (SEQ ID NO: 6401), VPTRL (SEQ ID NO: 6427) and APVKT (SEQ ID NO: 6379).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the reproduction system lineage, enhancing female fertility, treating, preventing, decreasing or suppressing female infertility or any diseases, conditions, disorders or pathologies related thereof, PEP7 is an amino acid or a peptide with between two and seven amino acids of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606); wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AAe is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of C, S and T; wherein AA7 is absent or is selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of S and C; and wherein at least one of AA, AA2, AA3, AA4, AA5, AA or AA7 is not absent. In one particular example, PEP7 is selected from the group consisting of KIPKAXX (SEQ ID NO: 6445), SIPKAXX (SEQ ID NO: 6450), HVTKPTX (SEQ ID NO: 6443), YVPKPXX (SEQ ID NO: 6454), TVPKPXX (SEQ ID NO: 6453), AVPKAXX (SEQ ID NO: 6439), KVGKAXX (SEQ ID NO: 6446), KASKAXX (SEQ ID NO: 6444), GSAGPXX (SEQ ID NO: 6441), AAPASXX (SEQ ID NO: 6436), STPPTXX (SEQ ID NO: 6452), HVPKPXX (SEQ ID NO: 6442) and RVPSTXX (SEQ ID NO: 6449).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the reproduction system lineage, enhancing female fertility, treating, preventing, decreasing or suppressing female infertility or any diseases, conditions, disorders or pathologies related thereof, PEP9 is a peptide of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7-PEP5; wherein PEP5 is a peptide of formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, APT, TPT, VPA and APV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is selected from the group consisting of E, K, Q and R; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is selected from the group consisting of L, M and T; wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA17 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of C, S and T; wherein AA7 is selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of S and C. In one particular example, PEP9 is selected from the group consisting of KIPKAXXVPTEL (SEQ ID NO: 6535), SIPKAXXVPTEL (SEQ ID NO: 6563), HVTKPTXAPTKL (SEQ ID NO: 6511), YVPKPXXAPTKL (SEQ ID NO: 6583), TVPKPXXAPTQL (SEQ ID NO: 6575), AVPKAXXAPTKL (SEQ ID NO: 6479), KVGKAXXVPTKL (SEQ ID NO: 6543), KASKAXXVPTKL (SEQ ID NO: 6527), GSAGPXXTPTKM (SEQ ID NO: 6497), AAPASXXVPARL (SEQ ID NO: 6458), STPPTXXVPTRL (SEQ ID NO: 6573), HVPKPXXAPTKL (SEQ ID NO: 6503) and RVPSTXXAPVKT (SEQ ID NO: 6550).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the reproduction system lineage, enhancing female fertility, treating, preventing, decreasing or suppressing female infertility or any diseases, conditions, disorders or pathologies related thereof, PEP12 is a peptide of general formula PEP1-AA17-PEP11; wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T); wherein PEP1 is NAIS (SEQ ID NO: 6357).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the reproduction system lineage, enhancing female fertility, treating, preventing, decreasing or suppressing female infertility or any diseases, conditions, disorders or pathologies related thereof, PEP11 is a peptide with 3 amino acids of general formula AA18-AA19-AA20; wherein AA18 is selected from the group consisting of L, V, Q, A and R, in particular is L; wherein AA19 is selected from the group consisting of F, W, H, Y, I and K, in particular is Y; wherein AA20 is selected from the group consisting of L, F, Y, K, I, V and M, in particular is F. In one particular example, PEP11 is LYF.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the reproduction system lineage, enhancing female fertility, treating, preventing, decreasing or suppressing female infertility or any diseases, conditions, disorders or pathologies related thereof, PEP1 is NAIS (SEQ ID NO: 6357) and PEP11 is LYF.
The definitions of “PEP” pairs and triplets e.g. PEP3:PEP1, PEP5:PEP12, or PEP7:PEP5:PEP1, also most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the reproduction system lineage, enhancing female fertility, treating, preventing, decreasing or suppressing female infertility or any diseases, conditions, disorders or pathologies related thereof, are as already defined herein to the extent that PEP1, PEP3, PEP5, PEP7, PEP9, PEP11 and PEP12 are particularly useful for these applications as defined in the present fertility and reproduction section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the reproduction system lineage, enhancing female fertility, treating, preventing, decreasing or suppressing female infertility or any diseases, conditions, disorders or pathologies related thereof, said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the reproduction system lineage, enhancing female fertility, treating, preventing, decreasing or suppressing female infertility or any diseases, conditions, disorders or pathologies related thereof, said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
Lung
Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the lung cell lineage, regenerating lung tissues, and protecting patients from lung tissue degeneration-related diseases, conditions, disorders or pathologies.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the lung cell lineage, regenerating lung tissues, and protecting patients from lung tissue degeneration-related diseases, conditions, disorders or pathologies, PEP1 is selected from the group consisting of NAIS (SEQ ID NO: 6357), SATS (SEQ ID NO: 6361), SPIS (SEQ ID NO: 6364), EPIS (SEQ ID NO: 6353) and SPIN (SEQ ID NO: 6363).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the lung cell lineage, regenerating lung tissues, and protecting patients from lung tissue degeneration-related diseases, conditions, disorders or pathologies, PEP3 is selected from the group consisting of VPT, VPE, APT, TPT, VPA, APV, VPQ and VSO.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the lung cell lineage, regenerating lung tissues, and protecting patients from lung tissue degeneration-related diseases, conditions, disorders or pathologies, PEP5 is a peptide of general formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, VPE, APT, TPT, VPA, APV, VPQ and VSQ; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is selected from the group consisting of E, K, Q, R, A and D; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular selected from the group consisting of L, M and T. In one particular example, PEP5 is selected from the group consisting of VPTEL (SEQ ID NO: 6421), VPEKM (SEQ ID NO: 6406), APTKL (SEQ ID NO: 6369), APTQL (SEQ ID NO: 6372), VPTKL (SEQ ID NO: 6423), TPTKM (SEQ ID NO: 6388), VPARL (SEQ ID NO: 6401), VPTRL (SEQ ID NO: 6427), APVKT (SEQ ID NO: 6379), VPQAL (SEQ ID NO: 6410), VSODL (SEQ ID NO: 6429) and VPQDL (SEQ ID NO: 6411).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the lung cell lineage, regenerating lung tissues, and protecting patients from lung tissue degeneration-related diseases, conditions, disorders or pathologies, PEP7 is an amino acid or a peptide with between two and seven amino acids of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606); wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AAe is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of C, S and T; wherein AA7 is absent or is selected from the group consisting of S, T, C, E, Q, P and R, preferably is C or S; and wherein at least one of AA1, AA2, AA3, AA4, AA5, AAe or AA7 is not absent. In one particular example, PEP7 is selected from the group consisting of KIPKAXX (SEQ ID NO: 6445), GIPEPXX (SEQ ID NO: 6440), SIPKAXX (SEQ ID NO: 6450), HVTKPTX (SEQ ID NO: 6443), YVPKPXX (SEQ ID NO: 6454), TVPKPXX (SEQ ID NO: 6453), AVPKAXX (SEQ ID NO: 6439), KVGKAXX (SEQ ID NO: 6446), KASKAXX (SEQ ID NO: 6444), GSAGPXX (SEQ ID NO: 6441), AAPASXX (SEQ ID NO: 6436), STPPTXX (SEQ ID NO: 6452), HVPKPXX (SEQ ID NO: 6442), RVPSTXX (SEQ ID NO: 6449), ASAAPXX (SEQ ID NO: 6437) and ASASPXX (SEQ ID NO: 6438).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the lung cell lineage, regenerating lung tissues, and protecting patients from lung tissue degeneration-related diseases, conditions, disorders or pathologies, PEP9 is a peptide of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7-PEP5; wherein PEP5 is a peptide of formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, VPE, APT, TPT, VPA, APV, VPQ and VSO; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular E, K, Q, R, A and D; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular selected from the group consisting of L, M and T; wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of C, S and T; wherein AA7 is selected from the group consisting of S, T, C, E, Q, P and R, preferably is C or S. In one particular example, PEP9 is selected from the group consisting of KIPKAXXVPTEL (SEQ ID NO: 6535), GIPEPXXVPEKM (SEQ ID NO: 6491), SIPKAXXVPTEL (SEQ ID NO: 6563), HVTKPTXAPTKL (SEQ ID NO: 6511), YVPKPXXAPTKL (SEQ ID NO: 6583), TVPKPXXAPTQL (SEQ ID NO: 6575), AVPKAXXAPTKL (SEQ ID NO: 6479), KVGKAXXVPTKL (SEQ ID NO: 6543), KASKAXXVPTKL (SEQ ID NO: 6527), GSAGPXXTPTKM (SEQ ID NO: 6497), AAPASXXVPARL (SEQ ID NO: 6458), STPPTXXVPTRL (SEQ ID NO: 6573), HVPKPXXAPTKL (SEQ ID NO: 6503), RVPSTXXAPVKT (SEQ ID NO: 6550), ASAAPXXVPQAL (SEQ ID NO: 6468), ASASPXXVSQDL (SEQ ID NO: 6478) and ASASPXXVPQDL (SEQ ID NO: 6476).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the lung cell lineage, regenerating lung tissues, and protecting patients from lung tissue degeneration-related diseases, conditions, disorders or pathologies, PEP12 is a peptide of general formula PEP1-AA17-PEP11; wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T); wherein PEP1 is selected from the group consisting of NAIS (SEQ ID NO: 6357), SATS (SEQ ID NO: 6361), SPIS (SEQ ID NO: 6364), EPIS (SEQ ID NO: 6353) and SPIN (SEQ ID NO: 6363).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the lung cell lineage, regenerating lung tissues, and protecting patients from lung tissue degeneration-related diseases, conditions, disorders or pathologies, PEP11 is a peptide with 3 amino acids of general formula AA18-AA19-AA20; wherein AA18 is selected from the group consisting of L, V, Q, A and R, in particular is L; wherein AA19 is selected from the group consisting of F, W, H and Y (in particular is a polar aromatic amino acid such as Y); wherein AA2 is selected from the group consisting of L, F, Y, K, I, V and M, in particular is selected from the group consisting of L, F, Y, and K. In one particular example, PEP11 is selected from the group consisting of LYF, LYY, LYK and LYL.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the lung cell lineage, regenerating lung tissues, and protecting patients from lung tissue degeneration-related diseases, conditions, disorders or pathologies, PEP1 is selected from the group consisting of NAIS (SEQ ID NO: 6357), SATS (SEQ ID NO: 6361), SPIS (SEQ ID NO: 6364), EPIS (SEQ ID NO: 6353) and SPIN (SEQ ID NO: 6363); PEP11 is selected from the group consisting of LYF, LYY, LYK and LYL; and the pair PEP1:PEP11 is selected from the group consisting of NAIS (SEQ ID NO: 6357):LYF, SATS (SEQ ID NO: 6361):LYY, SPIS (SEQ ID NO: 6364):LYK, EPIS (SEQ ID NO: 6353):LYL and SPIN (SEQ ID NO: 6363):LYF.
The definitions of “PEP” pairs and triplets e.g. PEP3:PEP1, PEP5:PEP12, or PEP7:PEP5:PEP1, also most particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the lung cell lineage, regenerating lung tissues, and protecting patients from lung tissue degeneration-related diseases, conditions, disorders or pathologies, are as already defined herein to the extent that PEP1, PEP3, PEP5, PEP7, PEP9, PEP11 and PEP12 are particularly useful for these applications as defined in the present lung section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the lung cell lineage, regenerating lung tissues, and protecting patients from lung tissue degeneration-related diseases, conditions, disorders or pathologies, said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the lung cell lineage, regenerating lung tissues, and protecting patients from lung tissue degeneration-related diseases, conditions, disorders or pathologies, said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
Muscle
Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the muscle cell lineage, regenerating muscle tissues, enhancing of myogenesis, reinforcing muscle tissues, repairing damaged muscles, and protecting a subject from one or more muscle tissue degeneration-related diseases, disorders, conditions or pathologies.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the muscle cell lineage, regenerating muscle tissues, enhancing of myogenesis, reinforcing muscle tissues, repairing damaged muscles, and protecting a subject from one or more muscle tissue degeneration-related diseases, disorders, conditions or pathologies, PEP1 is RSVK (SEQ ID NO: 6359) or RPVQ (SEQ ID NO: 6358).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the muscle cell lineage, regenerating muscle tissues, enhancing of myogenesis, reinforcing muscle tissues, repairing damaged muscles, and protecting a subject from one or more muscle tissue degeneration-related diseases, disorders, conditions or pathologies, PEP3 is selected from the group consisting of VPQ, VSO and VPT.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the muscle cell lineage, regenerating muscle tissues, enhancing of myogenesis, reinforcing muscle tissues, repairing damaged muscles, and protecting a subject from one or more muscle tissue degeneration-related diseases, disorders, conditions or pathologies, PEP5 is a peptide of general formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPQ, VSO and VPT; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular A, D, E and G; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular L, E and Q. In one particular example, PEP5 is selected from the group consisting of VPQAL (SEQ ID NO: 6410), VSQDL (SEQ ID NO: 6429), VPQDL (SEQ ID NO: 6411), VPTEE (SEQ ID NO: 6420) and VPTGQ (SEQ ID NO: 6422).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the muscle cell lineage, regenerating muscle tissues, enhancing of myogenesis, reinforcing muscle tissues, repairing damaged muscles, and protecting a subject from one or more muscle tissue degeneration-related diseases, disorders, conditions or pathologies, PEP7 is an amino acid or a peptide with between two and seven amino acids of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606); wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably C, S, or E; wherein AA7 is absent or is selected from the group consisting of S, T, C, E, Q, P and R, preferably is S or C; and wherein at least one of AA, AA2, AA3, AA4, AA5, AA or AA7 is not absent. In one particular example, PEP7 is selected from the group consisting of ASAAPXX (SEQ ID NO: 6437), ASASPXX (SEQ ID NO: 6438) and NDEGLEX (SEQ ID NO: 6447).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the muscle cell lineage, regenerating muscle tissues, enhancing of myogenesis, reinforcing muscle tissues, repairing damaged muscles, and protecting a subject from one or more muscle tissue degeneration-related diseases, disorders, conditions or pathologies, PEP9 is a peptide of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7-PEP5; wherein PEP5 is a peptide of formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPQ, VSQ and VPT; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular A, D, E and G; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular L, E and Q; wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably C, S, or E; wherein AA7 is selected from the group consisting of S, T, C, E, Q, P and R, preferably is S or C. In one particular example, PEP9 is selected from the group consisting of ASAAPXXVPQAL (SEQ ID NO: 6468), ASASPXXVSQDL (SEQ ID NO: 6478), ASASPXXVPQDL (SEQ ID NO: 6476), NDEGLEXVPTEE (SEQ ID NO: 6545) and NDEGLEXVPTGQ (SEQ ID NO: 6546).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the muscle cell lineage, regenerating muscle tissues, enhancing of myogenesis, reinforcing muscle tissues, repairing damaged muscles, and protecting a subject from one or more muscle tissue degeneration-related diseases, disorders, conditions or pathologies, PEP12 is a peptide of general formula PEP1-AA17-PEP11; wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is I or M); wherein PEP1 is RSVK (SEQ ID NO: 6359) or RPVQ (SEQ ID NO: 6358).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the muscle cell lineage, regenerating muscle tissues, enhancing of myogenesis, reinforcing muscle tissues, repairing damaged muscles, and protecting a subject from one or more muscle tissue degeneration-related diseases, disorders, conditions or pathologies, PEP11 is a peptide with 3 amino acids of general formula AA18-AA19-AA20; wherein AA18 is selected from the group consisting of L, V, Q, A and R, in particular is A or R; wherein AA19 is selected from the group consisting of AAVII amino acids (in particular is K); wherein AA20 is selected from the group consisting of L, F, Y, K, I, V and M, in particular is V or I. In one particular example, PEP11 is AKV or RKI.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the muscle cell lineage, regenerating muscle tissues, enhancing of myogenesis, reinforcing muscle tissues, repairing damaged muscles, and protecting a subject from one or more muscle tissue degeneration-related diseases, disorders, conditions or pathologies, PEP1 is RSVK (SEQ ID NO: 6359) or RPVQ (SEQ ID NO: 6358); PEP11 is is AKV or RKI; and the pair PEP1:PEP11 is RSVK (SEQ ID NO: 6359):AKV or RPVQ (SEQ ID NO: 6358):RKI.
The definitions of “PEP” pairs and triplets e.g. PEP3:PEP1, PEP5:PEP12, or PEP7:PEP5:PEP1, also most particularly embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the muscle cell lineage, regenerating muscle tissues, enhancing of myogenesis, reinforcing muscle tissues, repairing damaged muscles, and protecting a subject from one or more muscle tissue degeneration-related diseases, disorders, conditions or pathologies, are as already defined herein to the extent that PEP1, PEP3, PEP5, PEP7, PEP9, PEP11 and PEP12 are particularly useful for these applications as defined in the present muscle section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the muscle cell lineage, regenerating muscle tissues, enhancing of myogenesis, reinforcing muscle tissues, repairing damaged muscles, and protecting a subject from one or more muscle tissue degeneration-related diseases, disorders, conditions or pathologies, said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the muscle cell lineage, regenerating muscle tissues, enhancing of myogenesis, reinforcing muscle tissues, repairing damaged muscles, and protecting a subject from one or more muscle tissue degeneration-related diseases, disorders, conditions or pathologies, said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
Blood
Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the blood cell lineage, regenerating blood tissues, and protecting patients from blood cell degeneration-related disease, conditions, disorders or pathologies.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the blood cell lineage, regenerating blood tissues, and protecting patients from blood cell degeneration-related disease, conditions, disorders or pathologies, PEP1 is SNIT (SEQ ID NO: 6362).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the blood cell lineage, regenerating blood tissues, and protecting patients from blood cell degeneration-related disease, conditions, disorders or pathologies, PEP3 is selected from the group consisting of TPT, VPA, VPT, APT, APV, VPQ, VSO, SRV and TQV.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the blood cell lineage, regenerating blood tissues, and protecting patients from blood cell degeneration-related disease, conditions, disorders or pathologies, PEP5 is a peptide of general formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of TPT, VPA, VPT, APT, APV, VPQ, VSO, SRV and TQV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is selected from the group consisting of K, R, A, D, H and Q; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is selected from the group consisting of M, L, T and H. In one particular example, PEP5 is selected from the group consisting of TPTKM (SEQ ID NO: 6388), VPARL (SEQ ID NO: 6401), VPTRL (SEQ ID NO: 6427), APTKL (SEQ ID NO: 6369), APVKT (SEQ ID NO: 6379), VPQAL (SEQ ID NO: 6410), VSODL (SEQ ID NO: 6429), VPQDL (SEQ ID NO: 6411), SRVHH (SEQ ID NO: 6382) and TQVQL (SEQ ID NO: 6393).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the blood cell lineage, regenerating blood tissues, and protecting patients from blood cell degeneration-related disease, conditions, disorders or pathologies, PEP7 is an amino acid or a peptide with between two and seven amino acids of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606); wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AAe is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of S, C, Q and R; wherein AA7 is absent or is selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of C, S and P; and wherein at least one of AA1, AA2, AA3, AA4, AA5, AA6 or AA7 is not absent. In one particular example, PEP7 is selected from the group consisting of GSAGPXX (SEQ ID NO: 6441), AAPASXX (SEQ ID NO: 6436), STPPTXX (SEQ ID NO: 6452), HVPKPXX (SEQ ID NO: 6442), RVPSTXX (SEQ ID NO: 6449), ASAAPXX (SEQ ID NO: 6437), ASASPXX (SEQ ID NO: 6438), SSVKXQP (SEQ ID NO: 6451) and RNVQXRP (SEQ ID NO: 6448).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the blood cell lineage, regenerating blood tissues, and protecting patients from blood cell degeneration-related disease, conditions, disorders or pathologies, PEP9 is a peptide of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7-PEP5; wherein PEP5 is a peptide of formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of TPT, VPA, VPT, APT, APV, VPQ, VSO, SRV and TQV; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is selected from the group consisting of K, R, A, D, H and Q; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular is selected from the group consisting of M, L, T and H; wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of S, C, Q and R; wherein AA7 is selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of C, S and P. In one particular example, PEP9 is selected from the group consisting of GSAGPXXTPTKM (SEQ ID NO: 6497), AAPASXXVPARL (SEQ ID NO: 6458), STPPTXXVPTRL (SEQ ID NO: 6573), HVPKPXXAPTKL (SEQ ID NO: 6503), RVPSTXXAPVKT (SEQ ID NO: 6550), ASAAPXXVPQAL (SEQ ID NO: 6468), ASASPXXVSQDL (SEQ ID NO: 6478), ASASPXXVPQDL (SEQ ID NO: 6476), SSVKXQPSRVHH (SEQ ID NO: 6565) and RNVQXRPTQVQL (SEQ ID NO: 6548).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the blood cell lineage, regenerating blood tissues, and protecting patients from blood cell degeneration-related disease, conditions, disorders or pathologies, PEP12 is a peptide of general formula PEP1-AA17-PEP11; wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, V and T); wherein PEP1 is SNIT (SEQ ID NO: 6362).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the blood cell lineage, regenerating blood tissues, and protecting patients from blood cell degeneration-related disease, conditions, disorders or pathologies, PEP11 is a peptide with 3 amino acids of general formula AA18-AA19-AA20; wherein AA18 is selected from the group consisting of L, V, Q, A and R, in particular is Q; wherein AA19 is selected from the group consisting of F, W, H, I and Y (in particular is 1); wherein AA20 is selected from the group consisting of L, F, Y, K, I, V and M, in particular is M. In one particular example, PEP11 is QIM.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the blood cell lineage, regenerating blood tissues, and protecting patients from blood cell degeneration-related disease, conditions, disorders or pathologies, PEP1 is SNIT (SEQ ID NO: 6362) and PEP11 is QIM.
The definitions of “PEP” pairs and triplets e.g. PEP3:PEP1, PEP5:PEP12, or PEP7:PEP5:PEP1, also most particularly embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the blood cell lineage, regenerating blood tissues, and protecting patients from blood cell degeneration-related disease, conditions, disorders or pathologies, are as already defined herein to the extent that PEP1, PEP3, PEP5, PEP7, PEP9, PEP11 and PEP12 are particularly useful for these applications as defined in the present blood section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the blood cell lineage, regenerating blood tissues, and protecting patients from blood cell degeneration-related disease, conditions, disorders or pathologies, said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the blood cell lineage, regenerating blood tissues, and protecting patients from blood cell degeneration-related disease, conditions, disorders or pathologies, said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
Adipose Tissues
Certain embodiments of the invention are particularly useful for inducing differentiation of mensenchymal or progenitor stem cells from the adipocyte lineage, regenerating adipose tissues and protecting patients from adipose tissue degeneration-related diseases, conditions, disorders or pathologies.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the adipocyte lineage, regenerating adipose tissues and protecting patients from adipose tissue degeneration-related diseases, conditions, disorders or pathologies, PEP1 is SAIS (SEQ ID NO: 6360) or NAIS (SEQ ID NO: 6357).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the adipocyte lineage, regenerating adipose tissues and protecting patients from adipose tissue degeneration-related diseases, conditions, disorders or pathologies, PEP3 is selected from the group consisting of VPT, VPE, APT, TPT, VPA, APV, VPQ and VSO.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the adipocyte lineage, regenerating adipose tissues and protecting patients from adipose tissue degeneration-related diseases, conditions, disorders or pathologies, PEP5 is a peptide of general formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, VPE, APT, TPT, VPA, APV, VPQ and VSO; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular is selected from the group consisting of E, K, Q, R, A and D; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular selected from the group consisting of L, M and T. In one particular example, PEP5 is selected from the group consisting of VPTEL (SEQ ID NO: 6421), VPEKM (SEQ ID NO: 6406), APTKL (SEQ ID NO: 6369), APTQL (SEQ ID NO: 6372), VPTKL (SEQ ID NO: 6423), TPTKM (SEQ ID NO: 6388), VPARL (SEQ ID NO: 6401), VPTRL (SEQ ID NO: 6427), APVKT (SEQ ID NO: 6379), VPQAL (SEQ ID NO: 6410), VSODL (SEQ ID NO: 6429) and VPQDL (SEQ ID NO: 6411).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the adipocyte lineage, regenerating adipose tissues and protecting patients from adipose tissue degeneration-related diseases, conditions, disorders or pathologies, PEP7 is an amino acid or a peptide with between two and seven amino acids of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606); wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AA6 is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of C, S and T; wherein AA7 is absent or is selected from the group consisting of S, T, C, E, Q, P and R, preferably is C or S; and wherein at least one of AA1, AA2, AA3, AA4, AA5, AA6 or AA7 is not absent. In one particular example, PEP7 is selected from the group consisting of KIPKAXX (SEQ ID NO: 6445), GIPEPXX (SEQ ID NO: 6440), SIPKAXX (SEQ ID NO: 6450), HVTKPTX (SEQ ID NO: 6443), YVPKPXX (SEQ ID NO: 6454), TVPKPXX (SEQ ID NO: 6453), AVPKAXX (SEQ ID NO: 6439), KVGKAXX (SEQ ID NO: 6446), KASKAXX (SEQ ID NO: 6444), GSAGPXX (SEQ ID NO: 6441), AAPASXX (SEQ ID NO: 6436), STPPTXX (SEQ ID NO: 6452), HVPKPXX (SEQ ID NO: 6442), RVPSTXX (SEQ ID NO: 6449), ASAAPXX (SEQ ID NO: 6437) and ASASPXX (SEQ ID NO: 6438).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the adipocyte lineage, regenerating adipose tissues and protecting patients from adipose tissue degeneration-related diseases, conditions, disorders or pathologies, PEP9 is a peptide of general formula AA1-AA2-AA3-AA4-AA5-AA6-AA7-PEP5; wherein PEP5 is a peptide of formula PEP3-AA11-AA12; wherein PEP3 is selected from the group consisting of VPT, VPE, APT, TPT, VPA, APV, VPQ and VSO; wherein AA11 is selected from the group consisting of E, K, Q, R, A, D, G and H, in particular E, K, Q, R, A and D; wherein AA12 is selected from the group consisting of L, M, T, E, Q and H, in particular selected from the group consisting of L, M and T; wherein AA1, AA2, AA3, AA4, and AA5 are independently absent or AA1 as defined herein; wherein AAe is absent or selected from the group consisting of S, T, C, E, Q, P and R, preferably is selected from the group consisting of C, S and T; wherein AA7 is selected from the group consisting of S, T, C, E, Q, P and R, preferably is C or S. In one particular example, PEP9 is selected from the group consisting of KIPKAXXVPTEL (SEQ ID NO: 6535), GIPEPXXVPEKM (SEQ ID NO: 6491), SIPKAXXVPTEL (SEQ ID NO: 6563), HVTKPTXAPTKL (SEQ ID NO: 6511), YVPKPXXAPTKL (SEQ ID NO: 6583), TVPKPXXAPTQL (SEQ ID NO: 6575), AVPKAXXAPTKL (SEQ ID NO: 6479), KVGKAXXVPTKL (SEQ ID NO: 6543), KASKAXXVPTKL (SEQ ID NO: 6527), GSAGPXXTPTKM (SEQ ID NO: 6497), AAPASXXVPARL (SEQ ID NO: 6458), STPPTXXVPTRL (SEQ ID NO: 6573), HVPKPXXAPTKL (SEQ ID NO: 6503), RVPSTXXAPVKT (SEQ ID NO: 6550), ASAAPXXVPQAL (SEQ ID NO: 6468), ASASPXXVSQDL (SEQ ID NO: 6478) and ASASPXXVPQDL (SEQ ID NO: 6476).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the adipocyte lineage, regenerating adipose tissues and protecting patients from adipose tissue degeneration-related diseases, conditions, disorders or pathologies, PEP12 is a peptide of general formula PEP1-AA17-PEP11; wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, V and T); wherein PEP1 is SAIS (SEQ ID NO: 6360) or NAIS (SEQ ID NO: 6357).
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the adipocyte lineage, regenerating adipose tissues and protecting patients from adipose tissue degeneration-related diseases, conditions, disorders or pathologies, PEP11 is a peptide with 3 amino acids of general formula AA18-AA19-AA20; wherein AA19 is selected from the group consisting of L, V, Q, A and R, in particular is L; wherein AA19 is selected from the group consisting of F, W, H and Y (in particular is a polar aromatic amino acid such as Y); wherein AA2 is selected from the group consisting of L, F, Y, K, I, V and M, in particular is L or F. In one particular example, PEP11 is LYL or LYF.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the adipocyte lineage, regenerating adipose tissues and protecting patients from adipose tissue degeneration-related diseases, conditions, disorders or pathologies, PEP1 is SAIS (SEQ ID NO: 6360) or NAIS (SEQ ID NO: 6357); PEP11 is LYL or LYF; and the pair PEP1:PEP11 is SAIS (SEQ ID NO: 6360):LYL or NAIS (SEQ ID NO: 6357):LYF.
The definitions of “PEP” pairs and triplets e.g. PEP3:PEP1, PEP5:PEP12, or PEP7:PEP5:PEP1, also most particularly embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the adipocyte lineage, regenerating adipose tissues and protecting patients from adipose tissue degeneration-related diseases, conditions, disorders or pathologies, are as already defined herein to the extent that PEP1, PEP3, PEP5, PEP7, PEP9, PEP11 and PEP12 are particularly useful for these applications as defined in the present adipose tissue section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the adipocyte lineage, regenerating adipose tissues and protecting patients from adipose tissue degeneration-related diseases, conditions, disorders or pathologies, said GFR-binding compound is a synthetic molecule as defined herein in the definition section.
In certain embodiments useful for inducing differentiation of mensenchymal or progenitor stem cells from the adipocyte lineage, regenerating adipose tissues and protecting patients from adipose tissue degeneration-related diseases, conditions, disorders or pathologies, said GFR-binding compound is a synthetic peptide, or a variant or analog thereof, or a peptidomimetic.
Tissue Closure
In certain embodiments useful for promoting tissue closure, the choice of PEP1, PEP3, PEP5, PEP7, PEP9, PEP12, PEP11 and AA17 will depend on the type of specific tissue closure to be performed and may include any of the suitable amino acids, peptides, analog or variant thereof, or peptidomimetic, already disclosed herein with respect to the bone, cartilage, vascular, wound healing, neuronal, eye-retinal, kidneys, liver, L/T and skin applications. For instance, in certain embodiments, during bone repair surgery, different layers of tissue such as skin, muscle and blood vessel are incised in order to reach the damaged bone part. Thus, suitable PEP1, PEP3, PEP5, PEP7, PEP9, PEP12, PEP11 and AA17 for implementing embodiments of the invention in this specific situation may include such amino acids, peptides, analog or variant thereof, or peptidomimetic, already described herein with respect to skin, muscle, vascular and bone tissue regeneration/formation and cell migration. Likewise, for example, in certain embodiments, during heart surgery, different layers of tissue such as skin, muscle and blood vessel, are incised in order to reach the patient's heart. Thus, suitable PEP1, PEP3, PEP5, PEP7, PEP9, PEP12, PEP11 and AA17 for implementing embodiments of the invention in this specific situation include such amino acids, peptides, analog or variant thereof, or peptidomimetic, already described herein with respect to the skin, muscle and blood vessel tissue regeneration/formation and cell migration.
II. Bioactive Carriers
The present invention may achieve its intended therapeutic and/or cosmetic action(s) e.g. through efficient tissue induction, by functional combination (or association) with a bioactive carrier.
In one example, said GFR-binding compound and said bioactive carrier are thus operably associated, combined, linked or connected as defined herein and thus may form a pharmaceutical, dermatological, prophylactic, diagnostic, imaging or cosmetic association or combination for uses and methods as defined herein.
As may be used herein, the term “bioactive carrier”, “biocompatible carrier”, “bioactive material”, “biocompatible material”, “bioactive substance”, “bio-substance”, “biocompatible substance”, are used interchangeably.
A suitable bioactive carrier is compatible with living cells, tissues, organs or systems posing little to no risk of injury, toxicity or rejection by the immune system. Bioactive carriers suitable for implementing embodiments of the present invention include, but are not limited to, (a) a biopolymer such as (a1) collagen, (a2) fibrin; (b) a synthetic polymer such as (b1) ultra-high molecular weight polyethylene (UHMWPE), (b2) polyurethane (PE), (b3) polyurethane (PU), (b4) polytetrafuoroethylene (PTFE), (b5) polyacetal (PA), (b6) polymethylmethacrylate (PMMA), (b7) polyethylene terepthalate (PET), (b8) silicone rubber (SR), (b9) polyetheretherketone (PEEK), (b10) poly(lactic acid) (PLA), (b11) polysulfone (PS), (b12) PLLA, (b13) PLGA or (b14) PLDA; (c) metals and metal oxides such as (c1) gold and gold alloys, (c2) silver and silver alloys, (c3) platinum and platinum alloys, (c4) tantalum, (c5) Ti6Al4V, (c6) 316L stainless steel, (c7) Co—Cr Alloys, (c8) titanium alloys such as such as □-type, β-type, □+□-type Ti alloy, Ti—Nb alloys such as Ti29Nb13Ta4.6Zr or Ti35Nb4Sn); (d) metallic glasses; (e) amorphous alloys such as Zr-based alloys; (f) porous metals such as the ones reported in Ryan et al., 2006, Biomaterials, 27, 2651; Lopez-Heredia et al. 2008, Biomaterials, 29, 2608; Ryan et al., 2008, Biomaterials, 29, 3625; Li et al., 2007, Biomaterials, 28, 2810; or Hollander et al., 2006, Biomaterials, 27, 955; all being incorporated herein in their entirety; (g) gel or solid ceramics such as (g1) alumina, (g2) zirconia, (g3) carbon, (g4) titania, (g5) bioglass, or (g6) hydroxyapatite (HA); (h) composites such as (h1) silica/SR, (h2) CF/UHMWPE, (h3) CF/PTFE, (h4) HA/PE, (h5) CF/epoxy, (h6) CF/PEEK, (h7) CF/C or (h8) Al2O3/PTFE; (i) hydrogels such as (i1) polyisocyanopeptide hydrogels such as oligo(ethylene)glycol polyisocyanopeptides as described, for instance, in Van Buul, et al.; Chem. Sci. 4, 2357-2363 (2013), incorporated herein by reference in its entirety, (i2) polysaccharides such as alginates, chitosans, chitins, guar gums, pectins, gellan gums, heparins, carrageenans, hyaluronans, starches, agars, xanthan gums, methylcellulose, carboxymethylcellulose, hydroxypropyl methyl cellulose, (i3) polyglycols such as polyethyleneglycol or polypropyleneglycol, (i4) polyvinylpyrrolidone, (i5) poly(vinylalcohol), (i6) polyacrylic acids, (i7) glycerophosphates, (i8) 2-acrylamido-2-methylpropanesulfonic acid, (i9) polyphosphazenes; (j) other suitable materials such as demineralized bone matrix; and any combinations thereof.
Suitable sources of bioactive carriers for implementing embodiments of the present invention include, but are not limited to, autographs, allographs, xenographs, plants, solutions, excipients, ceramics, metals, metal alloys, organic and inorganic polymers, bioglasses, carbon-containing structures, or combination thereof.
Particularly suitable as bioactive carriers for implementing embodiments of the present invention include bioactive carriers comprising at least one naturally occurring hydroxyl group on at least one surface thereof and bioactive carriers which do not naturally comprise at least one hydroxyl group on a surface thereof but which have been modified using conventional surface treatment techniques such that at least one hydroxyl group is present on a surface of the bioactive carrier. In one example, said hydroxyl group is an available hydroxyl group i.e. it is not prevented from interacting and/or reacting with a compound of the present disclosure. Suitable as bioactive carriers naturally containing hydroxyl groups on a surface thereof for implementing embodiments of the invention specifically include metal oxides such as titanium oxides and non-metal oxides such ceramics. Also suitable as bioactive carriers for implementing embodiments of the invention include bioactive carriers comprising at least one naturally occurring carboxylate group (—COOH) or amine group (—NH2) on at least one of a surface thereof and bioactive carriers which do not naturally comprise at least one carboxylate group (—COOH) or amine group (—NH2) onto a surface thereof but which have been modified using conventional surface treatment techniques such that at least one carboxylate group (—COOH) or amine group (—NH2) is present on a surface of the bioactive carrier.
In one example, said bioactive carrier includes a biomaterial. Suitable biomaterials for implementing certain embodiments of the present disclosure may be derived from nature or synthesized in the laboratory using a variety of chemical approaches utilizing metallic components, polymers, ceramics or composite materials. They are often used and/or adapted for a medical application, and thus comprise whole or part of a living structure or biomedical device. Suitable biomaterials for implementing certain embodiments of the present disclosure are commonly used in joint replacements, bone plates, bone cement, artificial ligaments and tendons, dental implants for tooth fixation, blood vessel prostheses, heart valves, skin repair devices (artificial tissue), cochlear replacements, contact lenses, breast implants, drug delivery mechanisms, sustainable materials, vascular grafts, stents, nerve conduits. Particularly suitable biomaterials for implementing certain embodiments of the present disclosure such as metals and alloys (pages 94-95), ceramics (pages 95-97), polymeric biomaterials (pages 97-98) and biocomposite materials (pages 98-99) are described in Nitesh et al., International Journal of Emerging Technology and Advanced Engineering, ISSN 2250-2459, Volume 2, Issue 4, 2012, which is herein incorporated by reference in its entirety.
In one particular example, said bioactive carrier is a biomaterial.
In certain embodiments, particularly suitable bioactive carriers are selected from the group consisting of bioinert biomaterials, bioactive biomaterials and bioresorbable biomaterials.
The nature of the biomaterial is an important parameter. Particularly good results have been obtained using bioactive carriers composed mostly with the main material component of the tissue to be regenerated and/or repaired. This generally allows for a better integration of the bioactive carrier, a better resorption from the surrounding cells already present and therefore a better regeneration or repair of the targeted tissue to be achieved. For example, it was discovered that particularly good results may be obtained when a solid ceramic component (granulated ceramic powder or ceramic scaffolds) or a gel ceramic component is used in combination of a GFR-binding peptide of the present disclosure to regenerate bone and protect from osteoporosis. For example, it was also discovered that particularly good results may be obtained when collagen, in particular collagen types I, II, III and XI, is used in combination of a GFR-binding peptide of the present disclosure to regenerate cartilage. For example, it was also discovered that particularly good results may be obtained when collagen, in particular collagen types I and III, or a biodegradable hydrogel is used in combination of a GFR-binding peptide of the present disclosure to regenerate muscle, skin, tendons and ligaments. For example, it was also discovered that particularly good results may be obtained when a collagen or a biodegradable hydrogel is used in combination of a GFR-binding peptide of the present disclosure to regenerate tissues and/or functions of vascular, neuron, eye retina, renal, wound healing, hair, fertility and reproduction, lung, and adipose tissues.
Bioinert biomaterials: As used herein, unless indicated otherwise or contradictory in context, the term “bioinert biomaterials” refers to any material that once placed in the human body has minimal interaction with its surrounding tissue. Examples of these are stainless steel, titanium, alumina, partially stabilised zirconia, and ultra-high molecular weight polyethylene. Generally a fibrous capsule might form around bioinert implants hence its biofunctionality relies on tissue integration through the implant.
Bioactive biomaterial: As used herein, unless indicated otherwise or contradictory in context, the term “bioactive biomaterial” refers to a material which, upon being placed within the human body, interacts with the surrounding bone and in some cases, even soft tissue. This occurs through a time-dependent kinetic modification of the surface, triggered by their implantation within the living bone. An ion-exchange reaction between the bioactive implant and surrounding body fluids, results in the formation of a biologically active carbonate apatite (CHAp) layer on the implant that is chemically and crystallographically equivalent to the mineral phase in bone. Examples of these materials are synthetic hydroxyapatite [Ca10(PO4)6(OH)2], glass ceramic A-W and bioglass®.
Bioresorbable Biomaterials: As used herein, unless indicated otherwise or contradictory in context, the term “bioresorbable biomaterials” refers to a material which, upon placement within the human body, starts to dissolve (resorbed) and slowly replaced by advancing tissue (such as bone). Examples of bioresorbable materials include, but are not limited to, tricalcium phosphate [Ca3(PO4)2], polylactic-polyglycolic acid copolymers, calcium oxide, calcium carbonate and gypsum.
Therefore, no particular limitation should be ascribed to the substance, material or molecule suitable as being bioactive carriers for implementing embodiments of the present invention insofar as said substance, material or molecule is (a) biocompatible as defined herein and (b) combinable or associable with a GFR-binding compound as defined herein. In one preferred example, said bioactive carrier has a stiffness of at least 5 kPa, more preferably at least 35 kPa and preferably not more than 3 or 5 GPa as measured using conventional Dynamic Mechanical Analysis such as described in details in Gong JP et al., Double-network hydrogels with extremely high mechanical strength, Adv Mater 2003, 15(14), 1155e8, which is incorporated herein by reference.
In one particular example, a biomaterial as defined herein for use in neuron-related applications has a stiffness comprised between about 0.01 kPa and about 3 kPa, preferably between about 0.01 kPa and about 1 kPa. In one particular example, a biomaterial as defined herein for use in muscle, cartilage and tendon/ligament—related applications has a stiffness comprised between about 3 kPa and about 200 kPa, preferably between about 10 kPa and about 30 kPa. In one particular example, a biomaterial as defined herein for use in bone-related applications has a stiffness comprised between about 30 kPa and about 3 GPa, preferably between about 70 kPa and about 200 kPa for instance in applications such as the treatment or prevention of osteoporosis and bone tissue regeneration. In one particular example, a biomaterial as defined herein for use in hair-related applications has a stiffness comprised between about 0.01 kPa and about 200 kPa, preferably between about 3 kPa and about 70 kPa. In one particular example, a biomaterial as defined herein for use in endothelization-related applications has a stiffness comprised between about 500 kPa and about 2.5 GPa. In one particular example, a biomaterial as defined herein for use in angiogenesis-related applications has a stiffness comprised between about 0.01 kPa and about 100 kPa. In one particular example, a biomaterial as defined herein for use in wound healing and skin-related applications has a stiffness comprised between about 0.01 kPa and about 70 kPa.
Available hydroxyl groups: As used herein, unless indicated otherwise or contradictory in context, the term “free hydroxyl” or “available hydroxyl” means an hydroxyl group, which may be —OH or a radical (—O′) or an anion (—O′) fully or partially ionised, which is able to/free to act as a nucleophile in a reaction with an electrophile such as compound (A) or compound (B) defined below.
Available hydroxyl-containing surface: As used herein, unless indicated otherwise or contradictory in context, the term “available hydroxyl-containing surface” or “free hydroxyl-containing surface” means a surface containing at least one free or available hydroxyl group as defined herein.
Ceramics: As used herein, unless indicated otherwise or contradictory in context, the term “ceramic” refers to an inorganic material with a high melting point, above 1000° C. Most typically, materials referred to as “ceramics” are obtained by a process in which raw material solid particles are heated in order to sinter them. Materials referred to as “ceramics” may broadly be split into two groups, these being “oxide ceramics” and “non-oxide ceramics”. “Oxide ceramics” include, but are not limited to, akaline earth oxides such as MgO and BaO, Al2O3 and aluminates, TiO2 and titanates, ZrO2 and zirconates, silicates such as clays and clay-derived materials. Since the term “ceramics” may encompass crystalline, partially amorphous and fully amorphous materials, the term “oxide ceramics” may also be interpreted as covering fully amorphous silicate glasses. “Non-oxide ceramics” include, but are not limited to, carbides and nitrides, and also borides and silicides, for example silicon carbide and silicon nitride, and also metal carbides and nitrides. In one particular example, solid ceramics e.g. in granulated powder or as a scaffold, is used as a bioactive carrier in the meaning of the present disclosure in bone-related applications. In one particular example, gel ceramics is used as a bioactive carrier in the meaning of the present disclosure in bone-related applications.
Metal oxides: As used herein, unless indicated otherwise or contradictory in context, the term “metal oxide” means a chemical compound that contains at least one oxygen atom and one other element in its chemical formula. Metal oxides typically contain an anion of oxygen in the oxidation state of −2. They can be obtained by hydrolysis or air/oxygen oxidation. Examples of such metal oxides are titanium oxides (e.g. TIO, Ti2O3, TiO2), silicon oxide (SiO2), aluminum oxide (Al2O3), iron (II, III) oxides such as Fe2O3, and zinc oxide (ZnO).
Biopolymer: As used herein, unless indicated otherwise or contradictory in context, the term “biopolymer” refers to a polymer produced by living organisms and includes, but is not limited to, polypeptides and proteins (such as collagen and fibrin), polysaccharides (such as cellulose, starch, chitin and chitosan), nucleic acids (such as DNA and RNA), and hydrides thereof.
Hydrogel: As used herein, unless indicated otherwise or contradictory in context, the term “hydrogel” refers to “Hydrogel” refers to a class of polymeric materials which are swollen in an aqueous medium, but which do not dissolve in water. Hydrogels are highly absorbent (they can contain over 99% water) natural or synthetic polymers. Hydrogels also possess a degree of flexibility very similar to natural tissue, due to their significant water content. U.S. Pat. No. 6,475,516, for example, provides hydrogels being covalently bound to the surface of an in-dwelling medical device such as an implant, which may be functionalized with a GFR-binding compound of the present disclosure using, for instance, a process as described herein. In one particular example, biodegradable hydrogels are used as bioactive carriers in the meaning of the present disclosure.
Collagen: As used herein, unless indicated otherwise or contradictory in context, the term “collagen” refers to the main structural protein of the various connective tissues in animals which is mostly found in fibrous tissues such as tendons, ligaments and skin, and is also abundant in corneas, cartilage, bones, blood vessels, the gut, and intervertebral discs. Collagen is typically composed of a triple helix and generally contains high hydroxyproline content. The most common motifs in its amino acid sequence glycine-proline-X and glycine-X-hydroxyproline, where X is any amino acid other than glycine, proline or hydroxyproline. 28 types of collagen have been identified and described in the literature, which are all presently contemplated to be suitable for implementing embodiments of the invention. The five most common types are: Collagen I which may be found in skin, tendon, vascular ligature, organs, bone (main component of the organic part of bone); Collagen II which may be found in cartilage (main component of cartilage); Collagen III which may be found in reticulate (main component of reticular fibers); Collagen IV which may be found in the basal lamina, the epithelium-secreted layer of the basement membrane; Collagen V which may be found on cell surfaces, hair and placenta. For example, in certain embodiments, suitable collagens for implementing embodiments of the present invention particularly include collagen type-I and type-IV. In one particular example, collagen, in particular collagen types I, II, III and XI, is used as a bioactive carrier in the meaning of the present disclosure in cartilage-related applications. In one particular example, collagen, in particular collagen types I and III, is used as a bioactive carrier in the meaning of the present disclosure in muscle-related applications, skin-related applications, and T/L-related applications. In one particular example, any type of collagen is used as a bioactive carrier in the meaning of the present disclosure in vascular, neuron, eye retina, renal, wound healing, hair, fertility and reproduction, lung, adipose—related applications.
In certain embodiments, said association, combination, linkage or connection between said GFR-binding compound and a bioactive carrier may occur via a bioactive carrier-affinity-containing group as defined herein.
IV. Bioactive Carrier-Affinity-Containing Group
In one aspect, the present disclosure provides a GFR-binding compound as already defined herein modified or functionalised with at least one bioactive carrier-affinity-containing group. Said at least one bioactive carrier-affinity-containing group provides said GFR-binding compound with the ability to, covalently or non-covalently, interact with, or be connected to, a bioactive carrier as defined herein (in particular, a biomaterial as defined herein).
In such embodiments where affinity is required via covalent interaction or binding, said bioactive carrier-affinity-containing group may be a thiol (SH)-containing group or a cysteine-containing group, in particular, a thiol (SH)-containing peptide or a cysteine-containing peptide. In such embodiments where affinity is required via covalent interaction or binding, said bioactive carrier-affinity-containing group may particularly be a cysteine.
In such embodiments where affinity is required via non-covalent interaction or binding, said bioactive carrier-affinity-containing group may comprise (or be) a peptide group such as any one of the peptide groups disclosed in US patent application No. 2008/0268015 A1, which is hereby incorporated by reference in its entirety. In particular, peptides containing amino acid sequences rich in large aromatic amino acid residues (aromatic amino acid-containing peptides or peptidomimetics) that include one or more of Phe, Trp, Tyr such as sequences no: 1 to 45 described in US 2008/0268015 A1 are suitable as a biomaterial-affinity-containing fragment for implementing embodiments of the present invention. Said fragment may also be a peptide fragment such as any one of the peptide fragments disclosed in U.S. Pat. No. 6,818,620 B2, which is hereby incorporated by reference in its entirety. In particular, peptides of sequences no: 1 to 7 described in U.S. Pat. No. 6,818,620 B2 are suitable as a biomaterial-affinity-containing fragment for implementing embodiments of the present invention.
In one particular example, said bioactive carrier-affinity-containing group is a bioactive carrier high-affinity-containing group such as a biomaterial high-affinity-containing group.
In certain embodiments, said bioactive carrier-affinity-containing group has some affinity (preferably high affinity) with a given bioactive carrier (in particular, a biomaterial) such as collagen, apatite, titanium or any of those listed in e.g. US patent application No. 2008/0268015 A1, which is incorporated herein by reference. For instance, a group having some affinity with a biomaterial is any group capable to non-covalently interact/bind to a biomaterial with an affinity/specificity selected from at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 200%, at least 300%, at least 400%, at least 500%, or a higher percentage, with respect to an affinity where said group binds to an appropriate control such as, for example, a different material or surface, or a protein typically used for such comparisons such as bovine serum albumin. In one example, a biomaterial-affinity-containing group has a binding specificity that is characterized by a relative binding affinity as measured by an EC50 of 10 μM or less, and in certain embodiments, less than 1 μM. In certain embodiments, a relative affinity comprised between 1 μM and 100 μM, between 1 μM and 10 μM, or between 1 μM and 1 μM is particularly suitable. The EC50 is determined using any number of methods known in the art. In this case, the EC50 represents the concentration of fragment producing 50% of the maximal binding observed for that fragment in the assay.
In one particular example, said bioactive carrier-affinity-containing group is selected from the group consisting of GTPGP (SEQ ID NO: 6610), which may preferably non-covalently interact with a bioactive carrier such as an apatite, and WWFWG (SEQ ID NO: 6611), which may preferably non-covalently interact with a bioactive carrier such as a collagen.
In one particular example, said bioactive carrier-affinity-containing group is covalently or non-covalently (in particular, covalently) attached at an end (or extremity) of said GFR-binding compound.
V. Modified GFR-Binding Compound
Thus, in one aspect, the present disclosure provides a modified GFR-binding compound comprising a GFR-binding compound as defined in the present disclosure and a bioactive carrier-affinity-containing group; and wherein the RMSD of the GFR-binding compound is 2.45 Å or less.
For example, in certain embodiments, the present disclosure provides a modified GFR-binding compound comprising a GFR-binding compound as defined in the present disclosure and a bioactive carrier-affinity-containing group; wherein said bioactive carrier-affinity-containing group is selected from the group consisting of a thiol-containing group (in particular, a thiol-containing peptide), a cysteine-containing group (in particular, a cysteine-containing peptide and more particularly, a cysteine), and an aromatic amino acid-containing peptide or peptidomimetic; and wherein the RMSD of the GFR-binding compound is 2.45 Å or less.
For example, in certain embodiments, the present disclosure provides a modified GFR-binding compound comprising a GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8-30 amino acids, in particular between 8-25 amino acids or between 8-22 amino acids, more particularly between 18-22 amino acids, even more particularly between 19-21 or 20, comprising a peptide with four amino acids (PEP1) selected from the group consisting of SAIS (SEQ ID NO: 6360), SSLS (SEQ ID NO: 6365), NAIS (SEQ ID NO: 6357), SATS (SEQ ID NO: 6361), SPIS (SEQ ID NO: 6364), EPIS (SEQ ID NO: 6353), SPIN (SEQ ID NO: 6363), KPLS (SEQ ID NO: 6356), EPLP (SEQ ID NO: 6354), EPLT (SEQ ID NO: 6355), SNIT (SEQ ID NO: 6362), RSVK (SEQ ID NO: 6359) and RPVQ (SEQ ID NO: 6358); wherein said bioactive carrier-affinity-containing group is selected from the group consisting of a thiol-containing group (in particular, a thiol-containing peptide), a cysteine-containing group (in particular, a cysteine-containing peptide and more particularly, a cysteine), and an aromatic amino acid-containing peptide or peptidomimetic; and wherein the RMSD of the GFR-binding compound is 2.45 Å or less.
For example, in certain embodiments, the present disclosure provides a modified GFR-binding compound comprising a GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8-30 amino acids, in particular between 8-25 amino acids or between 8-22 amino acids, more particularly between 18-22 amino acids, even more particularly between 19-21 or 20, comprising a peptide with height amino acids of general formula (PEP12): PEP1-AA17-PEP11; wherein PEP1 is a peptide with four amino acids selected from the group consisting of SAIS (SEQ ID NO: 6360), SSLS (SEQ ID NO: 6365), NAIS (SEQ ID NO: 6357), SATS (SEQ ID NO: 6361), SPIS (SEQ ID NO: 6364), EPIS (SEQ ID NO: 6353), SPIN (SEQ ID NO: 6363), KPLS (SEQ ID NO: 6356), EPLP (SEQ ID NO: 6354), EPLT (SEQ ID NO: 6355), SNIT (SEQ ID NO: 6362), RSVK (SEQ ID NO: 6359) and RPVQ (SEQ ID NO: 6358); wherein PEP11 is a peptide with 3 amino acids of formula AA18-AA19-AA20; wherein AA17 is selected from the group consisting of G, A, V, L, I, P, F, M, W, T and S (in particular is selected from the group consisting of M, I, L, V and T); wherein AA18 is selected from the group consisting of L, V, Q, A and R; wherein AA19 is selected from the group consisting of F, W, H and Y (in particular is an aromatic, polar amino acid such as Y); wherein AA20 is selected from the group consisting of L, F, Y, K, I, V and M; wherein said bioactive carrier-affinity-containing group is selected from the group consisting of a thiol-containing group (in particular, a thiol-containing peptide), a cysteine-containing group (in particular, a cysteine-containing peptide and more particularly, a cysteine), and an aromatic amino acid-containing peptide or peptidomimetic; and wherein the RMSD of the GFR-binding compound is 2.45 Å or less.
For example, in certain embodiments, the present disclosure provides a modified GFR-binding compound comprising a GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, having the following general formula (I) (hereinafter may also be referred to as compound (I) or peptide (I)):
PEP(C)−PEP12 (I)
wherein PEP12 is a peptide with 8 amino acids of formula PEP1-AA17-PEP11 as defined herein; wherein one end of PEP(C) interacts covalently with PEP12 via one end of PEP1; wherein PEP(C) is a peptide with at least 5 amino acids, in particular a peptide with between 5 and 12 amino acids; wherein said bioactive carrier-affinity-containing group is selected from the group consisting of a thiol-containing group (in particular, a thiol-containing peptide), a cysteine-containing group (in particular, a cysteine-containing peptide and more particularly, a cysteine), and an aromatic amino acid-containing peptide or peptidomimetic; and wherein the RMSD of the GFR-binding compound is 2.45 Å or less.
For example, in certain embodiments, the present disclosure provides a modified GFR-binding compound comprising a GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, having the following general formula (II) (hereinafter may also be referred to as compound (II) or peptide (II)):
PEP7−PEP5−PEP12 (II)
wherein PEP12 is a peptide with 8 amino acids of formula PEP1-AA17-PEP11 as defined herein; wherein PEP5 is a peptide with five amino acids as defined herein; wherein PEP7 is an amino acid or a peptide with between two and seven amino acids as defined herein; wherein one end of PEP5 interacts covalently with one end of PEP12 via one end of PEP1; wherein another end of PEP5 interacts covalently with one end of PEP7 via AA7; wherein said bioactive carrier-affinity-containing group is selected from the group consisting of a thiol-containing group (in particular, a thiol-containing peptide), a cysteine-containing group (in particular, a cysteine-containing peptide and more particularly, a cysteine), and an aromatic amino acid-containing peptide or peptidomimetic; and wherein the RMSD of the GFR-binding compound is 2.45 Å or less.
For example, in certain embodiments, the present disclosure provides a modified GFR-binding compound comprising a GFR-binding compound and a bioactive carrier-affinity-containing group; wherein said GFR-binding compound is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, having the following general formula (III) (hereinafter may also be referred to as compound (III) or peptide (III)):
AA
1-AA2-AA3-AA4-AA5-AA6-AA7-AA-AA9-AA10-AA11-AA12-AA13-AA14-AA15-AA16-AA17-AA18-AA19-AA20 (III)
wherein AA1-AA2-AA3-AA4-AA5-AA6-AA7 (SEQ ID NO: 6606) is PEP7 as defined herein; wherein AA13-AA14-AA15-AA16-AA17-AA18-AA19-AA20 is PEP12 as defined herein; wherein AA8-AA9-AA10 is PEP3 as defined herein; wherein AA11 and AA12 are as defined herein; wherein AA1 may be an N-terminal amino acid or a C-terminal amino acid; wherein AA20 may be an N-terminal amino acid or a C-terminal amino acid; wherein said bioactive carrier-affinity-containing group is selected from the group consisting of a thiol-containing group (in particular, a thiol-containing peptide), a cysteine-containing group (in particular, a cysteine-containing peptide and more particularly, a cysteine), and an aromatic amino acid-containing peptide or peptidomimetic; and wherein the RMSD of the GFR-binding compound is 2.45 Å or less.
VI. Functionalised Bioactive Carriers
In one aspect, the present disclosure provides a functionalised bioactive carrier, which may be used for inducing, in-vitro, ex-vivo or in-vivo, tissue regeneration, comprising at least one GFR-binding compound (in particular, at least one modified GFR-binding compound) as defined in the present disclosure. In one example, said (modified) GFR-binding compound and bioactive carrier are both active principles/ingredients. In certain embodiments, said functionalised bioactive carrier is a modified, functionalised, coated or grafted biomaterial as defined herein, in particular, a modified, functionalised, coated or grafted tissue regeneration compatible-biomaterial.
In one example, said functionalised bioactive carrier comprises one (modified) GFR-binding compound. In one example, said functionalised bioactive carrier comprises two or more distinct (modified) GFR-binding compounds. In one example, said functionalised bioactive carrier comprises three or more distinct (modified) GFR-binding compounds. In one example, said functionalised bioactive carrier comprises four or more distinct (modified) GFR-binding compounds.
Active or bioactive principles or Ingredients: In the present description and unless otherwise indicated or contradictory in context, the term “(bio)active principle” or “(bio)active ingredient” generally refers to a molecule, compound or substance which is responsible for providing the desired biological effect. Without said active ingredient, the formulation or composition containing it, would not provide the desired biological effect. For example, in certain embodiments, formulation excipients are not considered as active ingredients in the pharmaceutical composition as defined herein.
In one example, said functionalised bioactive carrier is formed using a method comprising, or exclusively consisting of, contacting a bioactive carrier as defined herein and a (modified) GFR-binding compound under reacting conditions thereby functionalizing at least one part (or at least one part of a surface) of said bioactive carrier and thus forming a functional association, interaction or bond between said bioactive carrier and said (modified) GFR-binding compound.
In the present description and unless otherwise indicated or contradictory in context, the terms “functionally associated”, “functionally combined”, “functionalized”, “Immobilized”, “deposited”, “coated”, or “grafted” all refer to the action of associating or functionalising at least one part of a bioactive carrier with a (modified) GFR-binding compound so that the desired biological, therapeutic and/or cosmetic effect e.g. inducing tissue formation, is obtained. The association or combination may be covalent and form, between said (modified) GFR-binding compound and said bioactive carrier, a covalent interaction as already defined herein, or, the association or combination may be non-covalent and form, between said (modified) GFR-binding compound and said bioactive carrier, a non-covalent interaction as already defined herein.
For example, in certain embodiments, a (modified) GFR-binding compound interacts covalently (makes at least one functional covalent interaction) with said bioactive carrier.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound, wherein said (modified) GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, having growth factor receptor-binding capability or capabilities, having a molecular weight of between 600-4,000 Da, 600-3,000 Da, or 800-4,000 Da, in particular between 800 and 3,000 Da; and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound, wherein said (modified) GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, having growth factor receptor-binding capability or capabilities, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with four amino acids (PEP1); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound, wherein said (modified) GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with eight amino acids (PEP12); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound, wherein said (modified) GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with four amino acids (PEP1); wherein said GFR-binding compound further comprises a peptide with three amino acids (PEP3); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound, wherein said (modified) GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with eight amino acids (PEP12); wherein said GFR-binding compound further comprises a peptide with three amino acids (PEP3); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound, wherein said (modified) GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with four amino acids (PEP1); wherein said GFR-binding compound further comprises a peptide with five amino acids (PEP5); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound, wherein said (modified) GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with eight amino acids (PEP12); wherein said GFR-binding compound further comprises a peptide with five amino acids (PEP5); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound, wherein said (modified) GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with four amino acids (PEP1); wherein said GFR-binding compound further comprises a peptide with between six and twelve amino acids (PEP9); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound, wherein said (modified) GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with eight amino acids (PEP12); wherein said GFR-binding compound further comprises a peptide with between six and twelve amino acids (PEP9); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound, wherein said (modified) GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with four amino acids (PEP1); wherein said GFR-binding compound further comprises a peptide with three amino acids (PEP3), an amino acid or a peptide with between two and seven amino acids (PEP7); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound, wherein said (modified) GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with four amino acids (PEP12); wherein said GFR-binding compound further comprises a peptide with three amino acids (PEP3), an amino acid or a peptide with between two and seven amino acids (PEP7); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound, wherein said (modified) GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with four amino acids (PEP1); wherein said GFR-binding compound further comprises a peptide with five amino acids (PEP5), an amino acid or a peptide with between two and seven amino acids (PEP7); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound, wherein said (modified) GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, comprising a peptide with four amino acids (PEP12); wherein said GFR-binding compound further comprises a peptide with five amino acids (PEP5), an amino acid or a peptide with between two and seven amino acids (PEP7); and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound, wherein said (modified) GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, having the following general formula (I) (hereinafter may also be referred to as compound (I) or peptide (I)):
PEP(C)−PEP12 (I)
wherein PEP12 is a peptide with 8 amino acids of formula PEP1-AA17-PEP11 as defined herein; wherein one end of PEP(C) interacts covalently with PEP12 via one end of PEP1; wherein PEP(C) is a peptide with at least 5 amino acids, in particular a peptide with between 5 and 12 amino acids; and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound of general formula (I), wherein PEP(C) comprises PEP3; and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound of general formula (I), wherein PEP(C) comprises PEP5; and wherein the RMSD is 2.45 Å or less. In one particular example, PEP(C) is PEP5.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound of general formula (I), wherein PEP(C) comprises PEP9; and wherein the RMSD is 2.45 Å or less. In one particular example, PEP(C) is PEP9.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound of general formula (I), wherein PEP(C) comprises PEP3 and PEP7; and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound of general formula (I), wherein PEP(C) comprises PEP5 and PEP7; and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound, wherein said GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, or a peptidomimetic as defined herein, with (comprising, or exclusively consisting of, or constituted of) between 8 and 30 (in particular between 8-25 or between 8-22, more particularly between 18-22, even more particularly between 19-21 or 20) amino acids, having the following general formula (II) (hereinafter may also be referred to as compound (II) or peptide (II)):
PEP7−PEP5−PEP12 (II)
wherein PEP12 is a peptide with 8 amino acids of formula PEP1-AA17-PEP11 as defined herein; wherein PEP5 is a peptide with five amino acids as defined herein; wherein PEP7 is an amino acid or a peptide with between two and seven amino acids as defined herein; wherein one end of PEP5 interacts covalently with one end of PEP12 via one end of PEP1; wherein another end of PEP5 interacts covalently with one end of PEP7 via AA7; and wherein the RMSD is 2.45 Å or less.
In one particular aspect, the present disclosure provides a functionalised biomaterial comprising a (modified) GFR-binding compound; wherein said biomaterial is as defined herein; wherein said (modified) GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, with between 18-22 amino acids comprising a peptide PEP1 or a peptide PEP12, and a peptide PEP3 or a peptide PEP5; wherein said (modified) GFR-binding compound optionally further comprises a peptide PEP7; and wherein the RMSD is 2.45 Å or less.
In one particular aspect, the present disclosure provides a functionalised biomaterial comprising a (modified) GFR-binding compound; wherein said biomaterial is as defined herein; wherein said (modified) GFR-binding compound (before any modifications) is a peptidomimetic comprising between 18-22 amino acids comprising a peptide PEP1 or a peptide PEP12, and a peptide PEP3 or a peptide PEP5; wherein said (modified) GFR-binding compound optionally further comprises a peptide PEP7; and wherein the RMSD is 2.45 Å or less.
In one particular aspect, the present disclosure provides a functionalised biomaterial comprising a (modified) GFR-binding compound; wherein said biomaterial is as defined herein; wherein said (modified) GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, with between 19-21 amino acids comprising a peptide PEP1 or a peptide PEP12, and a peptide PEP3 or a peptide PEP5; wherein said (modified) GFR-binding compound optionally further comprises a peptide PEP7; and wherein the RMSD is 2.45 Å or less.
In one particular aspect, the present disclosure provides a functionalised biomaterial comprising a (modified) GFR-binding compound; wherein said biomaterial is as defined herein; wherein said (modified) GFR-binding compound (before any modifications) is a peptidomimetic comprising between 19-21 amino acids comprising a peptide PEP1 or a peptide PEP12, and a peptide PEP3 or a peptide PEP5; wherein said (modified) GFR-binding compound optionally further comprises a peptide PEP7; and wherein the RMSD is 2.45 Å or less.
In one particular aspect, the present disclosure provides a functionalised biomaterial comprising a (modified) GFR-binding compound; wherein said biomaterial is as defined herein; wherein said (modified) GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, with 21 amino acids comprising a peptide PEP1 or a peptide PEP12, and a peptide PEP3 or a peptide PEP5; wherein said (modified) GFR-binding compound optionally further comprises a peptide PEP7; and wherein the RMSD is 2.45 Å or less.
In one particular aspect, the present disclosure provides a functionalised biomaterial comprising a (modified) GFR-binding compound; wherein said biomaterial is as defined herein; wherein said (modified) GFR-binding compound (before any modifications) is a peptidomimetic comprising 21 amino acids comprising a peptide PEP1 or a peptide PEP12, and a peptide PEP3 or a peptide PEP5; wherein said (modified) GFR-binding compound optionally further comprises a peptide PEP7; and wherein the RMSD is 2.45 Å or less.
In one particular aspect, the present disclosure provides a functionalised biomaterial comprising a (modified) GFR-binding compound; wherein said biomaterial is as defined herein; wherein said (modified) GFR-binding compound (before any modifications) is a peptide, a variant or analog thereof, with 20 amino acids comprising a peptide PEP1 or a peptide PEP12, and a peptide PEP3 or a peptide PEP5; wherein said (modified) GFR-binding compound optionally further comprises a peptide PEP7; and wherein the RMSD is 2.45 Å or less.
In one particular aspect, the present disclosure provides a functionalised biomaterial comprising a (modified) GFR-binding compound; wherein said biomaterial is as defined herein; wherein said (modified) GFR-binding compound (before any modifications) is a peptidomimetic comprising 20 amino acids comprising a peptide PEP1 or a peptide PEP12, and a peptide PEP3 or a peptide PEP5; wherein said (modified) GFR-binding compound optionally further comprises a peptide PEP7; and wherein the RMSD is 2.45 Å or less.
In one aspect, the present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound, wherein said GFR-binding compounds may be any one of or a plurality of peptides of SEQ ID NO: 1 to 1085 and 1143 to 6352.
The present disclosure provides a functionalised bioactive carrier comprising a (modified) GFR-binding compound, wherein all of PEP1, PEP3, PEP5, PEP9, PEP11, PEP12 and AA17, pairs and triplets thereof, disclaimers and provisos, are as already defined herein.
Suitable covalent association or functionalization techniques for implementing embodiments of the present invention include, but are not limited to, reductive amination coupling or photo-grafting such as described in H. Freichel et al., Macromol. Rapid Commun. 2011, 32, 616-621 and V. Pourcelle et al., Biomacromol. 2009, 10, 966-974, the content of which is hereby incorporated by reference in its entirety.
In one aspect, the present disclosure provides a production method or process useful for producing a functionalised bioactive carrier according to the present disclosure wherein said bioactive carrier is a biomaterial such as a ceramic or a titanium, comprising, or exclusively consisting of, the contacting of a compound of formula (C—I) and a bioactive carrier as defined herein under suitable covalent-bond formation conditions thereby forming at least one covalent bond between said compound (C—I) and said bioactive carrier thus forming a functionalised bioactive carrier according to the present disclosure:
wherein X is Si; wherein Y is a divalent organic linker; wherein A is a (modified) GFR-binding compound according to the present disclosure, wherein R1 and R2 are both independently an organic spacing-compound other than a leaving group as defined herein, and wherein R3 is a leaving group as defined herein;
In one particular example, a process or method which may be used to functionally associate or combine a (modified) GFR-binding compound with a bioactive carrier such as a ceramic or a titanium is shown in Scheme 1:
Such syntheses involve the formation of a covalent interaction (or association) between a (modified) GFR-binding compound (represented as (A)-SH in Scheme 1) and a bioactive carrier as defined herein.
In one particular example, a process or method which may be used to functionally associate or combine a (modified) GFR-binding compound with a bioactive carrier is a method for covalent functionalization or depositing of a (modified) GFR-binding compound onto a polyetheretherketone polymer (PEEK) surface wherein (i) the polymer is treated with ethylene diamine (NH2═NH2) to create NH2 functions on a PEEK surface from ketone (═O) functions and (ii) the hereby modified PEEK-NH2 polymer is immersed in a solution of a chosen hetero-bifunctional cross-linker such as 3-succinimidyl-3-maleimidopropionate thereby reacting the maleimide group with a (modified) GFR-binding compound through e.g. a thiol group thereof.
In one particular example, a process or method which may be used to functionally associate or combine a (modified) GFR-binding compound with a bioactive carrier is a method for covalent functionalization or depositing of a (modified) GFR-binding compound onto a polylactic acid (PLLA) polymer wherein (i) the polymer is immersed in a solution containing, for instance, (dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride+N-hydroxysuccinimide in (2-(N-morpholino)-ethanesulfonic acid and then (ii) rinsed using e.g. MilliQ water.
Leaving groups: As used herein, unless indicated otherwise or contradictory in context, the term “leaving group” means a molecular fragment which possesses the ability to depart with a pair of electrons in a heterolytic bond cleavage. Leaving groups are anions or neutral molecules and possess the ability to stabilize the additional electron density that results from bond heterolysis. Common anionic leaving groups are halogen atoms such as chlorine (Cl), bromine (Br), and iodine (I), which leaves as a chloride ion (Cl−), a bromide ion (Br) and an iodide ion (I−), respectively. Other leaving groups include sulfonate esters, such as tosylate (TsO−). Conventional neutral molecule leaving groups are water and ammonia. Suitable as leaving groups for implementing embodiments of the invention preferably include the group consisting of a halogen, a substituted or unsubstituted alkoxy group (—OR), a substituted or unsubstituted aryloxy or heteroaryloxy group (—OAr), a substituted or unsubstituted alkylcarbonyloxy group (—O2CR), a substituted or unsubstituted arykcarbonyloxy or heteroarykcarbonyloxy group (—O2CAr), a substituted or unsubstituted alkylsulfonyloxy group (—O3SR), a substituted or unsubstituted arylsulfonyloxy or heteroarylsulfonyloxy group (—O3SAr). Substituents of leaving groups include halogens, alkyl (preferably C1 to C5-alkyl) groups and alkoxy (preferably C1 to C5-alkoxy) groups.
Y Group
In the present disclosure, the Y group is not aimed at being particularly limited and any moiety comprising at least one atom and having the ability to covalently or non-covalently, preferably covalently, link or interact with the X and A groups as defined herein thereby providing a stable connection between an active substance A and the X group as defined herein, is, unless contradictory or non-adapted in context, suitable for implementing embodiments of the present disclosure and is comprised within the scope of the invention.
Thus, in the present description and unless otherwise indicated, the term “linker”, when used in relation to a Y group, means any organic moiety comprising at least one atom and having the ability to interact covalently or non-covalently with an active substance A and covalently interact with an X group as defined herein.
In one example, Y groups include divalent organic radicals selected from the group consisting of a saturated or unsaturated, preferably saturated, hydrocarbon chain comprising between 1 and 30 carbon atoms, wherein said hydrocarbon chain is optionally interrupted by one or more non-carbon atom, preferably between 1 and 16, between 1 and 12 or between 1 and 8 non-carbon atoms as appropriate, wherein said non-carbon atom is selected, for instance, from the group consisting of —O—, —S—, —C(═O), —SO2—, —N(Ri)(C═O)—, —N(Ri)—, and the following radical:
wherein Ri is selected from the group consisting of a hydrogen atom, a C1-C6 alkyl group and a aryl group, and wherein said hydrocarbon chain is non-substituted or substituted, by at least one radical selected from the group consisting of a halogen, a hydroxyl group, a C1-C20 alkyl group and a aryl group.
Suitable as Y groups for implementing embodiments of the invention include saturated or unsaturated hydrocarbon chains comprising between 1 and 20 carbon atoms, saturated or unsaturated hydrocarbon chains comprising between 1 and 10 carbon atoms, saturated or unsaturated hydrocarbon chains comprising between 1 and 5 carbon atoms, saturated or unsaturated hydrocarbon chains comprising 1, 2 or 3 carbon atoms, all of which being specifically and individually preferred.
Also suitable as Y groups for implementing embodiments of the invention include saturated or unsaturated hydrocarbon chains comprising between 1 and 20 carbon atoms, saturated or unsaturated hydrocarbon chains comprising between 1 and 10 carbon atoms, saturated or unsaturated hydrocarbon chains comprising between 1 and 5 carbon atoms, saturated or unsaturated hydrocarbon chains comprising 1, 2 or 3 carbon atoms, and in which said hydrocarbon chain is optionally interrupted by one or more, preferably between 1 and 16, between 1 and 12 or between 1 and 8, non-carbon atom, selected from the group consisting of an oxygen atom, a nitrogen atom, a carbonyl group and/or the following radical:
all of which being specifically preferred and individually contemplated.
Also suitable as Y groups for implementing embodiments of the invention is:
wherein n is comprised betwwen 1 and 29, in particular between 1 and 5; and wherein m is comprised between 1 and 29, in particular between 1 and 5.
Suitable covalent-bond formation conditions: As used herein, unless indicated otherwise or contradictory in context, the term “suitable covalent-bond formation conditions” means reaction conditions such as pressure, temperature, reagent quantities, solvent's type and quantity, or stirring, under which starting materials may contact and provide at least one further material resulting from the formation of at least one covalent bond between said starting materials. Suitable as covalent-bond formation conditions for implementing embodiments of the present invention preferably include substantially atmospheric conditions.
Organic spacing-compound: In the present description and unless otherwise indicated, the term “organic spacing compound” means an organic chemical radical (preferably monofunctional radical) having the ability to create a steric effect/hindrance and/or electronic effect/hindrance in a direct vicinity of a (modified) GFR-binding compound of the present disclosure. Suitable organic spacing compounds include, but are not limited to, monovalent organic radicals independently selected from the group consisting of a saturated or unsaturated hydrocarbon chain of at most 20 nanometres (nm) in length, preferably at most 10 nm, 5 nm, 1 nm, 0.5 nm, 0.1 nm, 0.05 nm or 0.01 nm, wherein said hydrocarbon chain is optionally interrupted by one or more, preferably between 1 and 16, between 1 and 12 or between 1 and 8 non-carbon atoms as appropriate, wherein said non-carbon atom is selected from the group consisting of —O—, —S—, —C(—O), —SO2—, —N(R1)(C═O)—, and —N(Ri)—, wherein Ri is selected from the group consisting of a hydrogen atom, a C1-C6 alkyl group and an aryl group, and wherein said hydrocarbon chain is non-substituted or substituted by at least one radical selected from the group consisting of a halogen, a hydroxyl group, a C1-C20 alkyl group and an aryl group. In particular, organic spacing compounds include saturated or unsaturated hydrocarbon chains comprising between 1 and 80 carbon atoms, saturated or unsaturated hydrocarbon chains comprising between 1 and 60 carbon atoms, saturated or unsaturated hydrocarbon chains comprising between 1 and 40 carbon atoms, saturated or unsaturated hydrocarbon chains comprising between 1 and 20 carbon atoms, saturated or unsaturated hydrocarbon chains comprising between 1 and 10 carbon atoms, saturated hydrocarbon chains comprising 1, 2, 3, 4, 5 or 6 carbon atoms, all of which being specifically and individually preferred. In one example, the saturated hydrocarbon chain may be methyl, ethyl, propyl, butyl or pentyl. In one example, said unsaturated hydrocarbon chain may be ethylene, propene, 1- or 2-butene, 1-, 2- or 3-pentene, acetylene, propyne, 1- or 2-butyne, 1-, 2- or 3-pentyne.
Saturated hydrocarbon chain: In the present description and unless otherwise indicated, the terms “saturated hydrocarbon chain” means a chain of carbon atoms linked together by single bonds and has hydrogen atoms filling all of the other bonding orbitals of the carbon atoms.
Unsaturated hydrocarbon chain: In the present description and unless otherwise indicated, the terms “unsaturated hydrocarbon chain” means a chain of carbon that contains carbon-carbon double bonds or triple bonds, such as those found in alkenes or alkynes, respectively.
Atmospheric conditions: As used herein, unless indicated otherwise or contradictory in context, the term “atmospheric conditions” or “ambient conditions”, which are interchangeably used, refers to conditions which may be found naturally at an experimentation location. For example, in certain embodiments, typical atmospheric conditions in a chemistry/biology laboratory are a temperature of between about 15° C. and about 35° C. and a pressure of about 1 atm.
Solution: As used herein, unless indicated otherwise or contradictory in context, the term “solution” means a homogeneous mixture composed of only one phase, which is stable, which does not allow beam of light to scatter, in which the particles of solute cannot be seen by naked eye and from which a solute cannot be separated by filtration.
Suspension: As used herein, unless indicated otherwise or contradictory in context, the term “suspension” means a heterogeneous mixture containing solid particles that are sufficiently large for sedimentation. Typically, said solid particles are larger than one micrometer. In general, the internal phase (solid) is dispersed throughout the external phase (fluid) through mechanical agitation, with the use of certain excipients or suspending agents.
Suitable non-covalent association or functionalization techniques for implementing embodiments of the present invention include, but are not limited to, association(s) between a bioactive carrier-affinity containing group as already defined herein and at least part of a bioactive carrier. Such association(s) involves the formation of at least one non-covalent interaction (or attachment) between a (modified) GFR-binding compound and a bioactive carrier as defined herein.
In one example, said functionalised bioactive carrier is functionally associated with at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine or at least ten (modified) GFR-binding compounds, each possessing a different and distinct chemical structure.
In one example, said functionalised bioactive carrier does not comprise a layer of polysiloxane.
For example, in certain embodiments, a functionalised bioactive carrier as defined herein comprises at least one (modified) GFR-binding compound, and at least one bioactive carrier, wherein said bioactive carrier:
Porosity: As used herein, unless indicated otherwise or contradictory in context, the term “porosity” refers to the measure of the void spaces in a substance or material, and is a fraction of the volume of voids over the total volume, between 0 and 1, or as a percentage between 0 and 100%. There are many ways to test and measure the porosity of a substance or material, but for the purpose of the present disclosure, and for the avoidance of any doubts, porosity values are provided in manometers (nm) as obtained using atomic force microscopy for small pore diameters (up to 100 nm) and scanning electron microscopy for larger pore sizes.
Stiffness: As used herein, unless indicated otherwise or contradictory in context, the term “stiffness” refers to the rigidity of a substance or material i.e. the extent to which it resists deformation in response to an applied force. There are many ways to test and measure the stiffness of a substance or material, but for the purpose of the present disclosure, and for the avoidance of any doubts, stiffness values are provided in Pascal (Pa) as obtained using Dynamic Mechanical Analysis (DMA). Particularly preferred stiffness values are comprised between 1 kPa and 100 kPa and not more than 5 GPa depending on the tissue to be regenerated or repaired.
As already stated, the nature of the biomaterial is an important parameter. Particularly good results have been obtained using bioactive carriers composed mostly with the main material component of the tissue to be regenerated and/or repaired. This generally allows for a better integration of the bioactive carrier, a better resorption from the surrounding cells already present and therefore a better regeneration or repair of the targeted tissue to be achieved.
In one example, said bioactive carrier for use in neuroregeneration-related applications has a stiffness comprised between about 0.01 kPa and about 3 kPa, preferably between about 0.01 kPa and about 1 kPa. In one example, said bioactive carrier for use in muscle, cartilage and T/L—related applications has a stiffness comprised between about 3 kPa and about 200 kPa, preferably between about 10 kPa and about 30 kPa. In one example, said bioactive carrier for use in bone-related applications has a stiffness comprised between about 30 kPa and about 3 GPa, preferably between about 70 kPa and about 200 kPa for instance in applications such as the treatment or prevention of osteoporosis and bone tissue regeneration. In one example, said bioactive carrier for use in hair-related applications has a stiffness comprised between about 0.01 kPa and about 200 kPa, preferably between about 3 kPa and about 70 kPa. In one example, said bioactive carrier for use in endothelization-related applications has a stiffness comprised between about 500 kPa and about 2.5 GPa. In one example, said bioactive carrier for use in angiogenesis-related applications has a stiffness comprised between about 0.01 kPa and about 100 kPa. In one example, said bioactive carrier for use in wound healing and skin—related applications has a stiffness comprised between about 0.01 kPa and about 70 kPa. For example, in certain embodiments, a pharmaceutical, dermatological or cosmetic association or combination of the present invention may be in the form of a dry, sterile powder.
In one particular example, the concentration or density (as defined herein) of a (modified) GFR-binding compound in, or on the surface of, a bioactive carrier as defined herein is comprised between 0.05 and 50 pmol/mm2, in particular comprised between 0.1 and 30 pmol/mm2, comprised between 0.1 and 10 pmol/mm2, comprised between 0.1 and 5 pmol/mm2, or comprised between 0.1 and 2 pmol/mm2, each range being preferred and specifically contemplated to be combined with any other numerical or non-numerical ranges as described herein. Most particularly, the density is comprised between 0.2 and 2 pmol/mm2.
VII. Medical Devices
For in-vivo administration, GFR-binding compounds, modified GFR-binding compounds or functionalised bioactive carriers of the present invention may be injected e.g. using an appropriate syringe, to a specific target site so that they may be delivered directly to the interior of e.g. a body articulation or under the skin in close proximity with the cells to be treated via, for instance, a PTD or cell-permeable peptide. Alternately, a medical device or implant (or implantable medical device) comprising such GFR-binding compounds, modified GFR-binding compounds or functionalised bioactive carriers may be used. Implants may contain reservoirs in which to place the GFR-binding compound, modified GFR-binding compound or functionalised bioactive carrier of the invention for release into the surrounding tissue, or may comprise a porous composition which may be soaked in a solution containing one or more GFR-binding compounds or modified GFR-binding compounds of the present disclosure prior to implantation.
Hydrogels, time-release capsules or spheres, liposomes, microspheres, nanospheres, biodegradable polymers, or other such drug delivery systems may also be employed to deliver GFR-binding compounds of the present invention to target cells and tissues. U.S. Pat. No. 6,475,516, for example, provides hydrogels being covalently bound to the surface of an in-dwelling medical device such as an implant, which may be used with GFR-binding compounds of the present disclosure.
In one aspect, the present disclosure provides a medical device comprising at least one GFR-compound, modified GFR-binding compound or functionalised bioactive carrier as defined herein. In one particular example, the medical device of the invention may be, partly or entirely, made of a functionalised bioactive carrier as defined herein or contain, for example, in certain embodiments, within a cavity thereof, said functionalised bioactive carrier.
In one example, said medical device may comprise between 1 wt % and 100 wt % of a functionalised bioactive carrier of the invention with respect to the total weight of the medical device. In one example, said medical device comprises between about 50 wt % and 100 wt %, between about 60 wt % and 100 wt %, between about 70 wt % and 100 wt %, between about 80 wt % and 100 wt %, between about 90 wt % and 100 wt % of a functionalised bioactive carrier of the invention with respect to the total weight of the medical device, all of which being specifically and individually preferred.
In an example, at least one part of a surface of said medical device comprises a GFR-binding compound, a modified GFR-binding compound or a functionalised bioactive carrier of the invention. For example, in certain embodiments, said medical device is preferably an implantable medical device.
Also suitable as medical devices for implementing embodiments of the present invention include stents, stiches, powders, granules, sponges, putties, injectable and non-injectable liquids, curable compositions, moldable compositions, membranes, glues, sprays, pills, filaments, prosthesis, or combinations thereof.
In one aspect, the present disclosure provides a bone graft material comprising a GFR-binding compound or a modified GFR-binding compound of the invention and a collagen as defined herein. In the present description and unless otherwise indicated, the term “bone graft material” means a material suitable for bone grafting.
VIII. Antibody:GFR-Binding Compound Complex
In one aspect, the present disclosure provides an antibody:GFR-binding compound complex comprising at least one (modified) GFR-binding compound and at least one antibody or any functional fragment thereof; wherein said (modified) GFR-binding compound is as defined herein.
Antibody: As used herein, unless indicated otherwise or contradictory in context, the terms “antibody” or “antibodies” refer to a light chain and heavy chain protein of an antibody that are encoded by a gene or genes that are either a naturally occurring gene or a codon-optimized gene. The antibody light chain and heavy chain genes may be human antibody light chain and heavy chain genes. Antibodies, or immunoglobulins, are proteins produced by cells of the immune system to identify and neutralize foreign substances, such as bacteria, viruses, or improperly proliferating native cells. Immunoglobulins are one class of desired globulin molecules and include, but are not limited to, IgG, IgM, IgA, IgD, IgE, IgY, lambda chains, kappa chains and fragments thereof; bi-specific antibodies, and fragments thereof; scFv fragments, Fc fragments, and Fab fragments as well as dimeric, trimeric and oligomeric forms of antibody fragments. Suitable antibodies include, but are not limited to, naturally occurring antibodies, animal-specific antibodies, human antibodies, humanized antibodies, autoantibodies and hybrid antibodies. Suitable antibodies also include antibodies with the ability to bind specific ligands. Suitable antibodies also include, but are not limited to, primary antibodies, secondary antibodies, designer antibodies, anti-protein antibodies, anti-peptide antibodies, anti-DNA antibodies, anti-RNA antibodies, anti-hormone antibodies, anti-hypophysiotropic peptides, antibodies against non-natural antigens, anti-anterior pituitary hormone antibodies, anti-posterior pituitary hormone antibodies, anti-venom antibodies, anti-tumor marker antibodies, antibodies directed against epitopes associated with infectious disease, including, anti-viral, anti-bacterial, anti-protozoal, anti-fungal, anti-parasitic, anti-receptor, anti-lipid, anti-phospholipid, anti-growth factor, anti-cytokine, anti-monokine, antiidiotype, and anti-accessory (presentation) protein antibodies. Suitable antibodies also include, but are not limited to, 3F8, 8H9, Abagovomab, Abciximab, Abituzumab, Abrilumab, Actoxumab, Adalimumab, Adecatumumab, Aducanumab, Afelimomab, Afutuzumab, Alacizumab pegol, ALD518, Alemtuzumab, Alirocumab, Altumomab pentetate, Amatuximab, Anatumomab mafenatox, Anetumab ravtansine, Anifrolumab, Anrukinzumab, Apolizumab, Arcitumomab, Ascrinvacumab, Aselizumab, Atezolizumab, Atinumab, Atlizumab, Atorolimumab, Bapineuzumab, Basiliximab, Bavituximab, Bectumomab, Begelomab, Belimumab, Benralizumab, Bertilimumab, Besilesomab, Bevacizumab, Beziotoxumab, Biciromab, Bimagrumab, Bimekizumab, Bivatuzumab mertansine, Blinatumomab, Blosozumab, Bococizumab, Brentuximab vedotin, Briakinumab, Brodalumab, Brolucizumab, Brontictuzumab, Canakinumab, Cantuzumab mertansine, Cantuzumab ravtansine, Caplacizumab, Capromab pendetide, Carlumab, Catumaxomab, cBR96-doxorubicin immunoconjugate, CC49, Cedelizumab, Certolizumab pegol, Cetuximab, Ch.14.18, Citatuzumab bogatox, Cixutumumab, Clazakizumab, Clenoliximab, Clivatuzumab tetraxetan, Codrituzumab, Coltuximab ravtansine, Conatumumab, Concizumab, CR6261, Crenezumab, Dacetuzumab, Daclizumab, Dalotuzumab, Dapirolizumab pegol, Daratumumab, Dectrekumab, Demcizumab, Denintuzumab mafodotin, Denosumab, Derlotuximab biotin, Detumomab, Dinutuximab, Diridavumab, Dorlimomab aritox, Drozitumab, Duligotumab, Dupilumab, Durvalumab, Dusigitumab, Ecromeximab, Eculizumab, Edobacomab, Edrecolomab, Efalizumab, Efungumab, Eldelumab, Elgemtumab, Elotuzumab, Elsilimomab, Emactuzumab, Emibetuzumab, Enavatuzumab, Enfortumab vedotin, Enlimomab pegol, Enoblituzumab, Enokizumab, Enoticumab, Ensituximab, Epitumomab cituxetan, Epratuzumab, Erlizumab, Ertumaxomab, Etaracizumab, Etrolizumab, Evinacumab, Evolocumab, Exbivirumab, Fanolesomab, Faralimomab, Farletuzumab, Fasinumab, FBTA05, Felvizumab, Fezakinumab, Ficlatuzumab, Figitumumab, Firivumab, Flanvotumab, Fletikumab, Fontolizumab, Foralumab, Foravirumab, Fresolimumab, Fulranumab, Futuximab, Galiximab, Ganitumab, Gantenerumab, Gavilimomab, Gemtuzumab ozogamicin, Gevokizumab, Girentuximab, Glembatumumab vedotin, Golimumab, Gomiliximab, Gusekumab, balizumab, Ibritumomab tiuxetan, Icrucumab, Idarucizumab, Igovomab, IMAB362, Imalumab, Imciromab, Imgatuzumab, Inclacumab, Indatuximab ravtansine, Indusatumab vedotin, Infliximab, Inolimomab, Inotuzumab ozogamicin, Intetumumab, Ipilimumab, Iratumumab, Isatuximab, Itolizumab, Ixekizumab, Keliximab, Labetuzumab, Lambrolizumab, Lampalizumab, Lebrikizumab, Lemalesomab, Lenzilumab, Lerdelimumab, Lexatumumab, Libivirumab, Lifastuzumab vedotin, Ligelizumab, Lilotomab satetraxetan, Lintuzumab, Lirilumab, Lodelcizumab, Lokivetmab, Lorvotuzumab mertansine, Lucatumumab, Lulizumab pegol, Lumiliximab, Lumretuzumab, Mapatumumab, Margetuximab, Maslimomab, Matuzumab, Mavrilimumab, Mepolizumab, Metelimumab, Milatuzumab, Minretumomab, Mirvetuximab soravtansine, Mitumomab, Mogamulizumab, Morolimumab, Motavizumab, Moxetumomab pasudotox, Muromonab-CD3, Nacolomab tafenatox, Namilumab, Naptumomab estafenatox, Narnatumab, Natalizumab, Nebacumab, Necitumumab, Nemolizumab, Nerelimomab, Nesvacumab, Nimotuzumab, Nivolumab, Nofetumomab merpentan, Obiltoxaximab, Ocaratuzumab, Ocrelizumab, Odulimomab, Ofatumumab, Olaratumab, Olokizumab, Omalizumab, Onartuzumab, Ontuxizumab, Opicinumab, Oportuzumab monatox, Oregovomab, Orticumab, Otelixizumab, Otlertuzumab, Oxelumab, Ozanezumab, Ozoralizumab, Pagibaximab, Palivizumab, Panitumumab, Pankomab, Panobacumab, Parsatuzumab, Pascolizumab, Pasotuxizumab, Pateclizumab, Patritumab, Pembrolizumab, Pemtumomab, Perakizumab, Pertuzumab, Pexelizumab, Pidilizumab, Pinatuzumab vedotin, Pintumomab, Placulumab, Polatuzumab vedotin, Ponezumab, Priliximab, Pritoxaximab, Pritumumab, PRO 140, Quilizumab, Racotumomab, Radretumab, Rafivirumab, Ralpancizumab, Ramucirumab, Ranibizumab, Raxibacumab, Refanezumab, Regavirumab, Reslizumab, Rilotumumab, Rinucumab, Rituximab, Robatumumab, Roledumab, Romosozumab, Rontalizumab, Rovelizumab, Ruplizumab, Sacituzumab govitecan, Samalizumab, Sarilumab, Satumomab pendetide, Secukinumab, Seribantumab, Setoxaximab, Sevirumab, SGN-CD19A, SGN-CD33A, Sbrotuzumab, Sifalimumab, Siltuximab, Simtuzumab, Siplizumab, Sirukumab, Sofituzumab vedotin, Solanezumab, Solitomab, Sonepcizumab, Sontuzumab, Stamulumab, Sulesomab, Suvizumab, Tabalumab, Tacatuzumab tetraxetan, Tadocizumab, Talizumab, Tanezumab, Taplitumomab paptox, Tarextumab, Tefibazumab, Telimomab aritox, Tenatumomab, Teneliximab, Teplizumab, Teprotumumab, Tesidolumab, TGN1412, Ticilimumab, Tigatuzumab, Tildrakizumab, TNX-650, Tocilizumab, Toralizumab, Tosatoxumab, Tositumomab, Tovetumab, Tralokinumab, Trastuzumab, TRBS07, Tregalizumab, Tremelimumab, Trevogrumab, Tucotuzumab celmoleukin, Tuvirumab, Ublituximab, Ulocuplumab, Urelumab, Urtoxazumab, Ustekinumab, Vandortuzumab vedotin, Vantictumab, Vanucizumab, Vapaliximab, Varlilumab, Vatelizumab, Vedolizumab, Veltuzumab, Vepalimomab, Vesencumab, Visilizumab, Volociximab, Vorsetuzumab mafodotin, Votumumab, Zalutumumab, Zanolimumab, Zatuximab, Ziralimumab, or Zolimomab aritox.
In certain embodiments, said antibody:GFR-binding compound complex is a covalent complex. In certain embodiments, said antibody:GFR-binding compound complex is a non-covalent complex.
IX. Dendrimer:GFR-Binding Compound Complex
In one aspect, the present disclosure provides a dendrimer:GFR-binding compound complex comprising at least one (modified) GFR-binding compound and at least one dendrimer or any functional fragment thereof; wherein said (modified) GFR-binding compound is as defined herein; and wherein said dendrimer is as already defined herein.
In certain embodiments, said dendrimer:GFR-binding compound complex is a covalent complex. In certain embodiments, said dendrimer:GFR-binding compound complex is a non-covalent complex.
X. Polynucleotides
The extracellular biological action of the GFR-binding peptides may also be conveyed via expression, by a cell, of the appropriate polynucleotide sequence engineered to encode a particular GFR-binding peptide of interest. One may thus inject or administer, to a mammal subject, a GFR-binding-peptide-encoding polynucleotide (such as a messenger RNA), wherein said polynucleotide would enable the intracellular production of the encoded GFR-binding peptide, which may, once released outside the host cell, exert its extracellular action on the host cell and/or on neighbouring cells and/or distant cells. In other words, GFR-binding peptides may be produced ex-vivo (e.g. using a peptide synthesizer) or in-vivo (e.g. via cell expression of a GFR-binding-peptide-encoding polynucleotide), and in all cases have an extracellular biological action of activation of growth factor receptors to induce cell differentiation and/or tissue regeneration.
Thus, in one aspect, the present disclosure provides a polynucleotide encoding at least one peptide as disclosed herein. In one particular example, said polynucleotide is a messenger RNA or a primary construct thereof. Said messenger RNA may additionally have a 5′ cap structure chosen from the group consisting of m7G(5′)ppp (5′)A,G(5′)ppp(5′)A and G(5′)ppp(5′)G. In one example, the messenger RNA additionally has a poly-A tail of from about 10 to 200 adenosine nucleotides. In one example, the messenger RNA additionally has a poly-C tail of from about 10 to 200 cytosine nucleotides. In one example, the messenger RNA additionally codes a tag for purification chosen from the group consisting of a hexahistidine tag (HIS tag, polyhistidine tag), a streptavidin tag (Strep tag), an SBP tag (streptavidin-binding tag) or a GST (glutathione S-transferase) tag, or codes for a tag for purification via an antibody epitope chosen from the group consisting of antibody-binding tags, a Myc tag, a Swal 1 epitope, a FLAG tag or an HA tag. In one example, the messenger RNA additionally codes a signal peptide and/or a localization sequence, in particular a secretion sequence. In one example, said polynucleotide is a complementary DNA of said messenger RNA or a primary construct thereof.
In one aspect, the present disclosure also provides a vector comprising a polynucleotide as defined in the present disclosure.
In one aspect, the present disclosure also provides a cultured cell comprising a vector as defined in the present disclosure.
In one aspect, the present disclosure also provides a method of expressing a peptide of interest, variant or analog thereof, in a mammalian cell, said method comprising: (i) providing an mRNA as defined in the present disclosure; and (ii) introducing said mRNA to a mammalian cell under conditions that permit the expression of the peptide of interest by the mammalian cell.
In one aspect, the present disclosure also provides a mRNA as disclosed herein for use in a medical treatment or prophylactic method. In one example, said medical treatment method is a therapeutic, surgical, or diagnostic method. In one particular example, said method is a method for treating or preventing cell-degeneration-associated diseases, disorders, conditions, or pathologies as defined in the present disclosure. In one particular example, said method is a method for regenerating mammalian tissues as disclosed herein.
In one aspect, the present disclosure also provides a use of a RNA or mRNA as defined in the present disclosure for the preparation of a pharmaceutical composition for the treatment or prevention of cell-degeneration-associated diseases, disorders, conditions, or pathologies as disclosed herein.
In one aspect, the present disclosure also provides a medical composition comprising a polynucleotide, a vector, or a transfected cel, all as defined in the present disclosure, and a medically acceptable excipient or carrier.
Expression: As used herein, “expression” of a nucleic acid sequence refers to one or more of the following events: (1) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g., by splicing, editing, 5′ cap formation, and/or 3′ end processing); (3) translation of an RNA into a polypeptide or protein; and (4) post-translational modification of a polypeptide or protein.
mRNA: As used herein, the term “mRNA” refers to messenger RNA. Traditionally, the basic components of an mRNA molecule include at least a coding region, a 5′UTR, a 3′UTR, a 5′cap and a poly-A tail. Whereas the 5′UTR, 3′UTR, 5′cap and the poly-A tail are usually required to improve e.g. stability, translation and/or recognition by the ribosome, it is the coding region which comprises the sequence encoding the protein(s), polypeptide(s), or peptide(s) of (therapeutic) interest. Therefore, when the mRNA molecule as disclosed herein is conventionally described with reference to its coding region, any mRNA molecule also comprising at least one of a 5′UTR, a 3′UTR, a 5′cap or a poly-A tail forms an integral part of the present disclosure.
Coding region: As used herein, the term “coding region” or “coding sequence” refers to a portion of a polynucleotide that codes for a peptide or peptides of interest.
Primary RNA construct or transcript: As used herein, unless indicated otherwise or contradictory in context, the term “Primary RNA construct” or “Primary RNA transcript” refers to any precursor RNA molecule from a mature and functional (i.e. translatable) RNA molecule may be obtained. For instance, a precursor messenger RNA (pre-mRNA) is a type of primary transcript that becomes a messenger RNA (mRNA) after processing. Newly synthesized primary transcripts are modified in several ways to yield their mature form before they can be translated into a protein of interest. Such modifications include, but are not limited to, excision of introns, splicing of exons, addition of 5′cap and poly-A tail. Therefore, when reference is made to an RNA molecule, it shall be understood that it aims to cover all RNA molecules including, but not limited to, primary RNA transcripts or constructs at any stage of the modification process leading to a mature and functional RNA molecule e.g. with or without introns, exons, 5′cap, poly-A tail and/or any other conventional modifications, insofar as the RNA molecule contains a coding region or a precursor thereof allowing for a peptide of interest encoded by said coding region or precursor thereof to be expressed.
5′ Capping: As used herein, unless indicated otherwise or contradictory in context, the term “5′ Capping” ou “5′ Cap” refers to a 5′ cap structure of an mRNA that is involved in nuclear export, increasing mRNA stability and binds the mRNA Cap Binding Protein (CBP), which is responsible for mRNA stability in the cell and translation competency through the association of CBP with poly(A) binding protein to form the mature cyclic mRNA species. The cap further assists the removal of 5′ proximal introns removal during mRNA splicing. Endogenous mRNA molecules may be 5′-end capped generating a 5′-ppp-5′-triphosphate linkage between a terminal guanosine cap residue and the 5′-terminal transcribed sense nucleotide of the mRNA molecule. This 5′-guanylate cap may then be methylated to generate an N7-methyl-guanylate residue.
Poly-A tails: During RNA processing, a long chain of adenine nucleotides (poly-A tail) may be added to a polynucleotide such as an mRNA molecules in order to increase stability. Immediately after transcription, the 3′ end of the transcript may be cleaved to free a 3′ hydroxyl. Then poly-A polymerase adds a chain of adenine nucleotides to the RNA. The process, called polyadenylation, adds a poly-A tail that can be between, for example, approximately 100 and 250 residues long.
Untranslated regions: As used herein, the term “Untranslated regions” or UTRs of a gene refers to regions that are transcribed but not translated. The 5′UTR starts at the transcription start site and continues to the start codon but does not include the start codon; whereas, the 3′UTR starts immediately following the stop codon and continues until the transcriptional termination signal. The regulatory features of a UTR can be incorporated into the polynucleotides, primary constructs and/or mRNA of the present disclosure to enhance the stability of the molecule.
3′UTR: As used herein, unless indicated otherwise or contradictory in context, the term “3′UTR” or “three prime untranslated region” refers to the section of messenger RNA that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally influence gene expression.
5′UTR: As used herein, unless indicated otherwise or contradictory in context, the term “5′UTR” or “five prime untranslated region” refers to the section of mRNA that starts at the transcription start site and continues to the start codon but does not include the start codon. There is growing body of evidence about the regulatory roles played by the UTRs in terms of stability of the nucleic acid molecule and translation. Natural 5′UTRs bear features which play roles in for translation initiation. 5′UTR also have been known to form secondary structures which are involved in elongation factor binding.
Complementary DNA: As used herein, the term “complementary DNA” or “cDNA” refers to a DNA molecule containing an eukaryote gene which has been tailored or engineered to be expressed in a prokaryote host cell. cDNA is also called “intron-free” DNA as it lacks the gene regions encoding introns, its transcription yielding an intron-free mRNA molecule.
In one aspect, the present disclosure provides a vector comprising a polynucleotide encoding at least one peptide, variant or analog thereof, having growth factor receptor-binding capability or capabilities, as defined herein.
Vector: As used herein, unless indicated otherwise or contradictory in context, the term “vector” is used in its most general meaning and refers to any intermediary vehicle for a nucleic acid which enables said nucleic acid, for example, to be introduced into prokaryotic and/or eukaryotic cells and, where appropriate, to be integrated into a genome. Vectors of this kind are preferably replicated and/or expressed in the cells. Vectors may comprise plasmids, phagemids, bacteriophages or viral genomes.
Plasmid: As used herein, unless indicated otherwise or contradictory in context, the term “plasmid” refers to a double-stranded (which may be circular) DNA sequence that is capable of automatically replicating in a host cell.
In one aspect, the present disclosure provides a cultured cell (or transfected cell) comprising a polynucleotide encoding at least one peptide, variant or analog thereof, having growth factor receptor-binding capability or capabilities, as defined herein.
In one aspect, the present disclosure provides a medical composition comprising at least one of a polynucleotide encoding at least one peptide, variant or analog thereof, having growth factor receptor-binding capability or capabilities, as defined herein, a vector comprising such a polynucleotide, or a transfected cell comprising such a vector, and a medically acceptable carrier.
In one aspect, the present disclosure provides methods and uses for inducing cell differentiation, regenerating tissues and protecting a patient from cell-degeneration-related diseases, conditions, disorders or pathologies, using at least one of a polynucleotide encoding at least one peptide, variant or analog thereof, having growth factor receptor-binding capability or capabilities, as defined herein, a vector comprising such a polynucleotide, a transfected cell comprising such a vector, or a medical composition comprising them.
XI. Pharmaceutical Compositions
The present disclosure provides GFR-binding compounds, modified GFR-binding compounds and functionalised bioactive carrier, which may be used for inducing stem cell differentiation and tissue regeneration.
In one aspect, the present disclosure provides a composition such as a pharmaceutical, prophylactic, surgical, diagnostic, or imaging composition (hereinafter shorten as pharmaceutical or medical composition) comprising at least one (modified) GFR-binding compound or a functionalised bioactive carrier as defined herein and further comprising at least one pharmaceutically acceptable excipient carriers and/or vehicles.
Formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. Generally, such methods of preparation include the step of bringing the active ingredient(s) into association with an excipient and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
For example, in certain embodiments, a pharmaceutical composition as defined herein may contain between 0.01% and 100% by weight (over the total weight of the pharmaceutical composition) of a (modified) GFR-binding compound or a functionalised bioactive carrier, both as defined herein, as a pharmaceutically effective amount. The pharmaceutical composition particularly comprises between 0.01% and 95%, between 0.01% and 90%, between 0.01% and 85%, between 0.01% and 80%, between 0.01% and 75%, between 0.01% and 70%, between 0.01% and 65%, between 0.01% and 60%, between 0.01% and 55%, between 0.01% and 50%, between 0.01% and 45%, between 0.01% and 40%, between 0.01% and 35%, between 0.01% and 30%, between 0.01% and 25%, between 0.01% and 20%, between 0.01% and 15%, between 0.01% and 10%, between 0.01% and 5%, between 0.1% and 100%, between 0.1% and 95%, between 0.1% and 90%, between 0.1% and 85%, between 0.1% and 80%, between 0.1% and 75%, between 0.1% and 70%, between 0.1% and 65%, between 0.1% and 60%, between 0.1% and 55%, between 0.1% and 50%, between 0.1% and 45%, between 0.1% and 40%, between 0.1% and 35%, between 0.1% and 30%, between 0.1% and 25%, between 0.1% and 20%, between 0.1% and 15%, between 0.1% and 10%, and between 0.1% and 5% by weight (over the total weight of the pharmaceutical composition) of any one of a (modified) GFR-binding compound or a functionalised bioactive carrier as defined herein.
Generally, the (modified) GFR-binding compounds or functionalised bioactive carriers as defined herein may thus be administered as such or as part of a formulation in association with one or more pharmaceutically acceptable excipients, carriers and/or vehicles so as to form what is generally referred to as a pharmaceutical composition or pharmaceutical formulation.
Pharmaceutical effective amount: As used herein, unless indicated otherwise or contradictory in context, the term “pharmaceutical effective amount” or “therapeutically effective amount” refers to an amount of an agent to be delivered (e.g., nucleic acid, protein, peptide, drug, therapeutic agent, diagnostic agent, prophylactic agent, etc.) that is sufficient, when administered to a subject suffering from or susceptible to an infection, disease, disorder, condition and/or pathology, to produce/provide a therapeutically effective outcome. Thus, a “pharmaceutical effective amount” depends upon the context in which it is being applied. A pharmaceutical effective amount of a composition is provided based, at least in part, on the target tissue, target cell type, means of administration, physical characteristics of the pharmaceutical association or composition (e.g., size, 3D shape, etc.), and other determinants. For example, in certain embodiments, in the context of providing an agent that induces tissue regeneration, a pharmaceutical effective amount of an agent is, for example, in certain embodiments, an amount sufficient to achieve tissue regeneration, as compared to the response obtained without provision of the agent. For example, in certain embodiments, a therapeutically effective amount as used herein is any of the herein disclosed weight or molar amounts, ratios or ranges of the (modified) GFR-binding compound or functionalised bioactive carrier.
Therapeutically effective outcome: As used herein, unless indicated otherwise or contradictory in context, the term “therapeutically effective outcome” refers to an outcome that is sufficient in a subject suffering from or susceptible to an infection, disease, disorder, condition and/or pathology, to treat, improve symptoms of, diagnose, prevent, and/or delay the onset of the infection, disease, disorder, condition and/or pathology.
Therapeutic Agent: As used herein, unless indicated otherwise or contradictory in context, the term “therapeutic agent” refers to any agent that, when administered to a subject/patient/individual, has a therapeutic, diagnostic, and/or prophylactic effect and/or elicits a desired biological and/or pharmacological effect.
Pharmaceutically acceptable: As used herein, unless indicated otherwise or contradictory in context, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the ambit of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable excipients: As used herein, unless indicated otherwise or contradictory in context, the term “pharmaceutically acceptable excipient” refers to any ingredient other than the compounds described herein (i.e. GFR-binding compounds, bioactive carriers as defined herein or any further active principles) and satisfying to the herein defined definition of pharmaceutically acceptable for a patient. Excipients may include, for example: inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, oils, printing inks, sweeteners, and/or waters of hydration. The choice of excipient(s) will largely depend on factors such as the particular mode of administration, the effect of the excipient(s) on solubility and stability, and the nature of the dosage form. In one embodiment, the pharmaceutically acceptable excipient is not a naturally occurring excipient.
Diluents: As used herein, unless indicated otherwise or contradictory in context, diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, powdered sugar and/or any combinations thereof.
Buffering agents: As used herein, unless indicated otherwise or contradictory in context, buffering agents include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, potassium acetate, potassium chloride, monobasic potassium phosphate, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, phosphoric acid, calcium hydroxide phosphate, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol and any combinations thereof.
Granulating and/or dispersing agents: As used herein, unless indicated otherwise or contradictory in context, granulating and/or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone), sodium carboxymethyl starch, carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, methylcellulose, pregelatinized starch, microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate, sodium lauryl sulfate, quaternary ammonium compounds and/or any combinations thereof.
Surface active agents and/or emulsifiers: As used herein, unless indicated otherwise or contradictory in context, surface active agents and/or emulsifiers include, but are not limited to, colloidal clays (such as aluminum silicates and magnesium aluminum silicates), natural emulsifiers (such as acacia, agar, sodium alginate, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, cholesterol, wax, and lecithin), long chain amino acid derivatives, high molecular weight alcohols (such as stearyl, cetyl and oleyl alcohols, triacetin monostearate, ethylene glycol distearate and glyceryl monostearate), carbomers (such as carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, carrageenan, cellulosic derivatives (such as carboxymethylcellulose sodium, hydroxymethyl cellulose, hydroxypropyl methylcellulose and methylcellulose), sorbitan fatty acid esters (such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan, polyoxyethylene sorbitan monooleate, sorbitan monopalmitate and glyceryl monooleate), polyoxyethylene esters, sucrose fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene ethers, poly(vinyl-pyrrolidone), and any combinations thereof.
Binding agents: As used herein, unless indicated otherwise or contradictory in context, binding agents include, but are not limited to, natural and synthetic gums (such as acacia, sodium alginate, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate and poly(vinyl-pyrrolidone), gelatin, starch, sugars (such as sucrose, dextrose, glucose, dextrin, lactose, and mannitol), alignates, magnesium aluminum silicates, polyethylene glycol, polyethylene oxide, inorganic calcium salts, water, alcohol, silicic acid, waxes, and any combinations thereof.
Preservatives: As used herein, unless indicated otherwise or contradictory in context, preservatives include, but are not limited to, antioxidants, chelating agents, antifungal preservatives, antimicrobial preservatives, acidic preservatives, and alcohol preservatives.
Antioxidants: As used herein, unless indicated otherwise or contradictory in context, antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, propionic acid, potassium metabisulfite, propyl gallate, sodium metabisulfite, sodium ascorbate, and sodium sulfite.
Chelating agents: As used herein, unless indicated otherwise or contradictory in context, chelating agents include ethylenediaminetetraacetic acid (EDTA), fumaric acid, malic acid, phosphoric acid, citric acid monohydrate and tartaric acid.
Antimicrobial preservatives: As used herein, unless indicated otherwise or contradictory in context, antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, benzyl alcohol, bronopol, cetylpyridinium chloride, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenoxyethanol, phenylmercuric nitrate, phenylethyl alcohol, phenol, and propylene glycol.
Antifungal preservatives: As used herein, unless indicated otherwise or contradictory in context, antifungal preservatives include, but are not limited to, benzoic acid, hydroxybenzoic acid, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, potassium benzoate, sodium propionate, potassium sorbate, and/or sorbic acid.
Alcohol preservatives: As used herein, unless indicated otherwise or contradictory in context, alcohol preservatives include, but are not limited to, phenol, phenolic compounds, bisphenol, ethanol, polyethylene glycol, chlorobutanol and hydroxybenzoate.
Acidic privatives: As used herein, unless indicated otherwise or contradictory in context, acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, acetic acid, citric acid, dehydroacetic acid, and sorbic acid.
Lubricating agents: As used herein, unless indicated otherwise or contradictory in context, lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, sodium benzoate, sodium acetate, sodium chloride, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, magnesium lauryl sulphate and any combinations thereof.
Sweeteners: As used herein, unless indicated otherwise or contradictory in context, sweeteners include, but are not limited to, any natural or synthetic sugar substitutes. Natural sugar substitutes include, but are not limited to, brazzein, curculin, erythritol, glycyrrhizin, glycerol, hydrogenated starch hydrolysates, inulin, isomalt, lactitol, mogroside mix, mabinlin, maltitol, malto-oligosaccharide, mannitol, miraculin, monatin, monellin, osladin, pentadin, sorbitol, stevia, tagatose, thaumatin, and xylitol. Synthetic sugar substitutes include, but are not limited to, acesulfame potassium, advantame, alitame, aspartame, salt of aspartame-acesulfame, sodium cyclamate, dulcin, glucin, neohesperidin dihydrochalcone, neotame, P-4000, saccharin, Sucralose.
Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Suitable excipients for use in the present invention also include, but are not limited to, water, phosphate buffered saline (PBS), Ringer's solution, dextrose solution, serum-containing solutions, Hank's solution, other aqueous physiologically balanced solutions, oils, esters and glycols. Aqueous excipients can contain suitable auxiliary substances required to approximate the physiological conditions of the recipient, for example, in certain embodiments, by enhancing chemical stability and isotonicity.
Pharmaceutically acceptable carriers: As used herein, unless indicated otherwise or contradictory in context, the term “pharmaceutically acceptable carriers” or “carriers” refers to pharmaceutically acceptable excipients and/or delivery vehicles suitable for delivering a pharmaceutical or therapeutic composition useful in a therapeutic method and uses of the present invention to a suitable in-vivo or ex-vivo site.
Preferred pharmaceutically acceptable carriers are capable of maintaining a composition containing an active combination or association of a (modified) GFR-binding compound and a bioactive carrier as defined herein, in a form that, upon arrival of the combination to a target cell, site or tissue, the active combination is capable of performing one or more biological functions thereof the protein at the cell or tissue site. One type of pharmaceutically acceptable carrier includes a controlled release formulation that is capable of slowly releasing a composition or combination into an animal. In one example, a controlled release formulation comprises an active combination or association as defined herein in a controlled release vehicle. Suitable controlled release vehicles include, but are not limited to, microparticles, biocompatible polymers, other polymeric matrices, capsules, microcapsules, osmotic pumps, bolus preparations, diffusion devices, liposomes, lipospheres, and transdermal delivery systems. Such suitable controlled release vehicle may be combined with at least one targeting moiety. In one embodiment, the pharmaceutically acceptable carrier Is not a naturally occurring carrier.
Targeting Moieties: In one example, the functionalised bioactive carrier disclosed herein includes at least one binding partner which functions to target the cell to a specific tissue space or to interact with a specific moiety, either in-vivo, ex-vivo or in-vitro. Suitable binding partners include antibodies and functional fragments thereof, scaffold proteins, or peptides.
In one example, said excipients, carriers or vehicles are compatible with the (modified) GFR-binding compounds or functionalised bioactive carriers defined herein so that they do not disrupt, tamper, modify, de-organise, de-combine or de-associate said the (modified) GFR-binding compounds or functionalised bioactive carriers. In contrast, said excipients, carriers or vehicles preserves, maintains or reinforces the stability of the (modified) GFR-binding compounds or functionalised bioactive carriers so as to preserve their biological activity.
In one example, the present pharmaceutical compositions also include pharmaceutically acceptable salts and/or solvates and/or prodrugs and/or isotopically-labelled derivatives of the substances and compounds described herein such as the (modified) GFR-binding compounds or any other active principles.
Pharmaceutically acceptable salts: As used herein, unless indicated otherwise or contradictory in context, the term “pharmaceutically acceptable salts” refers to derivatives of the disclosed substances and compounds wherein the parent substance or compound is modified by converting an existing acid or base moiety to its salt form (e.g., by reacting the free base group with a suitable organic acid). The degree of ionization in the salt may vary from completely ionized to almost non-ionized. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or akaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, in certain embodiments, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are generally found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and in Pharmaceutical Salts: Properties, Selection, and Use, P. H. Stahl and C. G. Wermuth (eds.), Wiley-VCH, 2008, each of which being incorporated herein by reference in its entirety. In one embodiment, the pharmaceutically acceptable salt is not a naturally occurring salt.
Pharmaceutically acceptable solvate: As used herein, unless indicated otherwise or contradictory in context, the term “pharmaceutically acceptable solvate,” refers to a compound, substance, association or combination wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered. For example, in certain embodiments, solvates may be prepared by crystallization, recrystallization, or precipitation from a solution that includes organic solvents, water, or a mixture thereof. Examples of suitable solvents are ethanol, water (For example, in certain embodiments, mono-, di-, and tri-hydrates), N-methylpyrrolidinone (NMP), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), [Nu],[Nu]′-dimethylacetamide (DMAC), 1,3-dimethyl-2-imidazolidinone (DMEU), 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPU), acetonitrile (ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone, benzyl benzoate, and the like. When water is the solvent, the solvate is referred to as a “hydrate”. In one embodiment, the pharmaceutically acceptable solvate Is not a naturally occurring solvate.
Pharmaceutically acceptable Isotopically-labelled compounds: In one example, the present invention also includes all pharmaceutically acceptable isotopically-labelled derivatives, which are identical to the compounds, substances, combinations or associations described herein but wherein one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be incorporated into GFR-binding compound(s) as defined herein include isotopes of hydrogen, carbon, chlorine, fluorine, iodine, nitrogen, oxygen, and sulfur, such as 2H, 3H, 11C, 13C, 14C, 36Cl, 18F, 123I, 13N, 15N, 17O, 18O, and 35S, respectively. It should be understood that compounds, substances, combinations, associations, prodrugs, and pharmaceutical acceptable salts thereof described herein which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the invention. Certain isotopically labeled of the compounds, substances, combinations, associations, prodrugs, and salts thereof such as, for example, in certain embodiments, those incorporating a radioactive isotope such as 3H and 14C, are useful in drug and/or substrate tissue distribution studies. Tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly preferred due to their ease of preparation and detection. Further, substitution with heavier isotopes such as deuterium, i.e. 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example, in certain embodiments, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Isotopically labeled compounds, substances, combinations, associations, prodrugs, and salts thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples by substituting a readily available non-isotopically labeled reagent for an isotopically labeled reagent.
Prodrugs: As used herein, unless indicated otherwise or contradictory in context, the term “prodrug” refers to a compound, substance, combination or association that is transformed in vivo to yield a compound, substance, combination or association as defined herein or a pharmaceutically acceptable salt or solvate thereof. The transformation may occur by various mechanisms, such as via hydrolysis in blood. A prodrug of a compound, substance, combination or association defined herein may be formed in a conventional manner with one or more functional groups in the compound, such as an amino, hydroxyl or carboxyl group. For example, in certain embodiments, if a compound defined herein contains a carboxylic acid functional group, a prodrug can comprise: (1) an ester formed by the replacement of a hydrogen of the acid group with a group such as (C1-C6)alkyl or (C6-C10) aryl; (2) an activated ester formed by the replacement of the hydrogen of the acid group with groups such as —(CR2)COOR′, where CR2 is a spacer and R can be groups such as H or methyl and R′ can be groups such as (C1-C6)alkyl or (C6-C10) aryl; and/or (3) a carbonate formed by the replacement of the hydrogen of the acid with groups such as CHROCOOR′ where R can be groups such as H or methyl and R′ can be groups such as (C1-C6)alkyl or (C6-C10)aryl. Similarly, if a compound defined herein contains an alcohol functional group, a prodrug can be formed via the replacement of the hydrogen of the alcohol with groups such as (C1-C6)alkanoyloxymethyl or (C1-C6)akanoyloxyaryl or by forming an ester via condensation with, for example, in certain embodiments, an amino acid. Where a compound defined herein contains a primary or secondary amino group, a prodrug may comprise, for example, in certain embodiments, an amide formed by the replacement of one or both of the hydrogen atoms of the amino group with (C1-C10)alkanoyl or (C6-C10)aroyl. Other prodrugs of amines are well known to those skilled in the art. Alternatively, certain compounds defined herein may themselves act as prodrugs of other compounds defined herein. Discussions regarding prodrugs and their use can be found in, for example, in certain embodiments, “Prodrugs as Novel Delivery Systems,” T. Higuchi and W. Stella, Vol. 14 of the ACS Symposium Series, and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association). Examples of other prodrug types may be found in the aforementioned reference which is hereby incorporated by reference.
XI. Administration Routes and Procedures
(Modified) GFR-binding compounds, substances, functionalised bioactive carrier to be delivered and/or pharmaceutical, dermatological, prophylactic, diagnostic, or imaging compositions or formulations thereof in accordance with the present disclosure may be administered by any route of administration effective for preventing, treating, diagnosing, or imaging a disease, disorder, or condition and/or treating or alleviating at least one symptoms thereof and/or inducing tissue formation/regeneration and/or reducing or preventing tissue degeneration.
Suitable administration protocols include any in-vitro, in-vivo or ex-vivo administration protocol. The preferred types and routes of administration will be apparent to those of skill in the art, depending on the type of condition or disease to be prevented or treated or the nature of tissue to regenerate; whether the composition is nucleic acid based, protein based, cell based or combinations or mixtures thereof; and/or the target cell/tissue.
Ex-vivo and In-vitro administration: As used herein, unless indicated otherwise or contradictory in context, the term “ex-vivo administration” refers to performing the regulatory step outside of the subject/patient, such as administering a (modified) GFR-binding compounds, functionalised bioactive carrier or medical compositions as defined herein to a population of cells (e.g., mesenchymal stem cells) removed from a subject/patient for e.g. diagnostic, analysis and/or academic purposes.
Cells, tissues or organs can be contacted ex vivo or in vitro with a (modified) GFR-binding compound or a functionalised bioactive carrier by any suitable method, including mixing or the use of a delivery vehicle. Effective in vitro or ex vivo culture conditions include, but are not limited to, effective media, bioreactor, temperature, pH and oxygen conditions that permit cell culture. An effective medium refers to any medium in which a given host cell or tissue is typically cultured. Such medium typically comprises an aqueous medium having assimilable carbon, nitrogen and phosphate sources, and appropriate salts, minerals, metals and other nutrients, such as vitamins. Cells can be cultured in conventional fermentation bioreactors, shake flasks, test tubes, microtiter dishes, and petri plates. Culturing can be carried out at a temperature, pH and oxygen content appropriate for a cell or tissue. Such culturing conditions are within the expertise of one of ordinary skill in the art.
In one aspect, the present disclosure thus also provides a method for inducing tissue formation, in-vitro or ex-vivo, said method comprising the administration to a cell (e.g. a non-fully differentiated cell) of an effective amount of a GFR-binding compound, a functionalised bioactive carrier or a composition thereof as defined herein.
In-vivo administration: In one example, (modified) GFR-binding compounds, functionalised bioactive carriers or pharmaceutical, prophylactic, diagnostic, or imaging compositions are administered by one or more of a variety of routes, including oral, intravenous, intramuscular, intra-arterial, intramedullary, rectal, intravaginal, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, intraperitoneal, topical (e.g. by ointments, creams, powders, lotions, gels, and/or drops), buccal, enteral, mucosal, nasal, vitreal, sublingual, by intra-tracheal instillation, bronchial instillation, and/or inhalation, as an oral spray, nasal spray, and/or aerosol, and/or through a portal vein catheter. In one example, (modified) GFR-binding compounds, functionalised bioactive carrier or pharmaceutical, prophylactic, diagnostic, or imaging compositions are administered by systemic intravenous injection. In one example, (modified) GFR-binding compounds, functionalised bioactive carrier or pharmaceutical, prophylactic, diagnostic, or imaging compositions may be administered in a way which allows them to cross the blood-brain barrier, vascular barrier, or other epithelial barrier.
Delivery: As used herein, unless indicated otherwise or contradictory in context, the term “delivery” refers to the act or manner of delivering a compound, substance, composition, entity, moiety, cargo or payload.
Delivery Agent: As used herein, unless indicated otherwise or contradictory in context, the term “delivery agent” refers to any substance which facilitates, at least in part, the in vivo delivery of a (modified) GFR-binding compounds, functionalised bioactive carriers or pharmaceutical, prophylactic, diagnostic, or imaging compositions defined herein to targeted cells.
Forms suitable for oral administration: A (modified) GFR-binding compound, functionalised bioactive carrier or pharmaceutical, prophylactic, diagnostic, or imaging compositions of the invention, for example, in certain embodiments, includes forms suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, or for parenteral injection as a sterile solution, suspension or emulsion. Pharmaceutical compositions suitable for the delivery of (modified) GFR-binding compounds, functionalised bioactive carrier or pharmaceutical, prophylactic, diagnostic, or imaging compositions defined herein and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in certain embodiments, in ‘Remington's Pharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995), which is hereby incorporated by reference in its entirety. Oral administration may involve swallowing, so that the compounds or associations enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations, such as tablets, capsules containing particulates, liquids, or powders; lozenges (including liquid-filled), chews; multi- and nano-particulates; gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, in certain embodiments, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, in certain embodiments, from a sachet. The pharmaceutical associations or compositions defined herein may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in the art.
Forms suitable for parenteral administration: In one example, (modified) GFR-binding compounds, functionalised bioactive carriers or pharmaceutical, prophylactic, diagnostic, or imaging compositions of the invention may be administered by parenteral injection. Exemplary parenteral administration forms include sterile solutions, suspensions or emulsions of the pharmaceutical association defined herein in sterile aqueous media, for example, in certain embodiments, aqueous propylene glycol or dextrose. In another embodiment, the parenteral administration form is a solution. Such parenteral dosage forms can be suitably buffered, if desired. Preferred sterile solutions include sodium chloride, 0.9%, UPS solution. Injectable formulations can be sterilized, for example, in certain embodiments, by filtration through a bacterial-retaining filter, and/or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
Forms suitable for rectal and vaginal administration: Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing compositions with suitable non-irritating excipients such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
Forms suitable for topical and/or transdermal administration: Dosage forms for topical and/or transdermal administration of a composition may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches. Generally, an active ingredient is admixed under sterile conditions with a pharmaceutically acceptable excipient and/or any needed preservatives and/or buffers as may be required.
Forms suitable for pulmonary administration: Dosage forms for pulmonary administration via the buccal cavity may comprise dry particles which comprise the active ingredient (e.g. the pharmaceutical association defined herein) and which have a diameter in the range from about 0.5 nm to about 7 nm. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant may be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Pharmaceutical compositions formulated for pulmonary delivery may provide an active ingredient in the form of droplets of a solution and/or suspension. Such formulations may be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
Forms suitable for nasal administration: Formulations described herein as being useful for pulmonary delivery are also useful for intranasal delivery of a pharmaceutical composition. Formulations suitable for nasal administration may, for example, in certain embodiments, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of active ingredient (e.g. the pharmaceutical association defined herein), and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition may be prepared, packaged, and/or sold in a formulation suitable for buccal administration. Such formulations may, for example, in certain embodiments, be in the form of tablets and/or lozenges made using conventional methods, and may, for example, in certain embodiments, 0.1% to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations suitable for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 nm to about 200 nm, and may further comprise one or more of any additional ingredients described herein.
Forms suitable for ophthalmic administration: Dosage forms for ophthalmic administration include, for example, in certain embodiments, eye drops including, for example, in certain embodiments, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient (e.g. the pharmaceutical association defined herein) in an aqueous or oily liquid excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of any additional ingredients described herein. Other ophthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this present disclosure.
Direct Injection: One preferred administration method for delivering (modified) GFR-binding compounds, functionalised bioactive carriers or pharmaceutical, prophylactic, diagnostic, or imaging compositions as defined herein is by local administration, in particular, by direct injection. Direct injection techniques are particularly useful for administering a composition to a cell or tissue that is accessible by surgery, and particularly, on or near the surface of the body. Administration of a composition locally within the area of a target cell refers to injecting the composition centimeters and preferably, millimeters from the target cell or tissue.
Dosage regimens: The dosage regimen of the (modified) GFR-binding compounds, functionalised bioactive carriers or pharmaceutical, prophylactic, diagnostic, or imaging compositions as defined herein may be adjusted to provide the optimum desired response. For example, in certain embodiments, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. The appropriate dosing regimen, the amount of each dose administered and/or the intervals between doses will depend upon the pharmaceutical association being used, the type of pharmaceutical composition, the characteristics of the subject in need of treatment and the severity of the condition being treated. Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the present invention. In general, pharmaceutical compositions in accordance with the present disclosure may be administered at dosage levels sufficient to deliver from about 0.0001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic, diagnostic, prophylactic, or imaging effect. The desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the present invention. For example, in certain embodiments, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the present invention encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regiments for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.
Effective dose parameters: The dosage regimen of the (modified) GFR-binding compounds or functionalised bioactive carriers and/or pharmaceutical compositions as defined herein may be adjusted to obtain effective dose parameters. Effective dose parameters can be determined using methods standard in the art for a particular disease or condition. In particular, the effectiveness of dose parameters of a therapeutic composition as defined herein can be determined by assessing response rates. Such response rates refer to the percentage of treated patients in a population of patients that respond with either partial or complete remission.
A pharmaceutical composition as defined herein may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses.
Unit dose: As used herein, unless indicated otherwise or contradictory in context, the term “unit dose” refers to a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, in certain embodiments, one-half or one-third of such a dosage.
Single unit dose: As used herein, unless indicated otherwise or contradictory in context, the term “single unit dose” refers to a dose of any therapeutic association or composition administered in one dose/at one time/single route/single point of contact, i.e., single administration event.
Split dose: As used herein, unless indicated otherwise or contradictory in context, the term “split dose” refers to the division of single unit dose or total daily dose into two or more doses.
Total dally dose: As used herein, unless indicated otherwise or contradictory in context, the term “total daily dose” refers to an amount given or prescribed in 24 hr period. It may be administered as a single unit dose.
The relative amounts of the active ingredient(s), the pharmaceutically acceptable excipients, carriers or vehicles, and any additional ingredients in a pharmaceutical composition defined herein will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. In addition to the active ingredient, a pharmaceutical composition of the invention may further comprise one or more additional pharmaceutically active agents.
Combination therapy: Compounds, associations, compositions or formulations defined herein may be used in combination with one or more other therapeutic, prophylactic, diagnostic, or imaging agents. As used herein, the term “in combination with” is not intended to imply that the agents must be administered at the same time and/or formulated for delivery together, although these methods of delivery are within the scope of the present disclosure. Compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. In some embodiments, they are administered within about 90, 60, 30, 15, 10, 5, or 1 minute of one another. In some embodiments, the administrations of the agents are spaced sufficiently closely together such that a combinatorial (e.g., a synergistic) effect is achieved. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. In one example, the present disclosure encompasses the delivery of pharmaceutical, prophylactic, diagnostic, or imaging compositions in combination with agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body. It will further be appreciated that therapeutically, prophylactically, diagnostically, or imaging active agents used in combination may be administered together in a single composition or administered separately in different compositions. In general, it is expected that agents used in combination with be used at levels that do not exceed the levels at which they are used individually. In one example, the levels used in combination will be lower than those utilized individually. The particular combination of therapies to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder, or they may achieve different effects (e.g., control of any adverse effects).
Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to mammals, in particular humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts, in particular to any member of the Vertebrate class. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions is contemplated include, but are not limited to, humans and/or other primates; mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, dogs, mice, and/or rats; and/or birds, including commercially relevant birds such as chickens, ducks, geese, and/or turkeys.
XIII. Dermatological Applications
When the cell or tissue to be regenerated, repaired or treated is a skin cell or tissue (mainly from the fibroblast lineage), the pharmaceutical composition defined herein may be a dermatological composition comprising at least one (modified) GFR-binding compound or at least one functionalised bioactive carrier, as all defined herein, and at least one dermatologically acceptable excipient.
For example, in certain embodiments, a dermatological composition for the uses of the invention may contain between 0.01% and 100% by weight (over the total weight of the dermatological composition) of a GFR-binding compound or functionalised bioactive carrier, both as defined herein, as a dermatological effective amount. The dermatological composition particularly comprises between 0.01% and 95%, between 0.01% and 90%, between 0.01% and 85%, between 0.01% and 80%, between 0.01% and 75%, between 0.01% and 70%, between 0.01% and 65%, between 0.01% and 60%, between 0.01% and 55%, between 0.01% and 50%, between 0.01% and 45%, between 0.01% and 40%, between 0.01% and 35%, between 0.01% and 30%, between 0.01% and 25%, between 0.01% and 20%, between 0.01% and 15%, between 0.01% and 10%, between 0.01% and 5%, between 0.1% and 100%, between 0.1% and 95%, between 0.1% and 90%, between 0.1% and 85%, between 0.1% and 80%, between 0.1% and 75%, between 0.1% and 70%, between 0.1% and 65%, between 0.1% and 60%, between 0.1% and 55%, between 0.1% and 50%, between 0.1% and 45%, between 0.1% and 40%, between 0.1% and 35%, between 0.1% and 30%, between 0.1% and 25%, between 0.1% and 20%, between 0.1% and 15%, between 0.1% and 10%, and between 0.1% and 5% by weight (over the total weight of the dermatological composition) of any one of a GFR-binding compound or a functionalised bioactive carrier.
Dermatologically acceptable: As used herein, unless indicated otherwise or contradictory in context, the term “dermatologically acceptable” means that the compound(s) or pharmaceutical association(s) used are adapted for use in contact with human skin without undue toxicity, incompatibility, instability, allergic response, or their equivalents.
Dermatological formulations: Suitable formulation for implementing dermatological embodiments of the invention include an aqueous or oil-based solution, a water-based cream or gel or an oily gel, usually in a jar or a tube, particularly a shower gel, shampoo, milk, emulsion, microemulsion or nanoemulsion, particularly oil-in-water or water-in-oil or multiple of silicone-based; a lotion, particularly in a glass or plastic bottle of a spray or aerosol bottle, a blister-pack, liquid soap, a dermatological bar of soap, a pomade, mousse, an anhydrous product, preferably liquid, cream or solid, for example in the form of a stick, particularly in the form of lipstick, a cataplasm or a patch.
Preferred administration routes include, but are not limited to, oral, topical or intradermal as already defined herein.
Dermatologically acceptable excipients: Suitable dermatologically acceptable excipients for implementing embodiments of the invention include, but are not limited to, preservatives, emollients, emulsifiers, surfactants, moisturizers, thickeners, conditioners, mattifying agents, stabilizers, antioxidants, texturizing agents, shine agents, filmogenic agents, solubilizers, pigments, colorants, perfumes, and solar filters. These excipients are preferably chosen from among the group consisting of amino acids and their derivatives, polyglycerols, esters, polymers and cellulose derivatives, lanoline derivatives, phospholipids, lactoferrins, lactoperoxidases, sucrose-based stabilizers, vitamin E and its derivatives, natural and synthetic waxes, vegetable oils, triglycerides, insaponifiables, phytosterols, plant esters, silicones and their derivatives, protein hydrolysates, jojoba oil and its derivatives, lipo/hydrosoluble esters, betaines, aminoxides, saccharose ester plant extracts, titanium dioxides, glycines, parabens, and even more preferably from among the group consisting of butylene glycol, glycol-15 stearyl ether, cetearyl alcohol, phenoxyethanol, methylparaben, propylparaben, butylparaben, butylenes glycol, natural tocopherols, glycerine, dihydroxycetyl sodium phosphate, isopropyl hydroxycetyl ether, le glycol stearate, triisononanoin, octyl cocoate, polyacrylamide, isoparaffin, laureth-7, carbomer, propylene glycol, glycerol, bisabolol, dimethicone, sodium hydroxide, PEG 30-dipolyhydroxysterate, capric/caprylic triglycerides, cetearyl octanoate, dibutyl adipate, grapeseed oil, jojoba oil, magnesium sulfate, EDTA, cyclomethicone, xanthan gum, citric acid, sodium lauryl sulfate, mineral waxes and oils, isostearyl isostearate, dipelargonate of propylene glycol, isostearate of propylene glycol, PEG 8, beeswax, glyceride of hydrogenated palm kernel oil, lanolin oil, sesame oil, cetyl lactate, lanolin alcohol, titanium dioxide, lactose, saccharose, low-density polyethylene, and isotonic salt solution.
In one example, the dermatological composition as defined herein may contain at least one other active agents and/or excipients and/or additives of pharmaceutical, especially dermatological, interest such as agents with the following properties:
The CTFA Cosmetic Ingredient Handbook, Second Edition (1992), which is hereby incorporated by reference in its entirety, describes different cosmetic and pharmaceutical ingredients currently used in the cosmetic and pharmaceutical industry that are particularly adapted to topical use and which may be used in a dermatological composition of the invention. Examples of these types of ingredients include but are not limited to the following compounds: abrasives, absorbent compounds, compounds with aesthetic purposes such as perfumes, pigments, colorants, essential oils, astringents, etc. (for example: clove oil, menthol, camphor, eucalyptus oil, eugenol, menthyl lactate, and hamelis distillate), anti-acne agents, anti-flocculant agents, anti-foaming agents, anti-microbial agents (for example iodopropyl butylcarbamate), les antioxidants, bonding agents, biological additives, tampon agents, swelling agents, chelatants, additives, biocidal agents, denaturants, external analgesics, film-forming materials, polymers, opacifying agents, pH adjusters, reducing agents, depigmenting or lightening agents (for example: hydroquinone, kojic acid, ascorbic acid, magnesium ascorbyl phosphate, ascorbyl glucosamine), conditioning agents (for example: humectants), calming agents for the skin and/or scarring agents (for example: panthenol and its derivatives, for example ethyl panthenol), aloe vera, pantothenic acid and its derivatives, allantoin, bisabolol and dipotassium glycyrrhizinate), thickeners, vitamins, and the derivatives or equivalents of these.
In one aspect, the present disclosure provides a (modified) GFR-binding compound, a functionalised bioactive carrier, or a dermatological composition, all as defined herein, for use in preventing and/or treating scars and/or inflammations such as gingivitis.
In one particular example, the dermatological composition is intended for treating skin in which the dermis is at least partially damaged, especially in subjects who have undergone a surgical operation, or who have been burned and/or injured. This treatment makes it possible to stimulate the proliferation and/or the activity of fibroblasts, in order to stimulate tissue repair and/or dermal reconstruction.
In one aspect, the present disclosure provides a (modified) GFR-binding compound, a functionalised bioactive carrier, or a dermatological composition, all as defined herein, for use in preventing and/or treating at least one of acne, alopecia areata, bowen's disease, congenital erythropoietic porphyria, contact dermatitis, darier's disease, eczema (atopic eczema), epidermolysis bullosa simplex, erythropoietic protoporphyria, fungal infections of nails, hailey-hailey disease, herpes simplex, hidradenitis suppurativa, hirsutism, hyperhidrosis, ichthyosis, impetigo, keloids, keratosis pilaris, lichen planus, lichen sclerosus, melasma, pemphigus vulgaris, plantar warts (verrucas), pityriasis lichenoides, polymorphic light eruption, psoriasis, pyoderma gangrenosum, rosacea, scabies, shingles and vitiligo.
In one aspect, the present disclosure also provides a dermatological care or treatment method for a subject having need thereof, said method comprising the topical application, intradermal injection or oral administration, preferably the topical application or the intradermal injection, of a (suitable amount of) at least one (modified) GFR-binding compound, functionalised bioactive carrier, or dermatological composition, all as defined herein.
Such a dermatological care or treatment method includes the applications cited herein.
Suitable as amounts of (modified) GFR-binding compounds or functionalised bioactive carrier for implementing embodiments of the invention in the dermatological field include the group consisting of between about 0.0001 μg/day to about 5000 mg/day, between about 0.0001 μg/day to about 1000 mg/day, between about 0.0001 μg/day to about 10 mg/day, between about 0.0001 μg/day to about 1 mg/day, or between about 0.0001 μg/day to about 100 μg/day, all being preferred for implementing embodiments of the invention.
Advantageously, the subject who has need thereof is a subject chosen from a population having an average age of more than 30 years old or who has had sunlight over-exposure, has a family history of skin conditions.
XIV. Ophthalmic Applications
Preferable dosage forms for the (modified) GFR-binding compound functionalised bioactive carrier or pharmaceutical composition, all as defined herein, for treating eye retina diseases, disorders or conditions include, for example, in certain embodiments, eye drops and eye ointments. These can be prepared using conventional techniques. For instance, eye drops may be prepared, using isotonic agents such as sodium chloride, buffers such as sodium phosphate, and preservatives such as benzalkonium chloride. A suitable pH is within an ophthalmologically acceptable range. Preferred pH is within pH 4 to 8.
Particularly preferred administration routes include vitreal and intraocular.
A suitable dose of (modified) GFR-binding compound, functionalised bioactive carrier, or pharmaceutical composition for treating eye disorders is appropriately selected, depending on the symptoms, age of patients, dosage form and the like. For eye drops, suitable concentration may be 0.0001 to 10 w/v %, preferably 0.0001 to 0.01 w/v % for administration into eyes once or several times a day.
XV. Surgical Treatments
The (modified) GFR-binding compounds, functionalised bioactive carriers, and pharmaceutical compositions, all as defined herein, may be used in surgical methods suitable for protecting (e.g. treating or preventing) a patient or subject from a disease, condition, disorder or pathology to whom a surgical intervention would be beneficial.
For example, in certain embodiments, said surgical method may be selected from the group consisting of bone-repair surgery, cartilage-repair surgery, heart surgery, kidneys or lung surgery, eye surgery, muscle-repair surgery, and tendon/ligament—repair surgery.
In one aspect, the present invention thus discloses a surgical method for surgical treatment comprising the contacting of at least one (modified) GFR-binding compound, at least one functionalised bioactive carrier, a pharmaceutical, prophylactic, diagnostic or imaging composition thereof, or medical device, all as defined herein, with a body part of a patient to be treated, wherein said contacting induces stem cell differentiation and tissue formation.
In one example, said surgical method comprises the placement or implantation of an implantable medical device comprising a (modified) GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical, prophylactic, diagnostic or imaging composition thereof, all as defined herein, inside a patient or subject in need of such a surgical treatment.
For example, in certain embodiments, the surgical treatment of the invention may include the use of a placement, insertion or depositing device for contacting said GFR-binding compound, said functionalised bioactive carrier, or a pharmaceutical, prophylactic, diagnostic or imaging composition thereof with a body part of a patient or subject in need of such a treatment. In one example, said placement, insertion or depositing device comprises an injection device such as a syringe.
In certain embodiments, said surgical method comprises the positioning of a GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical, prophylactic, diagnostic or imaging composition thereof, all as defined herein, inside said injection device for injection into a patient or into a body part of a patient.
In one example, said medical device comprises titanium and/or PEEK and/or PET and/or hydrogel and/or ceramic. In one particular example, said medical device replaces part of or all of a body part of a patient or subject. In one example, said body part is a malfunctioning or damaged body part such as, for instance, a bone, the skin, the hair scalp, an eye, etc.
XVI. Pharmaceutical Applications, Uses and Methods
Some growth factors interact with type I and II growth factor receptors belonging to the serine threonine kinase family. Conventionally, to mediate signaling pathways, growth factors interact with these receptors by forming specific dimeric or oligomeric structures. The type-II receptor, which is constitutively active, phosphorylates the type-I receptor, which then activates the transduction pathway Smad1/5/8. Receptors of both types are thus conventionally needed to form a functional complex in order to initiate further signaling events. Phosphorylated Smads then dissociate from the receptors and bind Smad4, a common mediator, leading to nuclear translocation, regulation of specific genes, and eventually may induce tissue regeneration.
Prior in-vitro and in-vivo scientific studies have reported that influencing the natural/conventional biology of human mesenchymal stem cells using exogenous entity or molecules such as recombinant growth factor proteins or peptide fragments thereof, may have an effect on cell differentiation and tissue regeneration. A (modified) GFR-binding compound or a functionalised bioactive carrier of the present disclosure may be one such exogenous entity or molecule.
For example, in certain embodiments, medical treatments may demonstrate the effect of the influence of an exogenous entity or molecule on human mesenchymal stem cells using a medical device onto or into which such an exogenous entity or molecule has been reversibly or irreversibly incorporated or deposited, both being equally preferred, and placed into a patient in need thereof.
In one example, medical treatments may provide the effect of the influence of an exogenous entity or molecule on human mesenchymal stem cells using a pharmaceutical composition containing such an exogenous entity or molecule and a pharmaceutically acceptable excipient or carrier, administered, for instance, orally, enterically, intravenously, peritoneally, subcutaneously, transdermally, parenterally, or rectally, to a patient in need of such a treatment.
As already stated herein, for in-vivo administration, compounds or compositions of the present invention may be injected at a target site so that they can be delivered in close proximity to the cells to be treated via, e.g. a PTD or cell-permeable peptide. Alternately, an implant (or medical device or implantable medical device) comprising a PTD/GFR-binding compound complex may be used.
The present invention generally provides for uses and methods of inducing mesenchymal stem cell or progenitor cell (at any stage of differentiation) differentiation and/or inducing, promoting, enhancing, controlling or regulating tissue regeneration/formation in-vitro, ex-vivo and in-vivo.
Conveniently, such a tissue formation process is generally achieved within less than 7 days. In particular, such a tissue formation process is generally achieved within less than 6 days. In particular, such a tissue formation process is generally achieved within less than 5 days. In particular, such a tissue formation process is generally achieved within less than 4 days. In particular, such a tissue formation process is generally achieved within less than 3 days. In particular, such a tissue formation process is generally achieved within less than 2 days. In particular, such a tissue formation process is generally achieved within less than 24 hours. In particular, such a tissue formation process is generally achieved within less than 18 hours.
In one aspect, the present disclosure provides a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition as defined herein for use in a method of non-mutagenically inducing tissue formation i.e. without modifying or altering the genome of the treated cells, in-vitro, ex-vivo or in-vivo. Also provided is a method of inducing tissue formation i.e. without modifying or altering the genome of the treated cells, comprising the in-vitro, ex-vivo or in-vivo administration of an effective amount of a (modified) GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition as defined herein.
In one aspect, the present disclosure provides a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition as defined herein for use in a method of extracellular induction of tissue formation. Also provided is a method of extracellular tissue formation induction, comprising the in-vitro, ex-vivo or in-vivo administration of an effective amount of a (modified) GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition as defined herein.
An extracellular treatment as used herein implies a biological action/effect to be provided or to occur outside the cell to be treated (i.e. a mesenchymal stem cell). In other words, the biologically active agent (e.g. the GFR-binding compound or the pharmaceutical composition as defined herein) delivers/provides its biological/pharmaceutical effect to the outside of the cell (e.g. on the cell's surface) without the need to penetrate through the cell membrane, inside the cell to be treated. Once the extracellular action/effect has been administered/delivered to the cell to be treated, said active agent may be, for instance, excreted from the host organism with or without being metabolised, and/or tagged to be destroyed through apoptotic routes, and/or internalised by nearby cells, etc. . . . .
In one aspect, the present disclosure provides a method of producing a physiologically functional and healthy cell, comprising the administration in-vitro, ex-vivo or in-vivo to a mesenchymal stem cell or progenitor cell (at any stage of differentiation) of an effective amount of a (modified) GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition as defined herein and wherein said physiologically functional and healthy cell is selected from the group consisting of an osteoblast, osteocyte, chondroblast, chondrocyte, neuroblast, neurocyte, Sertoli cells, Leydig cell, Germ cell, Myoblast, Myocyte, keratinocyte, endothelial cells, angioblast, fibroblast, fibrocyte, podocyte, areolar connective cells, adipocytes, pre-adipocytes/lipoblasts, epithelial cells, erythrocytes, alveolar cells, hematopoietic stem cells (HSC), myeloid progenitors, lymphoid progenitors, mast cells, myeloblasts, monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes, thrombocytes, dendritic cells, small lymphocytes, T-lymphocytes (T-cells), B-lymphocytes (B-cells), and natural killer (NK)-cells.
In one aspect, the present disclosure provides methods to activate a growth factor receptor present on the surface of a mesenchymal stem cell or progenitor cell (at any stage of differentiation), said method comprising administering to said mesenchymal stem cell or progenitor cell (at any stage of differentiation) an effective amount of a (modified) GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition as defined herein, wherein administering said GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition as defined herein activates the growth factor receptor present on the surface of the mesenchymal stem cell or progenitor cell (at any stage of differentiation).
In one aspect, the present disclosure provides methods of delivering a (modified) GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, in-vitro, ex-vivo or in-vivo to a mesenchymal stem cell or progenitor cell (at any stage of differentiation), comprising the contacting of said mesenchymal stem cell or progenitor cell (at any stage of differentiation) with said (modified) GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition.
In one aspect, the present disclosure provides methods of administering a (modified) GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, to a patient or subject comprising the contacting of at least one body part of said patient or subject with said (modified) GFR-binding compound, a functionalised bioactive carrier, or a pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition.
In one example, the (modified) GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, may be a mammal (preferably a human) tissue-inductive compound, bioactive carrier or composition, which has demonstrated the ability to induce tissue formation in vitro and/or in vivo.
In one aspect, the present disclosure provides an effective amount of at least one (modified) GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, for use in a medical method such as in therapy, surgery or in diagnostic methods.
In one aspect, the present disclosure provides a method of inducing or promoting or enhancing mesenchymal stem cell or progenitor cell (at any stage of differentiation) differentiation, the method comprising administering to the cell an effective amount of at least one (modified) GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein. In one aspect, the present invention discloses an effective amount of at least one (modified) GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, for use in a method of inducing or promoting or enhancing mesenchymal stem cell or progenitor cell (at any stage of differentiation) differentiation
In one aspect, the present disclosure provides a method of inducing or promoting or enhancing or controlling or regulating tissue regeneration/formation, the method comprising administering to a mesenchymal stem cell or to a progenitor cell at any stage of differentiation or to a mature cell an effective amount of at least one (modified) GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein. In one aspect, the present invention discloses an effective amount of at least one (modified) GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, for use in a method of inducing or promoting or enhancing or controlling or regulating tissue regeneration/formation.
In one aspect, the present disclosure provides a method of inducing and/or promoting and/or enhancing cell motility or single/collective cell migration, the method comprising administering to a mesenchymal stem cell or to a progenitor cell at any stage of differentiation or to a mature cell an effective amount of at least one (modified) GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein. In one aspect, the present invention discloses an effective amount of at least one (modified) GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, for use in a method of inducing and/or promoting and/or enhancing cell motility or single/collective cell migration.
In one aspect, the present invention discloses a method of inducing and/or promoting and/or enhancing cell maturation, the method comprising administering to a differentiated cell or to a mature cell an effective amount of at least one (modified) GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein. In one aspect, the present invention discloses an effective amount of at least one (modified) GFR-binding compound, at least one functionalised bioactive carrier, or at least one pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, for use in a method of inducing and/or promoting and/or enhancing cell maturation.
In one example, the (modified) GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, may be combined/mixed with adult stem cells and/or multipotent progenitor cells prior to be administered or implanted into a mammal (preferably a human) to promote tissue regeneration.
In one example, the (modified) GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, may be administered as such and may be combined/mixed with adult stem cells and/or multipotent progenitor cells prior to administration to a mammal (preferably a human) to promote tissue regeneration.
In particular, medical applications which may result from the mediation of type I and II growth factor receptors by a (modified) GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing of osteogenesis, inducing bone formation, inducing osteocyte maturation, and/or treating and/or preventing osteoporosis.
In one example, a (modified) GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, may thus be an osteoinductive compound, bioactive carrier or composition which has demonstrated an ability to induce bone formation in vitro and/or ex-vivo and/or in vivo.
In one aspect, the present disclosure thus provides:
In particular, medical applications which may result from the mediation of type I and II growth factor receptors by a (modified) GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing of chondrogenesis and/or inducing cartilage formation, and/or inducing chondrocyte maturation and/or treating and/or preventing at least one of osteoarthritis, costochondritis, Herniation, achondroplasia or relapsing polychondritis.
In one example, a (modified) GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, may be a chondroinductive compound, bioactive carrier or composition which has demonstrated the ability to induce cartilage formation in vitro and/or ex-vivo and/or in vivo.
In one aspect, the present disclosure thus provides:
In particular, medical applications which may result from the mediation of type I and II growth factor receptors by a GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing of endothelization and/or vascularization/angiogenesis and/or treating and/or preventing at least one of coronary artery disease (also known as coronary heart disease and ischemic heart disease), cardiomyopathy, hypertensive heart disease, heart failure, cor pulmonale, cardiac dysrhythmias, inflammatory heart disease, endocarditis, inflammatory cardiomegaly, myocarditis, valvular heart disease, cerebrovascular disease, peripheral arterial disease, congenital heart disease, or rheumatic heart disease.
In one example, a GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, may be an endothelization/vascularization/angiogenesis—promoting compound, bioactive carrier or composition which has demonstrated the ability to induce vascular tissue formation in vitro and/or ex-vivo and/or in vivo.
In one aspect, the present disclosure thus provides:
In particular, medical applications which may result from the mediation of type I and II growth factor receptors by a GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing axonal dendritic neuron growth thus promoting neuron-regeneration and/or treating and/or preventing and/or decreasing or suppressing neuron degeneration-related conditions and diseases.
In the present description and unless otherwise indicated, the term “neuron-regeneration” or “neuroregeneration” means the regrowth or repair of nervous tissues, cells or cell products involving the participation of stem cells. Such mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neurological disorders in which the present invention may thus be useful include, but are not limited to, ALS, Agraphia Alzheimer's disease, Amyotrophic lateral sclerosis, Angle man syndrome, Aphasia Apraxia, Arachnoiditis, Ataxia Telangiectasia, Attention deficit hyperactivity disorder, Auditory processing disorder, Autism, Alcoholism, asperger's syndrome, Bipolar disorder, Bells palsy, Brachial plexus injury, Brain damage, Brain injury, Canavan disease, Capgras delusion, Causalgia, Central pain syndrome, Central pontine myelinolysis, Centronuclear myopathy, Cephalic disorder, Cerebral aneurysm, Cerebral arteriosclerosis, Cerebral atrophy, Cerebral gigantism, Cerebral palsy, Cerebral vasculitis, Cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiari malformation, Chorea, Chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic pain, Coffin-Lowry syndrome, Coma, Complex regional pain syndrome, Compression neuropathy, Congenital facial diplegia, Corticobasal degeneration, Cranial arteritis, Craniosynostosis, Creutzfeldt-Jakob disease, Cumulative trauma disorders, Cushing's syndrome, Cytomegalic inclusion body disease (CIBD), Cytomegalovirus Infection, Dandy-Walker syndrome, Dawson disease, De Morsier's syndrome, Dejerine-Klumpke palsy, Dejerine-Sottas disease, Delayed sleep phase syndrome, Dementia, Dermatomyositis, Developmental coordination disorder, Diabetic neuropathy, Diffuse sclerosis, Downs syndrome, Dravet syndrome, Dysautonomia, Dyscalculia, Dysgraphia, Dyslexia, Dystonia, Empty sella syndrome, Encephalitis, Encephalocele, Encephalotrigeminal angiomatosis, Encopresis, Epilepsy, Erb's palsy, Erythromelalgia, Essential tremor, Fabry's disease, Fahr's syndrome, Fainting, Familial spastic paralysis, Febrile seizures, Fisher syndrome, Friedreich's ataxia, Fibromyalgia, Foville's syndrome, Fetal alcohol syndrome, Fragile X Tremor Ataxia Syndrome, Gaucher's disease, Gerstmann's syndrome, Giant cell arteritis, Giant cell inclusion disease, Globoid Cell Leukodystrophy, Gray matter heterotopia, Guillain-Barré syndrome, HTLV-1 associated myelopathy, Hallervorden-Spatz disease, Head injury, Headache, Hemifacial Spasm, Hereditary Spastic Paraplegia, Heredopathia atactica polyneuritiformis, Herpes zoster oticus, Herpes zoster, Hirayama syndrome, Holoprosencephaly, Huntington's disease, Hydranencephaly, Hydrocephalus, Hypercortisolism, Hypoxia, Immune-Mediated encephalomyelitis, Inclusion body myositis, Incontinentia pigmenti, Infantile Refsum disease, Infantile spasms, Inflammatory myopathy, Intracranial cyst, Intracranial hypertension, Joubert syndrome, Karak syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbourne syndrome, Kleine-Levin Syndrome, Klippel Feil syndrome, Krabbe disease, Kugelberg-Welander disease, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, Lateral medullary (Wallenberg) syndrome, Learning disabilities, Leigh's disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, Leukodystrophy, Lewy body dementia, Lissencephaly, Locked-In syndrome, Lou Gehrig's disease (See amyotrophic lateral sclerosis), Lumbar disc disease, Lumbar spinal stenosis, Lyme disease-Neurological Sequelae, Machado-Joseph disease (Spinocerebellar ataxia type 3), Macrencephaly, Macropsia, Megalencephaly, Mekersson-Rosenthal syndrome, Menieres disease, Meningitis, Menkes disease, Metachromatic leukodystrophy, Microcephaly, Micropsia, Migraine, Miller Fisher syndrome, Mini-stroke (transient ischemic attack), Misophonia, Mitochondrial myopathy, Mobius syndrome, Monomelic amyotrophy, Motor Neurone Disease—see amyotrophic lateral sclerosis, Motor skills disorder, Moyamoya disease, Mucopolysaccharidoses, Multi-infarct dementia, Multifocal motor neuropathy, Multiple sclerosis, Multiple system atrophy, Muscular dystrophy, Myalgic encephalomyelitis, Myasthenia gravis, Myelinoclastic diffuse sclerosis, Myoclonic Encephalopathy of infants, Myoclonus, Myopathy, Myotubular myopathy, Myotonia congenital, Narcolepsy, Neuro-Behçet's disease, Neurofibromatosis, Neuroleptic malignant syndrome, Neurological manifestations of AIDS, Neurological sequelae of lupus, Neuromyotonia, Neuronal ceroid lipofuscinosis, Neuronal migration disorders, Neuropathy, Neurosis, Niemann-Pick disease, Non-24-hour sleep-wake disorder, Nonverbal learning disorder, O'Sullivan-McLeod syndrome, Occipital Neuralgia, Occult Spinal Dysraphism Sequence, Ohtahara syndrome, Olivopontocerebellar atrophy, Opsoclonus myoclonus syndrome, Optic neuritis, Orthostatic Hypotension, Otosclerosis, Overuse syndrome, Palinopsia, Paresthesia, Parkinson's disease, Paramyotonia Congenita, Paroxysmal attacks, Parry-Romberg syndrome, Pelizaeus-Merzbacher disease, Periodic Paralyses, Peripheral neuropathy, Pervasive developmental disorders, Photic sneeze reflex, Phytanic acid storage disease, Pick's disease, Pinched nerve, PMG, Polyneuropathy, Polio, Polymicrogyria, Polymyositis, Porencephaly, Post-Polio syndrome, Postherpetic Neuralgia (PHN), Postural Hypotension, Prader-Willi syndrome, Primary Lateral Sclerosis, Prion diseases, Progressive hemifacial atrophy, Progressive multifocal leukoencephalopathy, Progressive Supranuclear Palsy, Quadriplegia, Rabies, Ramsay Hunt syndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome type Ill, Rasmussen's encephalitis, Reflex neurovascular dystrophy, Refsum disease, Repetitive stress injury, Restless legs syndrome, Retrovirus-associated myelopathy, Rett syndrome, Reye's syndrome, Rhythmic Movement Disorder, Romberg syndrome, Saint Vitus dance, Sandhoff disease, Schizencephaly, Sensory processing disorder, Septo-optic dysplasia, Shaken baby syndrome, Shingles, Shy-Drager syndrome, Sjögren's syndrome, Sleep apnea, Sleeping sickness, Snatiation, Sotos syndrome, Spasticity, Spina bifida, Spinal cord injury, Spinal muscular atrophy, Spinocerebellar ataxia, Split-brain, Steele-Richardson-Olszewski syndrome, Stiff-person syndrome, Stroke, Sturge-Weber syndrome, Subacute sclerosing panencephalitis, Subcortical arteriosclerotic encephalopathy, Superficial siderosis, Sydenham's chorea, Syncope, Synesthesia, Syringomyelia, Tarsal tunnel syndrome, Tardive dyskinesia, Tardive dysphrenia, Tarlov cyst, Tay-Sachs disease, Temporal arteritis, Tetanus, Tethered spinal cord syndrome, Thomsen disease, Thoracic outlet syndrome, Tic Douloureux, Todd's paralysis, Tourette syndrome, Toxic encephalopathy, Transient ischemic attack, Transmissible spongiform encephalopathies, Transverse myelitis, Traumatic brain injury, Tremor, Trigeminal neuralgia, Tropical spastic paraparesis, Trypanosomiasis, Tuberous sclerosis, Ubisiosis, Von Hippel-Lindau disease (VHL), Viliuisk Encephalomyelitis (VE), Wallenberg's syndrome, Werdnig-Hoffman disease, West syndrome, Whiplash, Williams syndrome, Wilson's disease and Zellweger syndrome.
In one example, a GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, may be a neuroregenerative or neurodegeneration regulator/modulator/inhibitor compound, bioactive carrier or composition which has demonstrated the ability to induce neuroregeneration and/or prevention, decrease or suppression of neuron degeneration in vitro and/or ex-vivo and/or in vivo.
In one aspect, the present disclosure thus provides:
In particular, medical applications which may result from the mediation of type I and II growth factor receptors by a GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing/promoting eye retina cell regeneration and/or treating and/or preventing and/or decreasing or suppressing eye retina cell degeneration-related conditions or diseases.
Eye-related diseases or disorders in which the present invention may thus be useful include, but are not limited to, Focal chorioretinal inflammation Focal such chorioretinitis, choroiditis, retinitis and retinochoroiditis, Disseminated chorioretinal inflammation, Posterior cyclitis, Harada's disease, Chorioretinal scars such as Macula scars of posterior pole and Solar retinopathy, Choroidal degeneration such as Atrophy and Sclerosis, Hereditary choroidal dystrophy such as Choroideremia, Gyrate atrophy, Choroidal haemorrhage, Choroidal detachment, Chorioretinitis, Retinal detachment, Retinoschisis, Retinal vascular occlusions, Hypertensive retinopathy, Diabetic retinopathy, Retinopathy, Retinopathy of prematurity, Age-related macular degeneration, Macular degeneration, Epiretinal membrane, Peripheral retinal degeneration, Hereditary retinal dystrophy, Retinitis pigmentosa, Retinal haemorrhage, Central serous retinopathy, Retinal detachment and Macular edema.
In one example, a GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, may be an eye tissue-regenerative or eye tissue-degeneration regulator/modulator/inhibitor compound, bioactive carrier or composition which has demonstrated the ability to induce eye retina cell regeneration and/or prevent and/or decrease or suppress eye retina cell degeneration in vitro and/or ex-vivo and/or in vivo.
In one aspect, the present disclosure thus provides:
In particular, medical applications which may result from the mediation of type I and II growth factor receptors by a GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing/promoting renal functions such as enhancing/improving waste removal, body's fluid balance control and electrolytes balance control and/or preventing/treating kidneys failure and/or chronic kidney disease (CKD) and/or renal fibrosis.
In one example, a GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, may be a kidneys-function enhancing compound, bioactive carrier or composition which has demonstrated the ability to promote/improve kidneys functions and/or preventing/treating kidneys failure and/or chronic kidney disease (CKD) and/or renal fibrosis in vitro and/or ex-vivo and/or in vivo.
In one aspect, the present disclosure thus provides:
In particular, medical applications which may result from the mediation of type I and II growth factor receptors by a GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing/promoting fibrous tissue formation and tendon and ligament regeneration and/or preventing and/or decreasing or suppressing tendon/ligament cell degeneration.
In one example, a GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, may be a fibrous tissue formation promoting compound, bioactive carrier or composition which has demonstrated the ability to induce fibrous tissue formation in vitro and/or ex-vivo and/or in vivo.
In one aspect, the present disclosure thus provides:
In particular, medical applications which may result from the mediation of type I and II growth factor receptors by a GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, hair follicle tissue regeneration and formation (hair growth), hair follicle stem cell activation (loss of quiescence state) and/or preventing/treating alopecia areata, alopecia totalis, alopecia universalis, androgenic alopecia (male pattern baldness), telogen effluvium, anagen effluvium or chemotherapy-induced alopecia.
In one example, a GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, may be a hair follicle growth activation promoting compound, bioactive carrier or composition which has demonstrated the ability to induce hair follicle formation and/or hair follicle stem cell activation in vitro and/or ex-vivo and/or in vivo.
In one aspect, the present disclosure thus provides:
In particular, medical applications which may result from the mediation of type I and II growth factor receptors by a GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing tissue closure.
In one example, a GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, may be a tissue-closure-promoting compound or biomaterial which has demonstrated the ability to induce tissue closure in vitro and/or ex-vivo and/or in vivo.
In one aspect, the present disclosure thus provides:
In particular, medical applications which may result from the mediation of type I and II growth factor receptors by a GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing/promoting female fertility and/or preventing and/or decreasing or suppressing female infertility.
In one example, a GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, may be a female fertility enhancing or a female infertility regulator/modulator/inhibitor compound, bioactive carrier or composition which has demonstrated the ability to enhance/promote female fertility and/or prevent and/or decrease or suppress female infertility in vitro and/or ex-vivo and/or in vivo.
In one aspect, the present disclosure thus provides:
In particular, medical applications which may result from the mediation of type I and II growth factor receptors by a (modified) GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing of myogenesis, inducing muscle tissue formation, reinforcing muscle tissues, inducing myocyte maturation, repairing damaged muscles, preventing muscle tissue degeneration or damages, and/or protecting a subject from one or more muscle tissue-related diseases, disorders, conditions or pathologies such as myopathies, muscular atrophy, disuse atrophy, denervation atrophy, muscular dystrophies such as the Duchenne muscular dystrophy (DMD), and the Becker muscular dystrophy (BMD), fibrosis, fibrositis, muscle weakness, fatigue, cramps, fibromyalgia, or chronic muscle pain syndrome.
In one example, a (modified) GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, may thus be an myoinductive compound, bioactive carrier or composition which has demonstrated an ability to induce muscle tissue formation in vitro and/or ex-vivo and/or in vivo.
In one aspect, the present disclosure thus provides:
In particular, medical applications which may result from the mediation of type I and II growth factor receptors by a (modified) GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing blood tissue regeneration, inducing blood cell differentiation, or protecting a patient from a blood cell degeneration-related disease, condition, disorder, or pathology.
In one example, a (modified) GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, may thus be a blood cell degeneration inhibitor, bioactive carrier or composition which has demonstrated an ability to induce blood cell formation in vitro and/or ex-vivo and/or in vivo.
In one aspect, the present disclosure thus provides:
In particular, medical applications which may result from the mediation of type I and II growth factor receptors by a (modified) GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing of lung tissue regeneration, inducing lung cell differentiation, or protecting a patient from a lung cell degeneration-related disease, condition, disorder, or pathology.
In one example, a (modified) GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, may thus be a lung cell degeneration inhibitor, bioactive carrier or composition which has demonstrated an ability to induce lung cell formation in vitro and/or ex-vivo and/or in vivo.
In one aspect, the present disclosure thus provides:
In particular, medical applications which may result from the mediation of type I and II growth factor receptors by a (modified) GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, include, but are not limited to, enhancing adipose tissue regeneration, inducing adipocyte differentiation, or protecting a patient from a adipose tissue degeneration-related disease, condition, disorder, or pathology.
In one example, a (modified) GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, may thus be an adipose tissue degeneration inhibitor, bioactive carrier or composition which has demonstrated an ability to induce adipose tissue formation in vitro and/or ex-vivo and/or in vivo.
In one aspect, the present disclosure thus provides:
Protected from a disease, condition, disorder or pathology refers to the treatment of the underlying cause of the disease, condition, disorder or pathology as well as reducing the symptoms of the disease, condition, disorder or pathology; and/or reducing the occurrence of the disease, condition, disorder or pathology; and/or reducing the severity of the disease, condition, disorder or pathology. Protecting a patient can refer to the ability of a therapeutic composition of the present invention, when administered to a patient, to prevent a disease, condition, disorder or pathology from occurring and/or to cure or to alleviate disease, condition, disorder or pathology symptoms, signs or causes. As such, to protect a patient from a disease, condition, disorder or pathology includes both preventing disease, condition, disorder or pathology occurrence (prophylactic treatment) and treating a patient that has a disease, condition, disorder or pathology or that is experiencing initial symptoms or later stage symptoms of a disease, condition, disorder or pathology (therapeutic treatment).
Treating: As used herein, unless indicated otherwise or contradictory in context, the term “treating” or “treatment” refers to partially or completely alleviating, ameliorating, improving, relieving, delaying onset of, inhibiting progression of, reducing severity of, and/or reducing incidence of one or more symptoms or features of a particular disease, disorder, pathology and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition and/or to a subject who exhibits only early signs of a disease, disorder, pathology and/or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
Preventing: As used herein, unless indicated otherwise or contradictory in context, the term “preventing” refers to partially or completely delaying onset of an infection, disease, disorder and/or condition; partially or completely delaying onset of one or more symptoms, features, or clinical manifestations of a particular infection, disease, disorder, and/or condition; partially or completely delaying onset of one or more symptoms, features, or manifestations of a particular infection, disease, disorder, and/or condition; partially or completely delaying progression from an infection, a particular disease, disorder and/or condition; and/or decreasing the risk of developing pathology associated with the infection, the disease, disorder, and/or condition.
Disease: As used herein, unless indicated otherwise or contradictory in context, the term “disease” refers to any deviation from the normal health of a patient and includes a state when disease symptoms are present, as well as conditions in which a deviation has occurred, but symptoms are not yet manifested. The same applies to “condition”, “disorder” and “pathology”.
In one aspect, the present disclosure provides methods of determining the effectiveness of a (modified) GFR-binding compound, a functionalised bioactive carrier or a pharmaceutical composition as defined herein for inducing cell differentiation, or inducing, promoting, enhancing, controlling or regulating tissue regeneration/formation in-vitro, ex-vivo and in-vivo comprising the administration of said (modified) GFR-binding compound, a functionalised bioactive carrier or a pharmaceutical composition to a cell; the measurement of the expression of specific differentiation markers as defined herein in the cell; the comparison of the expression of said specific differentiation markers in the cell to the expression of said specific differentiation markers in a cell treated with a reference (or control) functionalised bioactive carrier, compound or solvent; and determining the effectiveness of the (modified) GFR-binding compound, a functionalised bioactive carrier or a pharmaceutical composition relative to the reference pharmaceutical association or compound.
In one aspect, the present disclosure provides methods to activate, promote, support, improve, or increase the activity of a growth factor receptor present in, on the surface of a mesenchymal stem cell or progenitor cell (at any stage of differentiation thereof) such that said cell may undergo efficient cell differentiation.
In one aspect, the present disclosure provides methods of identifying, diagnosing, and optionally classifying subjects on these bases, which may include clinical diagnosis, biomarker levels, and other methods known in the art.
XVII. Wound Healing Applications
Specific applications of the invention in dermatology relate to wound healing and skin repair.
Thus, dermatological applications which may result from the mediation of type I and II growth factor receptors by a compound, functionalised bioactive carrier, or composition of the invention include, but are not limited to, enhancing wound healing, skin repair and cellular migration.
Skin repair: In the present description and unless otherwise indicated, the term “skin repair” means dermal and epidermal cells regeneration, collagen and other skin protein synthesis by epithelial cells.
Cellular migration: In the present description and unless otherwise indicated, the term “cellular migration” means a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations. The cells involved in cellular migration include the cells of the epithelial and dermal cell lineages forming the connective tissue i.e. the fibroblasts, fibrocytes, myofibroblasts, adipocytes, synoviocytes, macrophages, histiocytes, granulocytes, plasmocytes and mastocytes.
In one example, a (modified) GFR-binding compound, functionalised bioactive carrier, or pharmaceutical (therapeutic, dermatologic, ophthalmologic, diagnostic, etc.) composition, all as defined herein, may be a wound-healing-promoting compound, bioactive carrier, or composition which has demonstrated the ability to induce wound healing, skin repair and/or cellular migration in vitro, ex-vivo and/or in vivo.
In one aspect, the present disclosure thus provides:
XVII. Cosmetic Applications
Skin ageing is typically associated with a deregulation of the metabolism of cutaneous cells characterized by a diminishing of the proliferation of keratinocytes, a deregulation of the differentiation of keratinocytes, an accumulation of dead cells, and a diminishing of the innervation of the skin.
Cosmetic, non-therapeutic, applications which may result from the mediation of type I and II growth factor receptors by a GFR-binding compound, functionalised bioactive carrier, or compositions thereof, all as defined herein, include, but are not limited to, enhancing/promoting skin regeneration, preventing and/or attenuating and/or masking and/or removing wrinkles, firming the skin, preventing and/or decreasing or suppressing skin pigmentation.
In one example, a GFR-binding compound, functionalised bioactive carrier, or compositions thereof, all as defined herein, may be an anti-wrinkle/ageing and/or skin-firming and/or skin regeneration-promoting compound, bioactive carrier or composition which has demonstrated the ability to enhance/promote skin cosmetic regeneration, prevent and/or attenuate and/or mask and/or remove wrinkles, firm the skin, prevent and/or decrease or suppress skin pigmentation in vitro and/or in vivo.
In one aspect, the present disclosure provides a cosmetic or functional food composition comprising at least one GFR-binding compound or at least one functionalised bioactive carrier, all as defined herein, in combination with at least one suitable cosmetic carrier, preferably suitable for topical application.
Suitable cosmetic carrier: The terms “suitable cosmetic carrier” used here, mean that the composition or the components of the latter are suitable for use in contact with human skin without undue toxicity, incompatibility, instability, allergic response or their equivalents.
In one aspect, the present disclosure provides a use of a GFR-binding compound, or functionalised bioactive carrier, all as defined herein, in cosmetics or as a functional food.
In one aspect, the present disclosure provides a use of a GFR-binding compound, functionalised bioactive carrier, or composition thereof, all as defined herein, or a cosmetic or functional food composition as defined herein as an anti-wrinkle/ageing agent. For example, in certain embodiments, the GFR-binding compound, functionalised bioactive carrier, or composition thereof, all as defined herein, is used as active ingredient to prevent or treat skin-ageing in a cosmetic composition or a functional food composition.
In one aspect, the present disclosure provides a use of a GFR-binding compound or functionalised bioactive carrier, all as defined herein, or a cosmetic composition thereof as defined herein in a method of cosmetic care, wherein said method of cosmetic care comprises the administration or the application of between about 0.0001 □g/day to about 5000 mg/day, between about 0.0001 □g/day to about 1000 mg/day, between about 0.0001 □g/day to about 10 mg/day, between about 0.0001 □g/day to about 1 mg/day, or between about 0.0001 □g/day to about 100 □g/day of said compound, bioactive carrier or composition, all being preferred and specifically contemplated for implementing embodiments of the invention.
In one example, the administration comprises the oral administration of a tablet, capsule, pill, powder, sustained release formulations, solution or suspension containing said GFR-binding compound or functionalised bioactive carrier, all as defined herein, or cosmetic or functional food compositions thereof as defined herein.
In one preferred example, said use comprises the topical application of a GFR-binding compound or functionalised bioactive carrier, all as defined herein, or cosmetic composition thereof as defined herein.
Suitable formulations for use in cosmetic care treatment include, for instance, the ones described in U.S. Pat. No. 8,497,241 B2, which is hereby incorporated by reference.
In one example, said cosmetic use of the invention is a non-therapeutic cosmetic use.
In one aspect, the present disclosure provides a cosmetic care or treatment method in which the GFR-binding compound, the functionalised bioactive carrier, or the cosmetic composition, all as defined herein, is used via topical application to stimulate the proliferation and/or activity of the fibroblasts.
For example, in certain embodiments, said cosmetic care method of the invention include treatment of skin ageing, especially unesthetic and/or uncomfortable manifestations of skin ageing, such as slackness of the tissues, loss of firmness of the tissues, the appearance of wrinkles, fine lines, and grooves, and/or for the cosmetic treatment and/or care of stretch marks and/or scars.
In one example, the cosmetic care method of the invention is preferably for protecting the skin against skin ageing.
Topical application: In the present description and unless otherwise indicated, the term “topical application” means to apply or spray the composition of the present invention onto the surface of the skin.
Cosmetic compositions of the invention may comprise other active agents of cosmetic interest especially the conventional agents for anti-ageing compositions especially those chosen from hyaluronic acid, ascorbic acid, retinol, alpha-hydroxy acids (AHAs) and/or ursolic acid.
In one example, the cosmetic composition of the invention may contain at least one of the following agents:
GFR-binding compounds, or functionalised bioactive carrier in their cosmetic applications, optionally in the form of cosmetic compositions, are particularly suitable for protecting the skin against skin ageing that is natural and/or caused by climatic and environmental factors, especially the wind, pollution, UV rays, cigarette smoke and/or physiological factors, especially stress.
In one aspect, the present disclosure provides a cosmetic care or treatment method, for a subject having need thereof, said method comprising the application, preferably topical application, or administration of a cosmetic composition as defined herein.
In one example, the subject who has need of the cosmetic care of the invention is a subject chosen from a population having an average age of more than 30 years old, preferably of more than 40 years old, more preferably of more than 50 years old.
XIX. Hair Treatment Applications
Hair is subjected to a wide variety of severe stress, for example as a result of environmental influences, such as UV irradiation or weathering, mechanical stresses, such as combing, or various hair treatments, such as washing, drying with hot air, bleaching, coloring, perming, etc., which can lead to hair damage. Said damage includes e.g. dryness, reduced elasticity, brittleness, split ends, dullness, matt appearance, reduced fullness, rough surface and reduced mechanical strength. This leads to impaired combability, reduced shine, increased electrostatic charging, tendency to break and may go as far as hair loss in some cases. The hair wearer feels uneasy. Hair loss may be due to aging as through time, hair naturally tends to gradually thin. Other causes of hair loss include hormonal factors, medical conditions and medications. The most common cause of hair loss is a hereditary condition called male-pattern baldness or female-pattern baldness. In genetically susceptible people, certain sex hormones trigger a particular pattern of permanent hair loss. Most common in men, this type of hair thinning can begin as early as puberty. Hormonal changes and imbalances can also cause temporary hair loss. This could be due to pregnancy, childbirth, discontinuation of birth control pills or the onset of menopause. A variety of medical conditions may also cause hair loss, including, but not limited to, thyroid problems, alopecia areata, and scalp infections. Hair loss may further be caused by drugs used to treat Arthritis, depression, heart problems, high blood pressure, etc.
Medical or cosmetic applications which may result from the mediation of type I and II growth factor receptors by a (modified) GFR-binding compound, functionalised bioactive carrier or composition of the invention also include enhancing/promoting hair growth and/or preventing and/or decreasing or suppressing hair loss. Without wishing to be bound to any specific theories, this effect is thought to be achieved through activation of dormant (or quiescent) hair follicle stem cells by displacement of natural binding ligands such as BMP-6, strongly bound to their growth factor receptors.
In one example, a (modified) GFR-binding compound, or functionalised bioactive carrier as defined herein may be a hair growth-promoting or a hair loss-regulator/modulator/inhibitor compound or functionalised bioactive carrier which has demonstrated the ability to enhance/promote hair growth and/or prevent and/or decrease or suppress hair loss in vitro, ex-vivo and/or in vivo.
In one aspect, the present disclosure provides a hair cosmetic or functional food composition comprising at least one (modified) GFR-binding compound, or at least one functionalised bioactive carrier, all as defined herein, in combination with at least one suitable hair-cosmetic carrier, preferably suitable for topical application.
Topical applications may be performed by any end-user by, for instance, applying and optionally rubbing the hair scalp with a hair cosmetic composition of the invention e.g. formulated as a shampoo or conditioner.
In one aspect, the present disclosure provides a hair medical (pharmaceutical, prophylactic, diagnostic, imaging, etc.) composition comprising at least one (modified) GFR-binding compound, or at least one functionalised bioactive carrier, all as defined herein, in combination with at least one suitable hair-medical carrier, preferably suitable for scalp injection application.
Scalp injection applications may preferably be performed by experienced end-users such as dermatologists and/or surgeons, preferably in clinical/medical settings in clean or sterile environment. Several subcutaneous injections may be carried out under the scalp where needed and renewed every few weeks, preferably months if required.
In one aspect, the present invention discloses a use of a (modified) GFR-binding compound, or a functionalised bioactive carrier as defined herein, in hair cosmetics or as a functional food. In one aspect, the present invention discloses a (modified) GFR-binding compound, or a functionalised bioactive carrier as defined herein, for use in a hair medical method.
In one aspect, the present disclosure provides a use of a (modified) GFR-binding compound, a functionalised bioactive carrier, or a hair cosmetic or functional food composition, all as defined herein, as a hair growth-promoting agent or hair-loss-preventing agent. For example, in certain embodiments, the (modified) GFR-binding compound, or functionalised bioactive carrier as defined herein, is used as active ingredient to promote (enhance, regulate, modulate, improve) hair growth and/or prevent or treat hair-loss and/or embellish hair in a hair cosmetic composition or a functional food composition. In one aspect, the present disclosure provides a (modified) GFR-binding compound, a functionalised bioactive carrier, or a hair medical composition, all as defined herein, as a hair growth-promoting agent or hair-loss-preventing agent. For example, in certain embodiments, the (modified) GFR-binding compound, or functionalised bioactive carrier as defined herein, is used as active ingredient to promote (enhance, regulate, modulate, improve) hair growth and/or prevent or treat hair-loss and/or embellish hair in a hair medical composition.
In one aspect, the present disclosure provides a use of a (modified) GFR-binding compound, a functionalised bioactive carrier, or a hair cosmetic composition, all as defined herein, in a method of hair cosmetic care, wherein said method of hair cosmetic care comprises the administration or the application of between about 0.0001 to about 100 □g per day, more specifically between about 0.001 to about 10 □g per day or between about 0.0001 to about 100 □g per day of said compound, bioactive carrier or composition.
In one example, a (modified) GFR-binding compound, functionalised bioactive carrier, or hair-cosmetic composition, all as defined herein, may be combined/mixed with mesenchymal stem cells and/or follicle progenitor cells prior to be administered to, contacted with, or implanted into a mammal (preferably a human) to promote hair growth and/or prevent and/or decrease or suppress hair-loss.
In one example, the administration comprises the oral administration of a tablet, capsule, pill, powder, sustained release formulations, solution or suspension containing said (modified) GFR-binding compound, functionalised bioactive carrier, or hair-cosmetic composition, all as defined herein.
Suitable as forms of hair cosmetic compositions for implementing embodiments of the invention include hair rinse, hair mask, shampoo, conditioner, hair spray, hair foam, hair mousse, hair gel, hair tonic, hair setting composition, end fluid, neutralizer for permanent waves, hair colorant and bleach or hot-oil treatment.
Suitable formulations for use in hair treatment include, for instance, the ones described in US patent application No. 2011/0312884 A1, which is hereby incorporated by reference.
In one example, said hair cosmetic use of the invention is a non-therapeutic hair cosmetic use.
Hair cosmetic compositions of the invention may comprise at least one other active agent of hair cosmetic interest especially the conventional agents for hair treatment compositions especially at least one of the following agents:
In one aspect, the invention discloses a hair cosmetic care or treatment method, for a subject having need thereof, said method comprising the application, preferably topical or scalp injection applications, or administration of a hair cosmetic composition according to the present invention.
In one aspect, the present invention discloses a hair cosmetic care or treatment method in which the (modified) GFR-binding compound, functionalised bioactive carrier, or hair cosmetic composition, all as defined herein, is used to stimulate/activate hair follicle stem cells.
In one example, the subject who has need of the hair cosmetic care of the invention is a subject chosen from a population having an average age of more than 30 years old, preferably of more than 40 years old, more preferably of more than 50 years old.
XX. Diagnostic Methods
In one aspect, the present disclosure provides a (modified) GFR-binding compound, a functionalised bioactive carrier or a medical or cosmetic composition as defined herein for use in a diagnostic method of a disease or condition which may require mesenchymal stem cells or progenitor cells (at any stage of differentiation thereof) to be differentiated.
In one aspect, the present disclosure provides a diagnostic method for diagnosing of a disease or condition which may require mesenchymal stem cells or progenitor cells (at any stage of differentiation thereof) to be differentiated comprising the provision of a (modified) GFR-binding compound or a pharmaceutical association, combination or composition as defined herein, and the contacting or administration of said GFR-binding compound or pharmaceutical association, combination or composition with a body part of a subject to be diagnosed.
A method for the diagnosis of a disease or condition which may require mesenchymal stem cells or progenitor cells (at any stage of differentiation thereof) to be differentiated in a patient, comprising obtaining a biological sample from a patient and apply fluorescent and/or radiolabeled (modified) GFR binding compounds, wherein high localisation of these compounds indicates a disease or condition which may require mesenchymal stem cells or progenitor cells (at any stage of differentiation thereof) to be differentiated in the patient.
XXI. Screening Methods
In one aspect, the present disclosure provides a screening method for selecting a peptide or a peptidomimetic having the ability to induce tissue regeneration and cell differentiation.
In one aspect, the present disclosure provides a screening method for selecting a peptide or peptidomimetic having the ability to induce tissue regeneration and cell differentiation, the method comprising the steps of (a) providing a molecular model of the following 3D structure coordinates of PEPREF and (b) identifying a candidate analog having a RMSD value of 2.45 Å or less. In particular example, step (b) is performed using the method of RMSD calculation as already defined herein
In certain embodiments, the method can be performed using a computer (i.e., in silico). In some embodiments, the method can include providing the three-dimensional models of a plurality of peptides or peptidomimetics (i.e., a library or database of peptides or peptidomimetics) and screening each compound individually. Thus, in one aspect, the method of screening peptides or peptidomimetics generally includes computationally evaluating the potential of a selected peptide(s) or peptidomimetic(s) to structurally match with the computational model of the three-dimensional structure of PEPREF. For example, this method can include the steps of (a) employing a computational approach to perform a fitting operation between the selected peptide(s) or peptidomimetic(s) and the three-dimensional structure of PEPREF; and (b) analysing the results of the fitting operation to quantify the three-dimensional structural similarities between the peptide(s) or peptidomimetic(s) and PEPREF using the RMSD procedure as defined herein.
In one aspect, the present disclosure provides a method of producing a peptide or peptidomimetic having the ability to induce tissue regeneration and cell differentiation, the method comprising the steps of (a) providing a molecular model of the following 3D structure coordinates of PEPREF; b) identifying a candidate analog having a RMSD as defined herein of 2.45 Å or less (in particular 2, more particularly 1.79); and (c) producing the candidate analog identified in step (b). In one particular example, said method further comprising the step of determining whether the compound produced in step (c) has a cell differentiation and tissue regeneration activity. In one particular example, steps (a) and (b) are performed by means of an electronic processor. In certain embodiments, step (a) comprises storing a representation of the atomic co-ordinates of PEPREF in a computer memory.
In one aspect, the present disclosure provides a method of producing a peptide or peptidomimetic having the ability to induce tissue regeneration and cell differentiation, the method comprising the steps of: (a) providing in a computer memory atomic X-ray crystallographic co-ordinates of PEPREF; (b) generating with a processor a molecular model having a three-dimensional shape of PEPREF; (c) identifying a candidate analog having a RMSD of 2.45 Å or less (in particular 2, more particularly 1.79); (d) producing the candidate analog identified in step (c); and (e) determining whether the candidate analog produced in step (d) induces tissue regeneration and cell differentiation. In one particular example, said method comprises the additional step of producing the peptide or peptidomimetic in a commercially useful quantity.
In one aspect, the present disclosure provides a computer system comprising: (a) a memory comprising atomic X-ray crystallographic coordinates of PEPREF; and (b) a processor in electrical communication with the memory; wherein the processor generates a molecular model having a three dimensional shape representative of PEPREF. In one particular example, said coordinates are stored on a computer readable diskette.
XXII. Kits
The present disclosure provides a variety of kits for conveniently and/or effectively carrying out methods and uses of the present invention. Typically, kits will comprise sufficient amounts and/or numbers of components to allow a user to perform multiple treatments of a subject(s) and/or to perform multiple experiments.
In one aspect, the present disclosure provides kits for pharmaceutical, dermatological, prophylactic, diagnostic, imaging or cosmetic functional association, combination or composition production, comprising at least one (modified) GFR-binding compound as defined herein, at least one bioactive carrier (such as a biomaterial or medical device) as defined herein, optionally a pharmaceutically, dermatologically, prophylactically, diagnostically, imaging or cosmetically acceptable excipient, carrier, vehicle or solvent, each and every one of them provided in an amount effective to produce a pharmaceutical, dermatological, prophylactic, diagnostic, imaging or cosmetic association to induce cell differentiation, promote tissue regeneration or protect a subject from a disease, disorder or condition as defined herein, when administered in-vitro, ex-vivo or in-vivo to a mesenchymal stem cell, progenitor cell (at any stage of differentiation thereof) or to a subject carrying such a cell, and packaging and instructions.
Suitable as solvents for use in kits of the invention include physiologically acceptable solvents, PBS, filtered and deionised water such as Milli-Q® water, alpha-MEM, DMEM and/or IMDM. All physiologically acceptable solvents suitable for implementing embodiments of the present invention are preferably deoxygenated before use.
In one example, said kit further comprises an administration device. In one example, said administration device is a dispensing device such as a syringe.
In one example, said kit comprises a first container containing a (modified) GFR-binding compound as defined herein and a second container containing a bioactive carrier such as a biomaterial or a medical device and a third container containing stem cells, preferably MSCs.
In one preferred example, a kit of the invention comprises (i) a first, preferably suitable, sterile, individual, container containing a (modified) GFR-binding compound as defined herein preferably in lyophilised form, (ii) a second, preferably suitable, sterile, individual, container containing a physiologically acceptable, sterile liquid (e.g. a solvent), (iii) a third, preferably suitable, sterile, individual, container containing a conventional biomaterial/medical device such as an orthopaedic or dental implant and, (iv) optionally, a fourth, preferably suitable, sterile, individual, container containing suitable stem cells, in particular adult stem cells or mesenchymal stem cells. In practice, said kit may be provided to an end-user (e.g. a surgeon). Said end-user may firstly pour the content of the second container into the first container, optionally provide a form of agitation to solubilise or suspend the (modified) GFR-binding compound of the invention in the physiologically acceptable, sterile liquid, then pour (or immerse) the resulting solution or suspension in the third container containing the conventional biomaterial/medical device (optionally with prior activation of said biomaterial/medical device if required), optionally followed by the contacting of the resulting functionalised biomaterial/medical device with the content of the fourth container containing the stem cells prior to placement onto or into a patient's body, preferably at a defect site.
Alternatively, a kit of the invention may comprise a first, preferably suitable, sterile, individual, container containing an already functionalised biomaterial/medical device e.g. a biomaterial/medical device functioanlised with a (modified) GFR-binding compound as defined herein, optionally in a physiologically acceptable liquid, and a second, preferably suitable, sterile, individual, container containing suitable stem cells, in particular adult stem cells or mesenchymal stem cells. In practice, an end-user such as a surgeon may apply the stem cells onto the coated biomaterial by pouring the content of the second container into the first containing (and optionally apply a form of agitation) prior to placement onto or into a patient's body, preferably at a defect site.
In one particular example, said kits of the invention may suitably be provided in the form of a sterile packaging.
For example, in certain embodiments, said kits of the invention comprises more than 2, between 2 and 25, between 2 and 15, or between 2 and 10 of (modified) GFR-binding compound as defined herein, and more than 2, between 2 and 25, between 2 and 15, or between 2 and 10 (modified) GFR-binding compound as defined herein.
In one example, each (modified) GFR-binding compound and each conventional or functionalised bioactive carrier is conditioned in distinct and separated compartments, in lyophilised form, in solution or in suspension in a pharmaceutically dermatologically, prophylactically, diagnostically, imaging or cosmetically acceptable excipient, carrier or vehicle.
In one aspect, the invention discloses kit-of-parts comprising a bioactive carrier and a (modified) GFR-binding compound both as defined herein for uses and methods as defined herein.
XXIII. Sequence Listing
Sequence Listing Free Text: Xaa may be, as specified, either a serine (Ser, S) or a cysteine (Cys, C). Examples of (modified) GFR-binding compounds as defined herein are listed in the appended sequence listing which forms an integral part of the present application.
(Modified) GFR-binding compounds, functionalised bioactive carriers and compositions, all as defined in the present disclosure, has been found to lead to multiple and distinct advantages in terms of cell differentiation induction and tissue regeneration.
As supported by the examples of the present application, (modified) GFR-binding compounds, functionalised bioactive carriers or compositions thereof, all as defined herein, display advantages over (modified) GFR-binding compounds, functionalised bioactive carrier or compositions that do not contain it, such as:
For example, in certain embodiments, (modified) GFR-binding compounds, functionalised bioactive carriers, or compositions according to the present disclosure in which PEP1 is a peptide selected from the group consisting of SAIS (SEQ ID NO: 6360), NAIS (SEQ ID NO: 6357), SATS (SEQ ID NO: 6361) and SPIS (SEQ ID NO: 6364), and in which the RMSD is 2.45 Å or less, have been found to lead to unexpectedly fast and qualitatively and quantitatively important osteoinduction, producing highly functional differentiated cells.
For example, in certain embodiments, (modified) GFR-binding compounds, functionalised bioactive carriers, or compositions according to the present disclosure in which PEP1 is a peptide selected from the group consisting of SAIS (SEQ ID NO: 6360), NAIS (SEQ ID NO: 6357), SPIS (SEQ ID NO: 6364), EPLP (SEQ ID NO: 6354), and EPLT (SEQ ID NO: 6355), and in which the RMSD is 2.45 Å or less, have been found to lead to unexpectedly fast and qualitatively and quantitatively important chondroinduction, producing highly functional differentiated cells.
For example, in certain embodiments, (modified) GFR-binding compounds, functionalised bioactive carriers, or compositions according to the present disclosure in which PEP1 is a peptide selected from the group consisting of SNIT (SEQ ID NO: 6362), RPVQ (SEQ ID NO: 6358) and RSVK (SEQ ID NO: 6359), and in which the RMSD is 2.45 Å or less, have been found to lead to unexpectedly fast and qualitatively and quantitatively important vascular tissue induction, producing highly functional differentiated cells.
For example, in certain embodiments, (modified) GFR-binding compounds, functionalised bioactive carriers, or compositions according to the present disclosure in which PEP1 is selected from the group consisting of NAIS (SEQ ID NO: 6357), SPIS (SEQ ID NO: 6364) and EPIS (SEQ ID NO: 6353), and in which the RMSD is 2.45 Å or less, have been found to lead to unexpectedly fast and qualitatively and quantitatively important neuronal induction, producing highly functional differentiated cells.
For example, in certain embodiments, (modified) GFR-binding compounds, functionalised bioactive carriers, or compositions according to the present disclosure in which PEP1 is SPIN (SEQ ID NO: 6363), and in which the RMSD is 2.45 Å or less, have been found to lead to unexpectedly fast and qualitatively and quantitatively important eye-retina cells induction, producing highly functional differentiated cells.
For example, in certain embodiments, (modified) GFR-binding compounds, functionalised bioactive carriers, or compositions according to the present disclosure in which PEP1 is SPIN (SEQ ID NO: 6363), and in which the RMSD is 2.45 Å or less, have been found to lead to unexpectedly fast and qualitatively and quantitatively important renal cells induction, producing highly functional differentiated cells.
For example, in certain embodiments, (modified) GFR-binding compounds, functionalised bioactive carriers, or compositions according to the present disclosure in which PEP1 is a peptide selected from the group consisting of NAIS (SEQ ID NO: 6357), SPIS (SEQ ID NO: 6364), EPLP (SEQ ID NO: 6354) and EPLT (SEQ ID NO: 6355), and in which the RMSD is 2.45 Å or less, have been found to lead to unexpectedly fast and qualitatively and quantitatively important tenocytes and/or fibrous cells induction, producing highly functional differentiated cells.
For example, in certain embodiments, (modified) GFR-binding compounds, functionalised bioactive carriers, or compositions according to the present disclosure in which PEP1 is selected from the group consisting of SNIT (SEQ ID NO: 6362), RPVQ (SEQ ID NO: 6358) and RSVK (SEQ ID NO: 6359), and in which the RMSD is 2.45 Å or less, have been found to lead to unexpectedly fast and qualitatively and quantitatively important wound healing induction, producing highly functional differentiated cells.
For example, in certain embodiments, (modified) GFR-binding compounds, functionalised bioactive carriers, or compositions according to the present disclosure in which PEP1 is a peptide selected from the group consisting of EPLP (SEQ ID NO: 6354), EPLT (SEQ ID NO: 6355), RSVK (SEQ ID NO: 6359) and RPVQ (SEQ ID NO: 6358), and in which the RMSD is 2.45 Å or less, have been found to lead to unexpectedly fast and qualitatively and quantitatively important skin cells induction, producing highly functional differentiated cells.
For example, in certain embodiments, (modified) GFR-binding compounds, functionalised bioactive carriers, or compositions according to the present disclosure in which PEP1 is SSLS (SEQ ID NO: 6365), and in which the RMSD is 2.45 Å or less, have been found to lead to unexpectedly fast and qualitatively and quantitatively important hair follicle cells induction, producing highly functional differentiated cells.
For example, in certain embodiments, (modified) GFR-binding compounds, functionalised bioactive carriers, or compositions according to the present disclosure in which PEP1 is NAIS (SEQ ID NO: 6357), and in which the RMSD is 2.45 Å or less, have been found to lead to unexpectedly fast and qualitatively and quantitatively important ovarian cells induction, producing highly functional differentiated cells.
For example, in certain embodiments, (modified) GFR-binding compounds, functionalised bioactive carriers, or compositions according to the present disclosure in which PEP1 is selected from the group consisting of NAIS (SEQ ID NO: 6357), SATS (SEQ ID NO: 6361), SPIS (SEQ ID NO: 6364), EPIS (SEQ ID NO: 6353) and SPIN (SEQ ID NO: 6363), and in which the RMSD is 2.45 Å or less, have been found to lead to unexpectedly fast and qualitatively and quantitatively important lung cells induction, producing highly functional differentiated cells.
For example, in certain embodiments, (modified) GFR-binding compounds, functionalised bioactive carriers, or compositions according to the present disclosure in which PEP1 is RSVK (SEQ ID NO: 6359) or RPVQ (SEQ ID NO: 6358), and in which the RMSD is 2.45 Å or less, have been found to lead to unexpectedly fast and qualitatively and quantitatively important muscle cells induction, producing highly functional differentiated cells.
For example, in certain embodiments, (modified) GFR-binding compounds, functionalised bioactive carriers, or compositions according to the present disclosure in which PEP1 is SNIT (SEQ ID NO: 6362), and in which the RMSD is 2.45 Å or less, have been found to lead to unexpectedly fast and qualitatively and quantitatively important blood cells induction, producing highly functional differentiated cells.
For example, in certain embodiments, (modified) GFR-binding compounds, functionalised bioactive carriers, or compositions according to the present disclosure in which PEP1 is SAIS (SEQ ID NO: 6360) or NAIS (SEQ ID NO: 6357), and in which the RMSD is 2.45 Å or less, have been found to lead to unexpectedly fast and qualitatively and quantitatively important adipocytes induction, producing highly functional differentiated cells.
For example, in certain embodiments, microenvironments comprising a plurality of structurally distinct/different (modified) GFR-binding compounds, functionalised bioactive carriers, or compositions according to the present disclosure in which each PEP1 is a peptide which may be selected from the group consisting of SAIS (SEQ ID NO: 6360), SSLS (SEQ ID NO: 6365), NAIS (SEQ ID NO: 6357), SATS (SEQ ID NO: 6361), SPIS (SEQ ID NO: 6364), EPIS (SEQ ID NO: 6353), SPIN (SEQ ID NO: 6363), KPLS (SEQ ID NO: 6356), EPLP (SEQ ID NO: 6354), EPLT (SEQ ID NO: 6355), SNIT (SEQ ID NO: 6362), RSVK (SEQ ID NO: 6359) and RPVQ (SEQ ID NO: 6358), and in which the RMSD is 2.45 Å or less, have been found to lead to unexpectedly fast and qualitatively and quantitatively important tissue closure induction, producing highly functional differentiated cells.
Accordingly, it is possible to achieve tissue (bone, cartilage, vascular, endothelial, blood, neuronal, eye-retina, kidneys, lung, adipose, ligament, tendon, hair follicle, skin, ovary, etc.) regeneration using e.g. orthopedic, dental implants, matrix injections or administrable compositions, efficiently and rapidly thus reducing the costs associated with such treatments, improving and accelerating tissue healing and patient recovery.
In addition, it has been found that using the compounds, bioactive carier and compositions of the present disclosure also permits a quasi-complete or complete control over the final chemical structure of the compounds, bioactive carier and compositions of the present disclosure, thereby avoiding any unwanted (e.g. post-translational) modifications and unpredicted short half-life and quick metabolization.
Remarkably, it has also been found that using the compounds, bioactive carier and compositions of the present disclosure allows for reduction (in most cases, important reduction) of the administered doses to provide a beneficial treatment to a patient in comparison with known technologies, thus decreasing or eliminating the risks of immune responses and reduce or eliminate drug/treatment toxicity.
It is another aspect of the present invention to solve the technical problem of providing a tissue regeneration environment/system being completely or at least partially devoid of one or more, preferably a plurality of the disadvantages of known treatments.
All combinations of any of the above-mentioned features described in all above part of the present description are specifically contemplated by the Applicant to be within the scope of the present invention unless contradictory in context. Examples of such combinations are detailed throughout the present description.
Further embodiments and advantages will become apparent to a skilled reader in light of the examples provided below.
Disclosed and described, it is to be understood that this invention is not limited to the particular examples, process steps, and materials disclosed herein as such process steps and materials may vary somewhat. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only and not intended to be limiting since the scope of the present invention will be limited only by the appended claims and equivalents thereof.
The following Examples are representative of techniques employed by the inventor in carrying out aspects of the present invention. It should be appreciated that while these techniques are exemplary of preferred embodiments for the practice of the invention, those of skill in the art, in light of the present disclosure, will recognize that numerous modifications can be made without departing from the spirit and intended scope of the invention.
The following starting materials and reagents were used:
The following general methods were used:
For X-ray photoelectron spectroscopy, AVG Scientific ESCALAB photoelectron spectrometer was used for the surface analysis with a non-monochromatized MgK 1253.6 eV source of 100 W. The area of the analytical X-ray spot on the sample surface was about 200 μm2. A 45° insert angle that corresponds to about 5 nm of analyzed depth was used. A flood gun was used for charge compensation. Acquisition of high resolution spectra was performed at constant pass energy of 20 eV.
The surface profiler system is a non-contact optical profiler that measures a wide range of surface heights.
The vertical scanning interferometry mode allows for the measurement of rough surfaces and steps of up to several micrometers. This mode was used in order to measure the thickness of the extracellular matrix produced by the cells. First, after 24 h of culture, the cells were fixed with paraformaldehyde in PBS (4%) for 30 minutes at 4° C. and the samples were dehydrated in increasing concentrations of ethanol (30, 70, 80, 90, 95 and 100%) and critical-point dried. To evaluate the extent of the newly synthesized extracellular matrix, a spatula was used to scratch the surface of the materials. The samples were then metallized for 10 sec with gold or titanium before being analyzed. This procedure did not affect the cell shape and dimensions.
The cells were first fixed for 20 min with 4% paraformaldehyde/PBS at 4° C. After fixation, the cells were permeabilized in PBS containing 1% Triton X-100 for 15 min. Runx2, Osterix, Stro-1, Vinculin, Phalloidin, Osteopontin, Sox2, Sox9 antibodies were visualized by treating the cells with 1% (v/v) specific monoclonal antibodies for 1 hour at 37° C. Then the samples were incubated with Alexa fluor® 568 or 647 (F(ab′)2 fragment of IgG(H+L)) during 30 min at room temperature. The cell nuclei were counterstained in 20 ng/mL DAPI for 10 min at room temperature.
For this type of quantification the freeware image analysis ImageJ® software was used. The raw image was first converted to an 8-bit file, and then the unsharp mask feature was used (settings 1:0.2) to remove the image background (rolling ball radius 10). After smoothing, the resulting image, which appears similar to the original photomicrograph but with minimal background, was then converted to a binary image by setting a threshold. Threshold values were determined empirically by selecting a setting, which gave the most accurate binary image for a subset of randomly selected photomicrographs. The cell area was determined by manual delineation on raw fluorescent images. Total contact area and mean contact area per cell were calculated by “analyse particules” in ImageJ®. A minimum of 30 cells per condition were analyzed. Stro-1, CD-34+, and CD-105 expressions were determined using this procedure.
Total RNA was extracted by using the RNeasy total RNA kit (Qiagen®) according to the manufacturer's instructions. Purified total RNA was used as a template in order to make cDNA by a reverse transcription reaction (Gibco BrI®) with random primers (Invitrogen®). The cDNA was then used as a template for a real-time PCR amplification in the presence of SYBR green reagents (Bio-Rad®) by using a thermocycler (iCycler, Biorad®). Data were analyzed with the iCycler IQ™® software and compared by the ΔΔCt method. Briefly, the mean Ct value of the target gene was normalized to its averaged Ct values of the housekeeping gene (HPRT) to give a ΔCt value, which was then normalized to a control sample to obtain a ΔΔCt value. The results were obtained from two series of experiments performed in a triplicate.
Total RNA was extracted by using the RNeasy Mini Kit (Qiagen) and 1 mg RNA was used for cDNA synthesis with AMV kit (Invitrogen®) according to the manufacturer' instructions. Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was performed with Taq DNA Polymerase (Invitrogen®) in a thermocycler (Bio-Rad®). The cDNA input was normalized to glyceraldehyde-3-phosphate dehydrogenase (HPRT). The PCR products were analyzed on 2% agarose gels. For the Aggrecan gene, the PCR bands were densitometrically quantified by using the BioCapt software (Vilber). Values were normalized to HPRT, and results were reported as relative gene expression.
Method 1: Hydrogel Surface Preparation and Covalent Grafting (Such as PLLA)
The preparation of poly(acrylamide-co-acrylic acid) gel substrates was shown as an example in order to illustrate the effect of the GFR-binding compounds as defined herein. The synthesis of hydrogels is based on acrylamide and acrylic acid by polymerization in the presence of N,N′-methylene-bis-acrylamide as a cross-linker in an aqueous medium. Practically, 0.3 g of acrylamide (AM, Merck) has been dissolved in 5 mL of PBS 1X (Invitrogen). 30 μL of acrylic acid (AA, Merck), then ×g (function as the stiffness) of N,N-methylene-bis-acrylamide was added under stirring. Then, a NaOH solution (1M, Aldrich) was added dropwise to reach a pH 8. The formation of hydrogel proceeded via free radical polymerization. The starting solution was degassed during 10 min by bubbling nitrogen in order to remove the oxygen which acts as an inhibitor for the free radical polymerization process. Nitrogen atmosphere was maintained above the solution and 50 μL (corresponding to 1/100 of the total volume) of Ammonium persulfate 10% (Biorad), (free radical initiator) and then 5 μL (corresponding to 1/1000 of total volume) of N,N,N′,N′-tetramethylethylenediamine (catalyst, Aldrich) were added. The polymerizing solution was vortexed gently. Promptly, 0.5 mL of this gel solution was placed before polymerization on a glass slide and another slide was placed on the top of this structure. Reactivity ratios calculated by the Finemann-Ross and Kelen-Tudos methods showed that the copolymers were random with a reactivity ratio of rAM=3.76 and rAA=0.28. The materials obtained here have various stiffnesses ranging from 0.1 to 600 kPa. Chemical functionalization with GFR-binding compounds as defined herein of poly(acrylamide-co-acrylic acid) gel substrates was performed via the —COOH (carboxyl) functions of their surface. Hydrogels were immersed in a solution of dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDC, 0.2 M)+N-hydroxysuccinimide (NHS, 0.1 M) in 2-(N-morpholino)-ethane sulfonic acid (MES buffer, 0.1 M in MilliQ water) overnight at room temperature without stirring and then rinsed in MilliQ water (50 mL during 30 min). The immobilization of the GFR-binding compounds as defined herein was achieved in a solution of peptides/PBS 1X (C=10−3 M) for 18 hours at room temperature by using an orbital shaker. After grafting, the modified hydrogels were rinsed with PBS 1X for one week.
Method 2: Solid Material Covalent Modification (Such as Ceramics or Titaniums)
The material modifications were performed in a controlled Atmosphere (Ar Atmosphere, Glove Box). The strategy for covalent modification of GFR-binding compounds as defined herein involved (1) grafting of (3-aminopropyl)-triéthoxysilane (concentration of 1×10−2M, 4 hours) onto the surface of the biopolymer, (2) substitution of the terminal amine by a hetero-bifunctional cross-linker, a 3-succinimidyl-3-maleimidopropionate (concentration of 1×10−3M, 4 hours) in order to (3) reacting of the “outer” maleimide group with the GFR-binding compounds as defined herein (concentration of 1×10−3M, 18 hours) via a thiol group present in the terminal cysteine. After grafting, the modified materials were rinsed with PBS 1X buffer for 5 days.
Method 3: Polymer Grafted by Peptides (Such as PET or PEEK)
The polymer used in this study is poly(ethylene terephthalate) (PET). The polymers were first treated in order to create—COOH (carboxyl) functions on the PET surfaces from —OH (hydroxyl) functions. Next, the PET-COOH samples were immersed in a solution of dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDC, 0.2 M)+N-hydroxysuccinimide (NHS, 0.1 M) in 2-(N-morpholino)-ethanesulfonic acid (MES) buffer (0.1 M in MilliQ water) and the samples were rinsed in MilliQ water (50 mL for 30 min). The same protocol was used for all the polymers containing —OH (hydroxyl) functions on their extreme surface. Finally, the covalent immobilization of the peptides was achieved by using a solution of peptides/1X PBS (C=10−3 M) incubated for 18 hours at room temperature. After grafting, the materials were rinsed in MilliQ water (100 ml) for 1 week.
The material modifications were performed in a Specific Atmosphere (Ar Atmosphere, Glove Box). The strategy for the covalent peptide immobilization involved (1) the grafting of (3-aminopropyl)-triethoxysilane (concentration of 1×10−2M, 4 hours) onto the surface of the implant, (2) substitution of the terminal amine by a hetero-bifunctional cross-linker: a 3-succinimidyl-3-maleimidopropionate (concentration of 1×10−3M, 4 hours) in order to (3) react the “outer” maleimide group with an osteogenic peptide (concentration of 1×10−3M, 24 hours) via a thiol group present in the terminal cysteine. After covalent immobilization, the modified materials were rinsed with Phosphate Buffered Saline (PBS 1X) buffer for 5 days. PBS is a buffer solution commonly used in the biological research. It is a water-based salt solution containing sodium phosphate, sodium chloride and, in some formulations, potassium chloride and potassium phosphate. The osmolarity and ion concentrations of the solutions match those of the human body (isotonic) and are thus physiological and non-toxic to the cells.
The following peptides were covalently deposited via the thiol group present in the terminal cysteine that was added to the GFR-binding compounds to allow covalent bonding to the surface of the biomaterial:
The biomaterial surface was characterized by covalently immobilizing fluorescent peptides (Herein SEQ ID NO: 1 coupled to fluorescein isothiocyanate (FITC),
A polyetheretherketone (PEEK) was treated with ethylene diamine (NH2═NH2) to create—NH2 (amine) functions on the PEEK surfaces from ketone (═O) functions. Next, the PEEK-NH2 samples were immersed in a solution of a hetero-bifunctional cross-linker: a 3-succinimidyl-3-maleimidopropionate (concentration of 1×10−3M, 4 hours) in order to react the “outer” maleimide group with the GFR-binding compounds as defined herein (concentration of 1×10−3M, 24 hours) via a thiol group present in the terminal cysteine. After grafting, the modified materials were rinsed with PBS 1X for 5 days.
The surfaces were characterized by grafting fluorescent peptides and by other methods such as X-ray photoelectron spectroscopy. The X-ray photoelectron spectroscopy was performed as described in the Methods section.
The results presented in Table 2 were obtained by using a PEEK covalently modified with SEQ ID NO: 7.
PLLA (Polylactic acid) was immersed in a solution of dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 0.2 M)+N-hydroxysuccinimide (NHS, 0.1 M) in (2-(N-morpholino)-ethanesulfonic acid (MES buffer, 0.1 M in MilliQ water) and then rinsed in MilliQ water (during 30 min). The covalent immobilization was performed in a solution of GFR-binding compounds as defined herein SEQ ID NO: 8 (concentration of 1×10−3M, 18 hours, room temperature). After the covalent immobilization, the modified materials were rinsed with PBS 1X for 5 days.
The surfaces were characterized by using fluorescent peptides and by using other methods such as X-ray photoelectron spectroscopy. The X-ray photoelectron spectroscopy was performed as described in the Methods section.
The results presented in Table 3 were obtained by using a PLLA covalently modified with SEQ ID NO: 8.
The effect of the GFR-binding compounds as defined herein (SEQ ID NO: 9 to 14) of the invention on the proliferation of osteoblast progenitors (MC3T3-E1 cells, ATCC®) was investigated. The stimulatory effect of apatite ceramics, covalently modified with at least one inducing peptide of the invention, on osteoblast progenitor cells was compared with the effect of non-modified apatite ceramics, which are conventionally used to manufacture bone implants suitable for humans and animals. The AlamarBlue® assay was used to compare the extent of cell proliferation on the different biomaterials based on detection of metabolic activity. Analysis of these data showed that the proliferation was increased significantly on apatite ceramics covalently modified with GFR-binding compounds as defined herein in comparison with conventional non-modified ceramics (
The biomaterial used was titanium Ti6A4V metal alloy pellets. Human Mesenchymal Stem Cells (hMSCs) were obtained from Lonza®, Inc. Cells were then cultured in low glucose Dulbecco's Modified Eagle Medium (DMEM, Invitrogen®) supplemented with 10% (v/v) fetal bovine serum (FBS), 1% penicillin/streptomycin and incubated in a humidified atmosphere containing 5% (v/v) C02 at 37° C. All the cells were used at a low passage number (≤passage 3), were subconfluently cultured and were seeded at 10 000 cells/cm2 for the purpose of the experiments. Stem cell phenotype was analyzed after 62 hours of cell culture on titanium covalently modified with GFR-binding compounds as defined herein (SEQ: ID NO: 15 to 20).
To probe this lineage specification, immunostaining for Runx2 and Osterix was performed after cell fixation as described in the Methods section. The quantification of Runx2 and Osterix positive contact numbers and areas was performed as described in the Methods section.
As shown in
A conventional PEEK carrier was covalently modified with the GFR-binding compounds as defined herein (SEQ ID NO: 21) to produce biomaterials of the invention, and mouse mesenchymal pre-osteoblastic cells (MC3T3-E1, from ATCC®) were cultured thereon. MC3T3-E1 cells were cultured in Alpha-MEM medium supplemented with 10% fetal calf serum (FCS) and 1% penicillin/streptomycin. All the cells were used at a low passage number (passage 4) and were subconfluently cultured. The cells were plated at 10 000 cells/cm2 for the purpose of these experiments. The extracellular matrix production was compared between cells cultured on conventional PEEK biomaterials and cells cultured on PEEK biomaterials covalently modified with the GFR-binding compounds as defined herein (SEQ ID NO: 21) after 24 h of cell culture. This was performed by using optical profilometry system probing as described in the Methods section.
As shown in
Finally, it was verified that the osteoblast progenitors were transformed into mature osteoblasts when cultured on the covalently modified PEEK biomaterials by analyzing the expression of the osteogenic biomarker Runx2, also called Cbfa-1. An increase in the Runx2 gene expression after 24 hours of culture (
Non-covalent modifications of the materials were performed in Air Atmosphere at room temperature. The non-covalent coating strategy consisted in using a mixture of inducing peptide (SEQ ID NO: 23; concentration of 1×10−3M) with an apatite ceramics implant or a mixture of inducing peptide (SEQ ID NO: 22; concentration of 1×10−3M) with a type-I collagen sponge. The non-covalently coated conventional materials were characterized by using fluorescent peptides (Here SEQ ID NO: 22 and 23 covalently bound to fluorescein isothiocyanate (FITC),
Peptides that were non-covalently deposited through specific peptide fragments (such as WWFWG or GTPGP) added to GFR-binding compounds of the invention are as follows:
The effect of the GFR-binding compounds as defined herein (SEQ ID NO: 24 to 27) of the present invention on the proliferation of osteoblast progenitors was investigated. MC3T3-E1 cells were cultured in Alpha-MEM medium supplemented with 10% fetal calf serum (FCS) and 1% penicillin/streptomycin. All the cells were used at a low passage number (passage 4), were subconfluently cultured and were plated at 10 000 cells/cm2 for the purpose of the experiments. The stimulatory effect of the osteogenic peptides, coupled to apatite ceramics or to type-I collagen on osteoblast progenitor cells, was compared to the effect of native apatite ceramics or of native type-I collagen sponge, which are already being used as bone graft/LT-Cage® lumbar tapered fusion devices designed to aid in the treatment of the degenerative disc disease (DDD) in humans. The AlamarBlue® assay was used to compare cell proliferation on the different biomaterials based on detection of metabolic activity. Analysis of these data showed that the cell proliferation proceeded more significantly on apatite ceramics and type-I collagen sponge when coupled to osteogenic peptides as compared to native apatite ceramics and native type-I collagen sponge (
GFR-binding compounds as defined herein were non-covalently deposited on apatite ceramics or type-I collagen onto apatite ceramics or onto type-I collagen sponge. Human Mesenchymal Stem Cells (hMSCs) were obtained from Lonza®, Inc. Cells were then cultured in low glucose Dulbecco's Modified Eagle Medium (DMEM, Invitrogen®) supplemented with 10% (v/v) fetal bovine serum (FBS), 1% penicillin/streptomycin and incubated in a humidified atmosphere containing 5% (v/v) C02 at 37° C. All cell culture experiments were carried out without any serum in the medium for the first 8 hours of culture. All cells were used at a low passage number (≤passage 3), were subconfluently cultured and were seeded at 10 000 cells/cm2 for the purpose of the experiments.
The cell phenotype was analyzed after 96 hours of cell culture on apatite ceramics coupled with osteogenic peptides or on a type-I collagen sponge coupled with osteogenic peptides (SEQ: ID NO: 28 to 31). On GFR-binding compounds as defined herein-coupled apatite ceramics and type-I collagen sponge, the vast majority of the human bone marrow mesenchymal stem cells adhere, spread, and differentiate into osteoblast-like cells as confirmed by analysis of Runx2 and Osterix expression (
Finally, it was verified that the hMSCs were differentiated into mature osteoblasts by analyzing the activity of the osteogenic biomarker ALP (Alkaline Phosphatase Activity). We observed an increase in the ALP activity after 1 week of culture on type-I collagen sponge coupled with GFR-binding compounds as defined herein (SEQ ID NO: 32) (
Mature osteoblasts are the cells responsible for bone formation and are derived from precursor osteoblasts. Mature osteoblasts were obtained and characterized by the expression of osteoblastic markers such as Runx2 and the synthesis of extracellular matrix proteins.
The effect of these GFR-binding compounds as defined herein (SEQ ID NO: 33) on the differentiation of osteoblast progenitors was evaluated. These osteoblast progenitors were seeded onto the apatite ceramics or on type-I collagen sponge that were both coupled with osteogenic peptides. The cells were differentiated into mature osteoblasts after 48 hours of culture on these non-covalently coated materials. The differentiated osteoblast progenitors produced extensive amounts of extracellular matrix proteins such as Osteopontin (OPN) as compared to the osteoblast precursors cultured on a native type-I collagen sponge. This was seen from Osteopentin immunofluorescence staining after cell fixation as described in the Methods section (
Finally, it was verified that the osteoblast progenitors were differentiated into mature osteoblasts by analyzing the expression of the osteogenic biomarker Runx2. An increase in the Runx2 gene expression after 24 hours of culture (
hMSCs were cultured on native hydrogels ((poly(acrylamide-co-acrylic acid)) having a stiffness of 14 kPa and on hydrogels (also at a stiffness of 14 kPa) covalently modified with GFR-binding compounds as defined herein (SEQ ID NO: 36 and 37). The expression of the Sox9 protein was observed after 96 hours of culture suggesting that hMSCs have committed towards chondrocyte like cell differentiation (
Human umbilical-vein endothelial cells were cultured on a native polymer (PET) and on a polymer (PET) covalently modified with endothelialization GFR-binding compounds as defined herein (SEQ ID NO: 38). An increase in the area of the adherent junctions (CD31) was observed after 36 hours of culture on the covalently modified PET (
Human umbilical-vein endothelial cells were cultured on a native polymer (PET) and on a polymer (PET) covalently modified with vascular peptides (SEQ ID NO: 39). The formation of tube-like structures was observed after 18 hours of culture on the covalently modified PET (
Human epithelial cells were cultured on a native polymer (PET) and on a polymer (PET) covalently modified with tissue-closure peptides (SEQ ID NO: 40). A usual scratch test was applied (Nat Protoc 2: 329-333) on a monolayer of these epithelial cells in culture (
Isolated Hair Follicle Stem Cells were cultured on native hydrogels ((poly(acrylamide-co-acrylic acid)) having a stiffness of 73 kPa and hydrogels (also at a stiffness of 73 kPa) covalently modified with hair follicle stem cells GFR-binding compounds as defined herein (SEQ ID NO: 41 and 42). An increase in the Sox2 protein expression was observed indicative of the activation of these stem cells (
hMSCs were cultured on native hydrogels ((poly(acrylamide-co-acrylic acid)) having a stiffness of 28 kPa and on hydrogels (having the same stiffness of 28 kPa) covalently modified with musculogenic peptides (SEQ ID NO: 43 to 48). We observed an increase in the cell area of the cells cultured on the covalently modified hydrogels after 62 hours of culture suggesting that hMSCs have committed towards muscle differentiation (
It was then verified that these hMSCs cultured on the covalently modified hydrogels were differentiated into muscle cells by analyzing the expression of the musculogenic biomarker COMP (Cartilage Oligomeric Matrix Protein). An increased expression of this gene was observed after 96 hours of culture (
Neurons were cultured on native titanium (control) and on titanium covalently modified with neurogenic peptides (SEQ ID NO: 49). A rapid establishment of cell-cell contacts via dendrite growth was observed after 6 hours of culture on the covalently modified titanium (
hMSCs were cultured on conventional cell culture plastic plates with or without the presence in the cell culture media of different GFR-binding compounds as defined hereins (SEQ ID NO: 50 to 104) in solution. A rapid (48 hours) loss of the sternness marker STRO-1 was observed for the cells cultured in the presence of GFR-binding compounds as defined herein in the cell media solution (
hMSCs were cultured on conventional cell culture plastic plates with or without the presence in the cell culture media of different GFR-binding peptides as described herein (SEQ ID NO: 1071 to 1085) grafted on a PET surface via the method already described above. A rapid (48 hours) loss of the sternness marker CD-34+ was observed for the cells cultured in the presence of GFR-binding peptides as described herein in the cell media solution. This was probed by CD-34+ immunostaining after cell fixation as described in the Methods section. The quantification of CD-34+ positive contact numbers and areas was performed as described in the Methods section. A minimum of 30 cells per condition were analyzed. CD-34+ positive marrow cells are multipotential and capable of differentiating into all the various blood cell types. All the sequences have a RMSD of 2.45Å or less as defined herein and as shown in table 5.
RMSD values are always calculated for a GFR-binding peptide sequence exempt from any bioactive-carrier-affinity-containing group as defined herein (e.g. cysteine, WWFWG, GTPGP, etc. . . . ). When needed i.e. when attachment to a bioactive carrier is contemplated, the bioactive-carrier-affinity-containing group is then present in the GFR-binding compound when it is biologically tested. Using the method detailed in the description, the RMSD of 57 previously reported peptide sequences have been determined (Table 6) and correlated with the expression of STRO-1 after grafted on a PET surface via a procedure as already described above. These data show that a calculated value of RMSD of more than 2.45 Å, in particular more than 2 Å, more particularly more than 1.79 Å, always correlates with no significant hMSCs commitment and/or differentiation of the treated cells. One should note that it is commonly admitted that the expression of STRO-1 in a cell is indicative of a cell that is in a substantially non-differentiated state and the decrease of its expression of at least about 20% is indicative of a cell that has started a processus of differentiation but which may not result in the differentiation of the cell. A decrease of more than 50% would be indicative of the presence of a significant shift towards a differentiated state. A decrease of more than 70% would be indicative of the presence of a very important shift towards a differentiated state. A sustained decrease (e.g. for at least 96 h) of more than 50% or 70% would be indicative of the presence of an even more important shift towards a differentiated state.
Likewise, using the method detailed in the description, the RMSD of 87 GFR-binding peptide sequence representatives of the invention have been determined (Table 7) and correlated with the expression of STRO-1 after grafted on a PET surface via a procedure as already described above. SEQ ID NO: 1 to 49 were tested in combination with a bioactive carrier as defined above in the Examples Section (i.e. titanium, ceramics, PEEK, hydrogel, etc. . . . ), whereas SEQ ID NO: 1143 to 1180 were tested in solution. These data show that a calculated value of RMSD of 2.45 Å or less, in particular 2 Å or less, more particularly 1.79 Å or less, always correlates with a significant hMSCs commitment and/or differentiation of the treated cells.
The following study alms at validating the osteoinduction, osteoconducion and osteoclast Inhibition activity properties of the GFR-binding compounds In a critical size fracture Induced defect in an osteoporosis rat model. The goal Is to induce the process of bone regeneration In a physiological way resulting in osteogenesis without bone formation anomalies like ectopic growth or osteopetrosis.
A. Osteoporosis Rat Model
Given that the acceleration of bone turnover caused by oestrogen deficiency at menopause is the most common cause of osteoporosis, animal models that lose bone in response to oestrogen deficiency are preferred in the preclinical examination of therapeutic agents. This bone loss is characterized by an increased turnover rate, decreased bone mass as measured by densitometry and decreased bone volume. The ovariectomy-induced osteoporosis (OVX) rat model is most commonly used in research on osteoporosis and in preclinical animal studies. After ovariectomy, bone resorption exceeds bone formation, causing a rapid and reproducible bone loss in response to oestrogen deficiency.
B. Experimental Protocol
An overview of the experimental protocol is schematically represented in
B.1. Surgical Procedure
After 1 week of adaptation period, 3-month-old female rats (Sprague Dawley® strain) were subjected to bilateral ovariectomy (OVX) dorsal surgery. This procedure involves pain and therefore an analgesic administration was performed 30 minutes before surgery and 6 hours after surgery. Significant bone loss in the femoral condyle due to induced estrogen deficiency is typically obtained 8 weeks after the surgery with this animal model. One week before compound administration the OVX rats were randomly assigned to three different groups.
B.2. Compound Administration
Eight weeks after the surgery, a critical size defect of 3 mm was drilled in the femoral condyle of the OVX rats at J0 and a covalently bound GFR-binding compound (SEQ ID NO: 1181) was site administrated. This critical size defect would not heal alone through complete bone formation without external intervention at the experimental endpoints of the present study: 3 weeks and 12 weeks. The control conditions include a “No implantation” condition for which no implantations were performed in the defect as well as one ceramic (70% TCP30% HA) implant: a granulated ceramic powder (Control 2). SEQ ID NO: 1181 was grafted (via covalent binding of a N-terminal cysteine using a procedure already described herein) on a granulated ceramic powder (enabling osteoconduction). Hereinafter the various experimental conditions, the results for which are detailed below:
Two experimental endpoints were tested in the present study: 3 weeks and 12 weeks after compound administration. The first endpoint of 3 weeks allows the detection of an early osteogenesis process involving stem cells and progenitor cells differentiation towards the osteoblast lineage. The second endpoint of 12 weeks allows the detection of osteoporosis defect healing and the assessment of stably and efficiently induced osteogenesis. The experimenters were blinded to group assignment until the completion of the procedure, and again at the time of the results assessment analysis performed with various techniques.
B.3. Histopathological Analysis
For all the experimental conditions, the femoral defect sites were removed and resin embedded without prior demineralization, after which successive coronal sections were produced. A thorough histopathological analysis has been then performed on these sections in order to assess tissue and cellular structure and therefore the osteogenesis, osteoinduction, osteoconduction and bone resorption processes with the following stainings:
In addition, the tolerance rate of the various administrated compounds can be evaluated by examining tissue integrity at the defect site, presence and amount of necrotic tissue and presence of inflammatory cell infiltration such as immune cells and macrophages.
C. Results
Regarding the “No implantation” condition, 3 weeks after inducing a critical size defect, a thickening of the periosteum (fibrous tissue) can be observed at the defect entry for all the stainings (
Three weeks after HTD-PCL-M01 administration at the defect site, a periosteum closing of the defect entry has been initiated and completed at 12 weeks as observed on all the stainings (
D. Conclusions
The present CRO-conducted blind randomized preclinical pilot trial has validated the efficiency of a covalently bound representative GFR-binding compound as disclosed herein, for the treatment and prevention of osteoporosis and osteoporosis related fractures in an osteoporosis animal model. Osteoinductive activity was observed through bone tissue regeneration of critical size induced defects. The representative GFR-binding compounds were well tolerated and have efficiently induced bone formation as revealed by an increased osteoid and mineralized bone tissue formation at the defect area, 3 and 12 weeks after administration.
It was shown that HTD-PCL-M01 increased bone formation activity, increased the amount of osteoblast cells, decreased osteoclast (bone resorption) activity and increased ceramics resorption. This indicates that HTD-PCL-M01 triggers osteoinduction in addition to osteoconduction. HTD-PCL-M01 is therefore very well suited for efficient site administration as combined medical device for bone reconstruction of osteoporosis related fractures.
At 3 weeks, the compound has induced the early osteogenesis process involving stem cells and progenitor cells differentiation towards the osteoblast lineage. At 12 weeks the compound was proven efficient in inducing stable osteogenesis and inducing efficient osteoporosis defect healing. These results obtained after 12 weeks are of utmost importance for patients having osteoporotic related fractures, who usually remain significantly impaired for much longer periods of time or permanently.
Thus, GFR-binding compounds of the present disclosure represent new therapeutic solutions for osteoporosis with the unique ability to decouple bone resorption from bone formation by increasing bone formation and concomitantly decreasing bone resorption, which is required to achieve efficient bone strengthening in osteoporosis patients as compared to the existing treatments.
Advantageously, the animals used in the experiments did not present any deleterious side effects regardless of the experimental condition. In addition, the animal body weight was monitored twice a week during the course of the experiment, and a very slight weight loss was observed just after the ovariectomy surgery due to the anesthesia related decrease in food intake for all the animals, which is classically observed for this animal model. No compound administration related weight loss could be detected. Combined with the complete absence of deleterious side effects, this indicates that the administrated compound did not negatively interfere with the normal animal metabolism and physiology. Moreover, no animals were euthanized during the course of the experiment due to advanced state of morbidity or signs of pain. The animals were euthanized at the experimental endpoints 3 or 12 weeks after compound administration and a macroscopic post-mortem analysis was performed on the entire animal and specifically at the administration sites. The analysis has revealed no visible signs of inflammation or necrosis at the administration sites for all the animals. This indicates that the compound was well tolerated by the animals, which was also confirmed microscopically by the very small amount of immune cells at the administration sites. Finally, no animals with indications of the osteopetrosis disorder were detected.
| Number | Date | Country | Kind |
|---|---|---|---|
| 15307127.9 | Dec 2015 | EP | regional |
This application is a divisional of U.S. application Ser. No. 15/745,021 filed on 15 Jan. 2018, which is a U.S. National Stage application of International Application No. PCT/EP2016/070133 filed 25 Aug. 2016, which claims priority to U.S. Provisional Application No. 62/209,411 filed 25 Aug. 2015 and European Application No. 15307127.9 filed 23 Dec. 2015, the entire disclosures of which are hereby incorporated by reference in their entireties.
| Number | Date | Country | |
|---|---|---|---|
| 62209411 | Aug 2015 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 15745021 | Jan 2018 | US |
| Child | 18152624 | US |
