CARBOHYDRATE-BASED DRUG DELIVERY POLYMERS AND CONJUGATES THEREOF

BACKGROUND OF THE INVENTION

In recent years, human therapeutics have expanded past traditional small molecule drugs and into the realm of biopharmaceuticals. The discovery of novel proteins and peptides has led to the development of numerous protein and polypeptide biopharmaceuticals. Unfortunately, proteins and polypeptides, when utilized as therapeutics, often exhibit properties that make them extremely difficult to formulate or administer, such as short circulating half lives, immunogenicity, proteolytic degradation, and low solubility.

There is significant interest in using naturally occurring biopolymers as drug delivery and/or conjugating agents, as they are generally safe and because they are biodegradable. Both of these factors are very significant in selecting a polymer for drug delivery, as polymer safety and clearance rank among the most important issues in selecting a delivery polymer. Solubility in serum and in aqueous media is often very important for drug manufacture and drug delivery. By far the most successful water soluble polymer in use for drug delivery is polyethylene glycol (PEG) (see e.g. Harris, J. M. (1985), “Laboratory Synthesis of Polyethylene Glycol Derivatives”, JMS-Rev. Macromol. Chem. Phys. C25: 325-373; Harris, J. M. and Chess, R. B. (2003), “Effect of PEGylation on Pharmaceuticals”, Nature Reviews Drug Discovery 2: 214-221; Roberts, M. J., Bentley, M. D., and Harris, J. M. (2002), “Chemistry for peptide and protein PEGylation”, Adv. Drug Del. Rev. 54: 459-476; Pasut, G., Guiotto, A., and Veronese, F. M. (2004), “Protein, peptide and non-peptide drug PEGylation for therapeutic application”, Expert Opin. Ther. Patents 14:1-36; Filpula, D. and Zhao, H. (2008), “Releasable PEGylation of proteins with customized linkers”, Adv. Drug Del. Rev. 60: 29-49; Zhao, X and Harris, J. M. (1997), “Novel degradable poly(ethylene glycol) esters for drug delivery”, In: Harris J. M. and Zalipsky S. (eds): Poly(ethylene glycol) chemistry and biological applications, American Chemical Society, Washington, D.C., 458-472.)

Attempts have also been made to use carbohydrates for conjugation with and delivery of drugs. The most prominent examples are hydroxyethyl starch (HES) and polysialic acid (PSA). HES, a derivative of naturally occurring starch (amylopectin & amylose), has been described as the polymer of choice as a polyfunctional carrier for oligopeptide-polymer conjugates. It is non-toxic and nonimmunogenic and is degraded by α-amylase in the body.

HES is recommended as a polyfunctional carrier, since it has a large number of functional groups (primarily hydroxyl groups), making monofunctionalization virtually impossible. Thus, activation of HES for attachment of drug moieties provides a polyfunctional polymer with a diversity of sites; i.e. some polymer molecules have more functional sites than other polymer molecules, and the overall result is a polydisperse distribution of reactive sites. This is often acceptable for smaller drug molecules, where several drug molecules per polymer strand may be acceptable, as long as biodistribution is not affected by the polydisperse character of the conjugate. However, it is undesirable for larger molecules such as proteins, where a single protein molecule per polymer moiety is highly desired. In fact, in many cases, e.g. with very large proteins like Factor VIII, multiple polymer molecules may be desired to protect the protein. While PEGs are very suitable for such applications, because they can readily be engineered to provide only one active group per polymer molecule, it is very difficult to selectively activate only one functional group of a carbohydrate polymer.

Polysialic acid (PSA) and hyaluronic acid (HA) are acid carbohydrates that have also been promoted for drug delivery. However, the very high biodegradability of HA is problematic, as it is generally inadequately stable in vivo to be a good delivery agent. HA also suffers from its strong targeting properties which consistently steer it toward certain biotargets. PSA has enjoyed more recent attention. Like HES, however, PSA is only reasonably useful when polyfunctionality is acceptable. Thus, to this point, polysaccharides have not presented a significant commercial threat to the use of PEGs (PEGylation) for modification of the pharmacological properties of drugs; i.e. relatively little product development activity has occurred, and there are no launched products.

Another issue that must be dealt with in employing carbohydrates for drug delivery is control of molecular weight. It is possible, for example, to manufacture PEG with fairly precise control of molecular weight and polydispersity. Thus, it is common to see commercially available PEGs having moderate molecular weights (i.e. 20-40 kD) with a polydispersity of 1.10 or less. Since carbohydrates are biologically derived, often with variable molecular weights, obtaining a specific molecular weight for drug delivery is difficult. With respect to molecular weight distribution, commercially available dextrans often have polydispersity values of 2.0 or greater, or around 1.25-1.35 for purified materials.

Thus, there remains a need to overcome these barriers of polyfunctionality and polydispersity in order to take advantage of the desirable properties of these naturally occurring polymers.

SUMMARY

In one aspect, the invention provides a method of selectively monoderivatizing a water-soluble carbohydrate polymer at its reductive terminus, wherein said reductive terminus comprises a hemiacetal or ketal group or the corresponding aldehyde or ketone functionality, the method comprising:

contacting said carbohydrate polymer with a heterobifunctional oxyamine or hydrazine reagent, effective to produce a monoderivatized carbohydrate derivative having a functional group, not selected from oxyamine and hydrazine, linked via an oxyimine or hydrazone moiety at said terminus.

The method may further comprise reducing the double bond of said oxyimine or hydrazone moiety. Thus, the monoderivatized carbohydrate polymer may have a structure

POLY¹-C^aHR¹—NR³—X-L¹-G¹ (I)

where

POLY¹is said carbohydrate polymer and C^ais the anomeric carbon atom of said terminal hemiacetal or ketal group or corresponding aldehyde or ketone functionality;

R¹is H or hydroxymethyl;

X is oxygen or NR², where R²is hydrogen, methyl, lower alkyl, cycloalkyl, or aryl, and is preferably H or methyl, and more preferably H;

R³is H or methyl, and is typically H;

L¹is a linker group, and

G¹is an optionally protected functional group, not selected from oxyamine and hydrazine.

When the reduction step is not carried out, the 4. The method of claim 1, wherein the monoderivatized carbohydrate derivative monoderivatized carbohydrate polymer may have a structure

POLY¹-C^a(R¹)═N—X-L¹-G¹ (II)

where:

POLY¹is said carbohydrate polymer and C^ais the anomeric carbon atom of said terminal hemiacetal or ketal group or corresponding aldehyde or ketone functionality;

R¹is H or hydroxymethyl;

X is oxygen or NR², where R²is hydrogen, methyl, lower alkyl, cycloalkyl, or aryl, and is preferably H or methyl, and more preferably H;

L¹is said linker group, and

G¹is said optionally protected functional group, not selected from oxyamine and hydrazine.

The heterobifunctional oxyamine or hydrazine reagent used for such monoderivatization typically has the structure

R³HN—X-L¹-G¹ (III)

where:

X is oxygen or NR², where R²is hydrogen, methyl, lower alkyl, cycloalkyl, or aryl, and is preferably H or methyl, and more preferably H;

R³is H or methyl, and is generally H;

L¹is a linker group, and

G¹is an optionally protected functional group, not selected from oxyamine and hydrazine, which is unreactive under the conditions of said contacting.

In selected embodiments, X is oxygen (an oxyamine reagent) or NR², e.g. NH₂(a hydrazine reagent). X may also be sulfur.

R¹may be hydroxymethyl, when POLY¹is a ketose, or hydrogen, when POLY¹is an aldose, such as a dextran or a chitosan. POLY¹generally has a molecular weight in the range of 200 Da to 2,000,000 Da. Molecular weights such as 5 KDa, 10 KDa, 20 KDa, 40 KDa, and 70 KDa, for example, are typical.

L¹is a linker as defined further below. Preferably, L¹consists of moieties selected from alkylene, —CH₂CH₂O—, amide, carbamate, and combinations thereof; more preferably, L¹consists of alkylene moieties, —CH₂CH₂O— moieties, and combinations thereof. Generally, L¹is 1 to about 20 atoms in length, and may be 3-12, or 3-8 atoms in length.

The functional group G¹may be selected from amine, hydroxy, thiol, carboxylic acid, carboxylic acid ester, imide ester, orthoester, carbonate, isocyanate, isothiocyanate, aldehyde, acetal, ketone, ketal, thione, alkenyl, acrylate, methacrylate, acrylamide, sulfone, maleimide, disulfide, iodo, epoxy, sulfonate, thiosulfonate, silane, alkoxysilane, halosilane, and phosphoramidate; and in selected embodiments is selected from amine, hydroxy, thiol, carboxylic acid, carboxylic acid ester, imide ester, orthoester, carbonate, isocyanate, aldehyde, acetal, ketone, ketal, and maleimide.

The preparation method may also include a step of purifying the carbohydrate polymer. In particular, when the heterobifunctional reagent comprises an oxyamine or hydrazine at one terminus and a carboxylic acid or amine group at the other terminus, effective to produce a monoderivatized water-soluble carbohydrate polymer having a single terminal carboxylic acid or amine group, the method may further comprise purifying the amine- or carboxylic acid-terminated carbohydrate polymer by ion exchange chromatography.

In a related aspect, the invention provides a monofunctional water-soluble carbohydrate-based reagent having the structure

POLY¹-C^a(H)_x(R¹) custom-character N(R³)_x—X-L¹-G¹ (IV)

where:

POLY¹is a water-soluble carbohydrate polymer having a terminal anomeric carbon atom, where C^ais said terminal anomeric carbon atom;

custom-character represents a double bond when x=0 and a single bond when x=1;

R¹is H or hydroxymethyl;

X is oxygen or NR², where R²is hydrogen, methyl, lower alkyl, cycloalkyl, or aryl, and is preferably H or methyl, and more preferably H;

R³is H or methyl, and is typically H;

L¹is a linker group, and

G¹is a functional group, in reactive or protected form, not selected from oxyamine and hydrazine.

In selected embodiments, the carbohydrate reagent has a double bond represented by custom-character , such that x=0. In other embodiments, e.g. where the double bond is subjected to reduction, the carbohydrate reagent has a single bond represented by , such that x=1.

Selected embodiments of the components represented by X, R¹, POLY¹, L¹, and G¹are as described above.

Exemplary carbohydrate reagents include the reagent having a structure designated herein as dextran-O-(carboxymethyl)oxyimine (2); the reagent having a structure designated herein as oxyimine-linked dextran-butanoic acid (7); the reagent having a structure designated herein as oxyimine-linked dextran(40K)-butyraldehyde (16); the reagent having a structure designated herein as oxyimine-linked chitosan tetra(ethylene glycol) maleimidopropionamide (22); and the reagent having a structure designated herein as oxyimine-linked chitosan butanoic acid (23). The carbohydrate component in any of these structures may have any of a variety of molecular weights. The reagents also include protected versions of the terminal functional groups.

In another aspect, the invention provides a method of preparing a water-soluble carbohydrate reagent having a single terminal carboxylic acid group, the method comprising

oxidizing a water-soluble carbohydrate polymer, such as a dextran, having a terminal acetal or aldehyde group under mild conditions, effective to produce an oxidized carbohydrate having a single terminal carboxylic acid group and having substantially the same molecular weight as the carbohydrate prior to oxidation. Such conditions include reaction with iodine (I₂) and a hydroxide base as described herein.

The method may further comprise the step of purifying the carbohydrate reagent by ion exchange chromatography, such that the purified carbohydrate reagent is substantially free of unreacted carbohydrate and overoxidized byproducts. Such purification may also be effective to significantly reduce the polydispersity of the monocarboxylic acid reagent relative to that of the carbohydrate prior to oxidation.

In accordance with this method, the invention provides a water-soluble carbohydrate reagent, preferably a dextran, having a single terminal functional group which is a carboxylic acid. The carboxyl carbon of the carboxylic acid is the terminal anomeric carbon of the starting carbohydrate. Such carbohydrate monocarboxylic acids may have a molecular weight of 200 Da to 2,000,000 Da.

Also provided are the corresponding carboxylic acid derivatives, which can be readily prepared from the carbohydrate monocarboxylic acid. The carboxylic acid derivative may be selected from ester, activated ester, thioester, anhydride, amide, acid halide, nitrile, carbamate, carbonate, isocyanate, and isothiocyanate.

Also provided is a conjugate comprising the water-soluble carbohydrate monocarboxylic acid or derivative and a covalently attached biologically active molecule, which may be prepared by reaction of the carbohydrate monocarboxylic acid or derivative with a biologically active molecule having a suitable reactive group. In one embodiment, the biologically active molecule is a protein or peptide, where the reactive group is typically an amine.

In one embodiment, the biologically active molecule is insulin. Accordingly, the invention provides a method of reducing blood glucose levels in a diabetic subject, including a human subject, by administering a dextran monocarboxylic acid-insulin conjugate.

The invention also provides conjugates of a water-soluble carbohydrate reagent and a biologically active molecule, having the structure

POLY¹-C^a(H)_x(R¹) custom-character N(H)_x—X-L¹-G²-B (V)

where

POLY¹is a water-soluble carbohydrate polymer having a terminal anomeric carbon atom, where C^ais said terminal anomeric carbon atom;

custom-character represents a double bond when x=0 and a single bond when x=1;

R¹is H or hydroxymethyl;

X is oxygen or NR², where R²is hydrogen, methyl, lower alkyl, cycloalkyl, or aryl;

L¹is a linker group, and

G²is a covalent bond comprising a residue or converted form of functional group G¹, not selected from oxyamine and hydrazine, following reaction with a corresponding functional group on biomolecule B.

Selected embodiments of the components represented by the variables in structure (V) include those disclosed for structure (IV) above.

In selected embodiments, POLY¹is a chitosan. In further embodiments of this type, the biologically active molecule is an oligonucleotide, such as an RNA.

In other embodiments, POLY¹is a dextran. Exemplary dextran conjugates include conjugates of proteins or peptides, such as conjugates of lysozyme, protegrin-1, C-peptide, and insulin as described herein. In one embodiment, the biologically active molecule is insulin, which may be a partially acetylated insulin. Such conjugates include having the structure disclosed herein as 20. The dextran component in this conjugate may vary in molecular weight. In a preferred embodiment, the carbohydrate is dextran(40 KDa).

In a related aspect, the invention provides a method of reducing blood glucose levels in a diabetic subject, including a human subject, by administering a dextran-insulin conjugate having the structure designated as 20 herein.

These and other aspects of the invention will become apparent upon review of the following description and accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows gels produced by SDS-PAGE analysis (4-12% gel) of purified dextran-butyraldehyde-40K-protegrin-1, as described in Example 16. Dextran perturbs the gel migration of the dextran-peptide conjugate; the conjugate's band location is not indicative of its size. The marker (M) molecular weight unit is kDa.

FIG. 2 shows a MALDI-TOF spectrum for mono-Dextran_40K-C-peptide(S20C) conjugate, prepared as described in Example 17. The peaks at 43.2 kDa and 22.0 kDa agree with molecular weights of the singly and doubly charged forms of the conjugated peptide.

FIG. 3 shows gels produced by SDS-PAGE (4-12% Bis-Tris-Nu-PAGE, Invitrogen) analysis of purified dextran-butyrALD-40K-insulin, produced by conjugation of Dextran_40Ktetraethylene glycol butyraldehyde (16) with acetylated insulin, as described in Example 18B. Lane 1: Dextran-butyrALD-40K-insulin purified and concentrated by anion-exchange chromatography; Lane 2: Purified and concentrated dextran-butyrALD-40K-insulin after precipitation from water/DMSO with acetonitrile.

FIG. 4 shows the results of the in vitro competition binding assay described in Example 19, where the in vitro affinity for the insulin receptor of the insulin-dextran conjugate (20b) was evaluated.

FIG. 5 shows the effect of insulin and dextran-conjugated insulin on blood glucose levels in db/db diabetic mice, as described in Example 20.

DETAILED DESCRIPTION OF THE INVENTION
I. Definitions

Before describing the present invention in detail, it is to be understood that this invention is not limited to particular polymers, synthetic techniques, active agents, and the like, as such may vary.

As used in this specification and in the claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a polymer” includes a single polymer as well as two or more of the same or different polymers, reference to “a conjugate” refers to a single conjugate as well as two or more of the same or different conjugates, reference to “an excipient” includes a single excipient as well as two or more of the same or different excipients, and the like.

“Optional” and “optionally” mean that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.

In describing and claiming the present invention, the following terminology will be used in accordance with the definitions described below.

As used herein, the terms “therapeutic peptide” and “therapeutic peptides” mean one or more peptides having demonstrated or potential use in treating, preventing, or ameliorating one or more diseases, disorders, or conditions in a subject in need thereof, as well as related peptides. These terms may be used to refer to therapeutic peptides prior to conjugation to a water-soluble polymer as well as following the conjugation. Therapeutic peptides include, but are not limited to, those disclosed herein, including in Table 1. Therapeutic peptides include peptides found to have use in treating, preventing, or ameliorating one or more diseases, disorders, or conditions after the time of filing of this application. Related peptides include fragments of therapeutic peptides, therapeutic peptide variants, and therapeutic peptide derivatives that retain some or all of the therapeutic activities of the therapeutic peptide. As will be known to one of skill in the art, as a general principle, modifications may be made to peptides that do not alter, or only partially abrogate, the properties and activities of those peptides. In some instances, modifications may be made that result in an increase in therapeutic activities. Thus, in the spirit of the invention, the terms “therapeutic peptide” or “therapeutic peptides” are meant to encompass modifications to the therapeutic peptides defined and/or disclosed herein that do not alter, only partially abrogate, or increase the therapeutic activities of the parent peptide.

The term “therapeutic activity” as used herein refers to a demonstrated or potential biological activity whose effect is consistent with a desirable therapeutic outcome in humans, or to desired effects in non-human mammals or in other species or organisms. A given therapeutic peptide may have one or more therapeutic activities, however the term “therapeutic activities” as used herein may refer to a single therapeutic activity or multiple therapeutic activities. “Therapeutic activity” includes the ability to induce a response in vitro, and may be measured in vivo or in vitro. For example, a desirable effect may be assayed in cell culture, or by clinical evaluation, EC₅₀assays, IC₅₀assays, or dose response curves. In vitro or cell culture assays, for example, are commonly available and known to one of skill in the art for many therapeutic peptides as defined and/or disclosed herein. Therapeutic activity includes treatment, which may be prophylactic or ameliorative, or prevention of a disease, disorder, or condition. Treatment of a disease, disorder or condition can include improvement of a disease, disorder or condition by any amount, including elimination of a disease, disorder or condition.

As used herein, the terms “peptide,” “polypeptide,” and “protein,” refer to polymers comprised of amino acid monomers linked by amide bonds. Peptides may include the standard 20 α-amino acids that are used in protein synthesis by cells (i.e. natural amino acids), as well as non-natural amino acids (non-natural amino acids nay be found in nature, but not used in protein synthesis by cells, e.g., ornithine, citrulline, and sarcosine, or may be chemically synthesized), amino acid analogs, and peptidomimetics. Spatola, (1983) in Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins, Weinstein, ed., Marcel Dekker, New York, p. 267. The amino acids may be D- or L-optical isomers. Peptides may be formed by a condensation or coupling reaction between the α-carbon carboxyl group of one amino acid and the amino group of another amino acid. The terminal amino acid at one end of the chain (amino terminal) therefore has a free amino group, while the terminal amino acid at the other end of the chain (carboxy terminal) has a free carboxyl group. Alternatively, the peptides may be non-linear, branched peptides or cyclic peptides. Moreover, the peptides may optionally be modified or protected with a variety of functional groups or protecting groups, including on the amino and/or carboxy terminus.

Amino acid residues in peptides are abbreviated as follows: Phenylalanine is Phe or F; Leucine is Leu or L; Isoleucine is Ile or I; Methionine is Met or M; Valine is Val or V; Serine is Ser or S; Proline is Pro or P; Threonine is Thr or T; Alanine is Ala or A; Tyrosine is Tyr or Y; Histidine is His or H; Glutamine is Gln or Q; Asparagine is Asn or N; Lysine is Lys or K; Aspartic Acid is Asp or D; Glutamic Acid is Glu or E; Cysteine is Cys or C; Tryptophan is Trp or W; Arginine is Arg or R; and Glycine is Gly or G.

The terms “therapeutic peptide fragment” or “fragments of therapeutic peptides” refer to a polypeptide that comprises a truncation at the amino-terminus and/or a truncation at the carboxyl-terminus of a therapeutic peptide as defined herein. The terms “therapeutic peptide fragment” or “fragments of therapeutic peptides” also encompasses amino-terminal and/or carboxyl-terminal truncations of therapeutic peptide variants and therapeutic peptide derivatives. Therapeutic peptide fragments may be produced by synthetic techniques known in the art or may arise from in vivo protease activity on longer peptide sequences. It will be understood that therapeutic peptide fragments retain some or all of the therapeutic activities of the therapeutic peptides.

As used herein, the terms “therapeutic peptide variants” or “variants of therapeutic peptides” refer to therapeutic peptides having one or more amino acid substitutions, including conservative substitutions and non-conservative substitutions, amino acid deletions (either internal deletions and/or C- and/or N-terminal truncations), amino acid additions (either internal additions and/or C- and/or N-terminal additions, e.g., fusion peptides), or any combination thereof. Variants may be naturally occurring (e.g. homologs or orthologs), or non-natural in origin. The term “therapeutic peptide variants” may also be used to refer to therapeutic peptides incorporating one or more non-natural amino acids, amino acid analogs, and peptidomimetics. It will be understood that, in accordance with the invention, therapeutic peptide fragments retain some or all of the therapeutic activities of the therapeutic peptides.

The terms “therapeutic peptide derivatives” or “derivatives of therapeutic peptides” as used herein refer to therapeutic peptides, therapeutic peptide fragments, and therapeutic peptide variants that have been chemically altered other than through covalent attachment of a water-soluble polymer. It will be understood that, in accordance with the invention, therapeutic peptide derivatives retain some or all of the therapeutic activities of the therapeutic peptides.

“PEG”, “polyethylene glycol” and “poly(ethylene glycol)” as used herein, are meant to encompass any water-soluble poly(ethylene oxide). Typically, PEGs comprise the following structure “—O(CH₂CH₂O)_m—” where (m) is 2 to 4000. As used herein, PEG also includes “—(CH₂CH₂O)_m—” and “—CH₂CH₂—O(CH₂CH₂O)_m—CH₂CH₂-”, depending upon whether or not the terminal oxygens have been displaced. When the PEG further comprises a spacer moiety (to be described in greater detail below), the atoms comprising the spacer moiety, when covalently attached to a water-soluble polymer segment, do not result in the formation of an oxygen-oxygen bond (i.e., an “—O—O—” or peroxide linkage). The term “PEG” includes structures having various terminal or “end capping” groups and so forth. The term “PEG” also means a polymer that contains a majority, that is to say, greater than 50%, of —CH₂CH₂O— monomeric subunits. With respect to specific forms, the PEG can take any number of a variety of molecular weights, as well as structures or geometries such as “branched,” “linear,” “forked,” “multifunctional,” “dendrimeric”, and the like.

The terms “end-capped” or “terminally capped” are interchangeably used herein to refer to a terminal or endpoint of a polymer having an end-capping moiety. Typically, although not necessarily, the end-capping moiety comprises a hydroxy or C_1-20alkoxy group. Thus, examples of end-capping moieties include alkoxy (e.g., methoxy, ethoxy and benzyloxy), as well as aryl, heteroaryl, cyclo, heterocyclo, and the like. In addition, saturated, unsaturated, substituted and unsubstituted forms of each of the foregoing are envisioned. Moreover, the end-capping group can also be a silane. The end-capping group can also advantageously comprise a detectable label. When the polymer has an end-capping group comprising a detectable label, the amount or location of the polymer and/or the moiety (e.g., active agent) of interest to which the polymer is coupled to can be determined by using a suitable detector. Such labels include, without limitation, fluorescers, chemiluminescers, moieties used in enzyme labeling, colorimetric (e.g., dyes), metal ions, radioactive moieties, and the like. Suitable detectors include photometers, films, spectrometers, and the like.

“Non-naturally occurring”, with respect to a polymer or water-soluble polymer, indicates that the polymer in its entirety is not found in nature. A non-naturally occurring polymer or water-soluble polymer may, however, contain one or more subunits or portions of a subunit that are naturally occurring, so long as the overall polymer structure is not found in nature.

A “water-soluble polymer” is any polymer that is soluble in water at room temperature. Typically, a water-soluble polymer will transmit at least about 75%, more preferably at least about 95% of light, transmitted by the same solution after filtering. On a weight basis, a water-soluble polymer will preferably be at least about 35% (by weight) soluble in water, more preferably at least about 50% (by weight) soluble in water, still more preferably about 70% (by weight) soluble in water, and still more preferably about 85% (by weight) soluble in water. It is still more preferred, however, that the water-soluble polymer is about 95% (by weight) soluble in water and most preferred that the water-soluble polymer is completely soluble in water.

“Molecular weight”, in the context of a water-soluble polymer of the invention, such as PEG, can be expressed as either a number average molecular weight or a weight average molecular weight. Unless otherwise indicated, all references to molecular weight herein refer to the weight average molecular weight. Both molecular weight determinations, number average and weight average, can be made using gel permeation chromatography or other liquid chromatography techniques. Other methods for measuring molecular weight can also be used, such as end-group analysis or colligative properties (e.g., freezing-point depression, boiling-point elevation, or osmotic pressure) to determine number average molecular weight, or light scattering techniques, ultracentrifugation or viscometry to determine weight average molecular weight. The polymers of the invention are typically polydisperse (i.e., number average molecular weight and weight average molecular weight of the polymers are not equal), possessing low polydispersity values of preferably less than about 1.2, more preferably less than about 1.15, still more preferably less than about 1.10, yet still more preferably less than about 1.05, and most preferably less than about 1.03.

An “organic radical” as used includes, for example, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl.

“Alkyl” refers to a hydrocarbon chain, typically ranging from about 1 to 20 atoms in length. Such hydrocarbon chains are preferably but not necessarily saturated and may be branched or straight chain, although typically straight chain is preferred. Exemplary alkyl groups include ethyl, propyl, butyl, pentyl, isooctyl, decyl, 3-ethyl-3-pentyl, 2-methyl-1-hexyl, and the like. As used herein, “alkyl” includes cycloalkyl, when three or more carbon atoms are referenced, and lower alkyl. “Alkylene” refers to an unsaturated bivalent radical (e.g. —(CH₂)_n)—.

“Lower alkyl” refers to an alkyl group containing from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and may be straight chain or branched, as exemplified by methyl, ethyl, n-butyl, iso-butyl, and tert-butyl. When a group is defined as “alkyl” herein, lower alkyl is generally a preferred embodiment.

“Cycloalkyl” refers to a saturated or unsaturated cyclic hydrocarbon chain, including bridged, fused, or Spiro cyclic compounds, preferably made up of 3 to about 12 carbon atoms, more preferably 3 to about 8.

“Alkoxy” refers to an —O—R group, wherein R is alkyl or substituted alkyl, preferably C₁-C₂₀alkyl (e.g., methoxy, ethoxy, propyloxy, benzyl, perfluorobutyl, etc.), preferably C₁-C₇alkyl, more preferably C₁-C₇alkyl. “Alkoxyalkyl” refers to an —R—O—R group, where R is as defined above, and is preferably unsubstituted C₁-C₇alkyl.

“Aminoalkyl” refers to an —NHR or —NR₂group, where R is alkyl as defined above, and is preferably unsubstituted C₁-C₇alkyl, and the two R groups in —NR₂may be the same or different. The two R groups may also form a five- to seven-membered ring.

“Iminoalkyl(ene)” refers to an —R′—N═R″ group, where R″ represents CH₂, CHR, or CR₂, where each R is alkyl as defined above, and the two R groups in —CR₂may be the same or different. R′ is alkyl as defined above, i.e. an sp²hybridized carbon, or alkylene, i.e. an sp²hybridized carbon forming one member of a double bond. An R in CHR or CR₂taken together with the R′ may form a five- to seven-membered ring.

As used herein, “alkenyl” refers to a branched or unbranched hydrocarbon group of 2 to 15 atoms in length, containing at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, and the like.

The term “alkynyl” as used herein refers to a branched or unbranched hydrocarbon group of 2 to 15 atoms in length, containing at least one triple bond, ethynyl, n-butynyl, isopentynyl, octynyl, decynyl, and so forth.

“Aliphatic” refers to a group containing carbon and hydrogen which is not aromatic. As used herein, it can refer to linear, branched, or cyclic groups. It can refer to saturated or unsaturated groups, with saturated groups generally being preferred.

“Aryl” means one or more aromatic rings, each of 5 or 6 core carbon atoms. Aryl includes multiple aryl rings that may be fused, as in naphthyl, or unfused, as in biphenyl. Aryl rings may also be fused or unfused with one or more cyclic hydrocarbon, heteroaryl, or heterocyclic rings. As used herein, “aryl” includes heteroaryl. An aromatic moiety (e.g., Ar¹, Ar², and so forth), means a structure containing aryl.

“Heteroaryl” is an aryl group containing from one to four heteroatoms, preferably N, O, or S, or a combination thereof. Heteroaryl rings may also be fused with one or more cyclic hydrocarbon, heterocyclic, aryl, or heteroaryl rings.

“Heterocycle” or “heterocyclic” means one or more rings of 5-12 atoms, preferably 5-7 atoms, with or without unsaturation or aromatic character and having at least one ring atom which is not a carbon. Preferred heteroatoms include sulfur, oxygen, and nitrogen.

“Substituted heteroaryl” is heteroaryl having one or more non-interfering groups as substituents.

“Substituted heterocycle” is a heterocycle having one or more side chains formed from non-interfering substituents.

“Non-interfering substituents” are those groups that, when present in a molecule, are typically non-reactive with other functional groups contained within the molecule. Such groups include: lower alkyl, lower alkoxy, C3-C8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, and the like; halo, e.g., fluoro, chloro, bromo, and iodo; cyano; phenyl; substituted phenyl; and the like. For substitutions on a phenyl ring, the substituents may be in any orientation (i.e., ortho, meta, or para). Preferred non-interfering substituents include lower alkyl, lower alkoxy, cyclopropyl, fluoro, chloro, and cyano.

The term “substituted” as in, for example, “substituted alkyl,” refers to a moiety (e.g., an alkyl group) substituted with one or more non-interfering substituents, such as, but not limited to: C₃-C₈cycloalkyl, e.g., cyclopropyl, cyclobutyl, and the like; halo, e.g., fluoro, chloro, bromo, and iodo; cyano; alkoxy, lower phenyl (e.g., 0-2 substituted phenyl); substituted phenyl; and the like. “Substituted aryl” is aryl having one or more non-interfering groups as a substituent. For substitutions on a phenyl ring, the substituents may be in any orientation (i.e., ortho, meta, or para).

As used herein, the “halo” designator (e.g., fluoro, chloro, iodo, bromo, and so forth) is generally used when the halogen is attached to a molecule, while the suffix “ide” (e.g., fluoride, chloride, iodide, bromide, and so forth) is used when the halogen exists in its independent ionic form (e.g., such as when a leaving group leaves a molecule).

“Electrophile” refers to an ion or atom or collection of atoms, that may be ionic, having an electrophilic center, i.e., a center that is electron seeking, capable of reacting with a nucleophile.

“Nucleophile” refers to an ion or atom or collection of atoms that may be ionic having a nucleophilic center, i.e., a center that is seeking an electrophilic center or with an electrophile.

A basic or acidic reactant described herein includes neutral, charged, and any corresponding salt forms thereof.

As used herein, the term “ionizable hydrogen atom” (“H_α”) means a hydrogen atom that can be removed in the presence of a base, often a hydroxide or amine base. Typically, the “ionizable hydrogen atom” (“H_α”) will be a hydrogen atom attached to a carbon atom that, in turn, is attached to one or more aromatic moieties or another group or groups that in some way stabilize the carbanion that would form from loss of the ionizable hydrogen atom as a proton (or the transition state leading to said carbanion).

As used herein, the term “carboxylic acid” is a moiety having a —C(O)OH functional group, as well as moieties that are derivatives of a carboxylic acid, such derivatives including, for example, protected carboxylic acids. Thus, unless the context clearly dictates otherwise, the term carboxylic acid includes not only the acid form, but corresponding esters and protected forms as well. With regard to protecting groups suited for a carboxylic acid and any other functional group described herein, reference is made to Greene et al., “PROTECTIVE GROUPS IN ORGANIC SYNTHESIS”, 3^rdEdition, John Wiley and Sons, Inc., New York, 1999.

The term “reactive” or “activated” when used in conjunction with a particular functional group, refers to a reactive functional group that reacts readily with an electrophile or a nucleophile on another molecule. This is in contrast to those groups that require strong catalysts or highly impractical reaction conditions in order to react (i.e., a “nonreactive” or “inert” group).

The terms “protected” or “protecting group” or “protective group” refer to the presence of a moiety (i.e., the protecting group) that prevents or blocks reaction of a particular chemically reactive functional group in a molecule under certain reaction conditions. The protecting group will vary depending upon the type of chemically reactive functional group being protected as well as the reaction conditions to be employed and the presence of additional reactive or protecting groups in the molecule, if any. Protecting groups known in the art can be found in Greene et al., supra.

As used herein, the term “functional group” or any synonym thereof is meant to encompass protected forms thereof. In particular, recitation of specific functional groups such as carboxylic acids, aldehydes, or hydroxyl groups encompasses protected forms thereof.

“Multifunctional”, in the context of a polymer of the invention, means a polymer having 3 or more functional groups contained therein, where the functional groups may be the same or different. Multifunctional polymers of the invention will typically contain from about 3-100 functional groups, or from 3-50 functional groups, or from 3-25 functional groups, or from 3-15 functional groups, or from 3 to 10 functional groups, or will contain 3, 4, 5, 6, 7, 8, 9 or 10 functional groups within the polymer. A “difunctional” polymer means a polymer having two functional groups contained therein, either the same (i.e., homodifunctional) or different (i.e., heterodifunctional).

“Branched,” in reference to the geometry or overall structure of a polymer, refers to polymer having 2 or more polymer “arms.” A branched polymer may possess 2 polymer arms, 3 polymer arms, 4 polymer arms, 6 polymer arms, 8 polymer arms or more. One particular type of highly branched polymer is a dendritic polymer or dendrimer, which, for the purposes of the invention, is considered to possess a structure distinct from that of a branched polymer.

A “dendrimer” or dendritic polymer is a globular, size monodisperse polymer in which all bonds emerge radially from a central focal point or core with a regular branching pattern and with repeat units that each contribute a branch point. Dendrimers exhibit certain dendritic state properties such as core encapsulation, making them unique from other types of polymers.

In the context of the present description, the definition of a variable provided with respect to one structure or formula is applicable to the same variable repeated in a different structure, unless the context dictates otherwise. Thus, for example, the definition of “POLY,” “a spacer moiety,” “R^e1” and so forth with respect to a polymer can be equally applicable to a water-soluble polymer conjugate provided herein.

The terms “spacer” or “spacer moiety” (which may also be referred to as a linker or linker moiety) are used herein to refer to an atom or a collection of atoms optionally used to link one moiety to another, such as a water-soluble polymer segment to a functional moiety in a polymeric reagent. The spacer moieties of the invention are preferably hydrolytically stable but may include one or more physiologically hydrolyzable or enzymatically degradable linkages. Exemplary spacer moieties are described further below.

A “physiologically cleavable” or “hydrolyzable” bond is a relatively weak bond that reacts with water (i.e., is hydrolyzed) under physiological conditions. The tendency of a bond to hydrolyze in water will depend not only on the general type of linkage connecting two central atoms but also on the substituents attached to these central atoms. Appropriate hydrolytically unstable or weak linkages include, but are not limited to, carboxylate ester, phosphate ester, anhydrides, acetals, ketals, acyloxyalkyl ether, imines, ortho esters, peptides and oligonucleotides.

A “degradable linkage” includes, but is not limited to, a physiologically cleavable bond, a hydrolyzable bond, and an enzymatically degradable linkage. Thus, a “degradable linkage” is a linkage that may undergo either hydrolysis or cleavage by some other mechanism (e.g., enzyme-catalyzed, acid-catalyzed, base-catalyzed, and so forth) under physiological conditions. For example, a “degradable linkage” can involve an elimination reaction that has a base abstraction of a proton, (e.g., an ionizable hydrogen atom, H_α), as the driving force.

An “enzymatically degradable linkage” means a linkage that is subject to degradation by one or more enzymes.

A “hydrolytically stable” linkage or bond refers to a chemical bond, typically a covalent bond, that is substantially stable in water, that is to say, does not undergo hydrolysis under physiological conditions to any appreciable extent over an extended period of time. Examples of hydrolytically stable linkages include but are not limited to the following: carbon-carbon bonds (e.g., in aliphatic chains), ethers, amides, urethanes (carbamates), and the like. Generally, a hydrolytically stable linkage is one that exhibits a rate of hydrolysis of less than about 1-2% per day under physiological conditions. Hydrolysis rates of representative chemical bonds can be found in most standard chemistry textbooks. It must be pointed out that some linkages can be hydrolytically stable or hydrolyzable, depending upon (for example) adjacent and neighboring atoms and ambient conditions. One of ordinary skill in the art can determine whether a given linkage or bond is hydrolytically stable or hydrolyzable in a given context by, for example, placing a linkage-containing molecule of interest under conditions of interest and testing for evidence of hydrolysis (e.g., the presence and amount of two molecules resulting from the cleavage of a single molecule). Other approaches known to those of ordinary skill in the art for determining whether a given linkage or bond is hydrolytically stable or hydrolyzable can also be used.

As used herein, “drug release rate” means a rate (stated as a half-life) in which half of the total amount of polymer-active agent conjugates in a system will cleave into the active agent and a polymeric residue.

The terms “active agent,” “biologically active agent” and “pharmacologically active agent” are used interchangeably herein and are defined to include any agent, drug, compound, composition of matter or mixture that provides some pharmacologic, often beneficial, effect that can be demonstrated in-vivo or in vitro. This includes foods, food supplements, nutrients, nutraceuticals, drugs, proteins, vaccines, antibodies, vitamins, and other beneficial agents. As used herein, these terms further include any physiologically or pharmacologically active substance that produces a localized or systemic effect in a patient.

“Pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” refers to an excipient that can be included in the compositions of the invention and that causes no significant adverse toxicological effects to the patient.

“Pharmacologically effective amount,” “physiologically effective amount,” and “therapeutically effective amount” are used interchangeably herein to mean the amount of a polymer-active agent conjugate, typically present in a pharmaceutical preparation, that is needed to provide a desired level of active agent and/or conjugate in the bloodstream or in a target tissue. The exact amount will depend upon numerous factors, e.g., the particular active agent, the components and physical characteristics of the pharmaceutical preparation, intended patient population, patient considerations, and the like, and can readily be determined by one of ordinary skill in the art, based upon the information provided herein and available in the relevant literature.

The term “patient” refers to a living organism suffering from or prone to a condition that can be prevented or treated by administration of a conjugate as provided herein, and includes both humans and animals.

II. Carbohydrate-Based Reagents

Because of their very low toxicity and immunogenicity, carbohydrate polymers are attractive candidates for use in conjugating to biologically active molecules for drug delivery. However, because carbohydrates are generally very large polydisperse polymers with hundreds or even thousands of reactive functional groups, controlling the degree of functionality and the polydispersity are important considerations in such applications of carbohydrates.

Carbohydrate polymers, which may also be referred to as polysaccharides, include naturally occurring polysaccharides and materials derived from naturally occurring polysaccharides. Water soluble polymers are preferred. Well known examples are dextran, glycogen, and amylose, as well as chitosan (deacetylated chitin), which is a positively charged carbohydrate. The polymers can be obtained in a large range of molecular weights. For the present application, molecular weights in the range of 200 Da to 2,000,000 Da are contemplated, depending on the intended use of the carbohydrate reagent. Molecular weights such as 5 KDa, 10 KDa, 20 KDa, 40 KDa, and 70 KDa, for example, are typical.

Dextran is one of the most important polysaccharides for medical and industrial applications. It is produced primarily from sucrose by bacterial strains and structurally is a poly(glucose) having an α-(1-6) linked D-glucose main chain. It is commercially available in a variety of molecular weights, though generally with high polydispersity values.

Several existing dextran derivatives, used mainly for modification of small molecular weight drugs, are based on activation of hydroxyl groups present in each repeating unit of the polymer. This type of activation is not suitable for the single point attachment of a drug moiety; thus it is not applicable to protein modification, where a polymer having only one active group on the polymer chain is desired.

Chitosan, a carbohydrate polymer formed by deacetylation of the naturally occurring chitin, is particularly useful in certain drug delivery applications because it is a cationic polymer, having an amine group on each repeating unit.

The present disclosure is directed to monofunctional carbohydrate reagents for drug conjugation, prepared by activation of the reducing end (i.e. the anomeric carbon) of carbohydrates such as dextran. As is well known for aldoses in general, the reducing terminus of dextran can be represented in the closed ring acetal (pyranose) form or the open-chain aldehyde form, as follows:

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where the aldehyde carbon is the anomeric carbon. A similar conversion between closed ring forms (pyranose or furanose) and open chain (keto) forms exists for ketoses, where the open chain form terminates in —C(O)—CH₂OH.

Particular embodiments of the monofunctional carbohydrate polymers of the invention are described in the following sections. The terms “monoderivatized” and “monofunctional” in this context may be used interchangeably and refer to the fact that the carbohydrate polymer is modified such that it may be selectively conjugated at a single location, in this case a single terminus bearing a functional group.

A. Monocarboxylic Acid and Carboxylic Acid Derivatives

In one embodiment, a water soluble carbohydrate polymer terminating in a aldose group, such as dextran, is selectively oxidized at the reductive end of the polymer under mild conditions, effective to produce a single carboxylic acid functionality, without modifying the remaining structure of the polymer. The monoacid dextran reagent is designated (1) herein.

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Suitable oxidation conditions include iodine (I₂) and a hydroxide base, e.g. NaOH, such as described in Examples 1, 3, and 5 below. In general, oxidation conditions are such that the ratio of the desired monocarboxylic acid product to overoxidized side products (such as polymer oxidized at internal sites, including cleaved chain products) is greater than 15:1, preferably greater than 25:1, and more preferably greater than 50:1. Thus, the molecular weight of the oxidized polymer is essentially unchanged. Furthermore, the ratio of desired monocarboxylic acid product to dicarboxylic acid product is preferably greater than 25:1. The total conversion is preferably greater than 70-80%; that is, less than 20-30% of unreacted dextran remains. For example, the conditions described in Example 5 below produced a reaction mixture containing 3.1% of dextran diacid, 83.9% of dextran monoacid, and 13.0% of unreacted dextran. The procedure is effective on higher molecular weight water soluble carbohydrate polymers, as shown for dextran having a molecular weight of 40,000 in Examples 3 and 5.

Further to this embodiment, the polydispersity of a carbohydrate polymer can be significantly reduced by purifying the monocarboxylic product, prepared as described above, by ion exchange chromatography. A demonstration of the process using dextran (40K) monocarboxylic acid, designated herein as (1b), is given in Example 4. In another instance, a dextran monocarboxylic acid having a polydispersity of 2.34 was obtained from a starting dextran (molecular weight 6 KDa) having a polydispersity of 3.27 by mild oxidation, as described herein, followed by ion exchange chromatography.

Preferred polydispersities are less than 2.5, preferably less than 2.0, and more preferably less than 1.5. In some embodiments, polydispersities may be less than 1.35, or less than 1.20.

The low polydispersity carbohydrate monocarboxylic acid also provides access to a range of low polydispersity carbohydrate carboxylic acid derivatives. Such derivatives and their preparation are well known in the art and include functionalities such as ester, activated ester, thioester, anhydride, amide, acid halide, nitrile, carbamate, carbonate, isocyanate, and isothiocyanate. These can of course be further converted to any number of different functionalities by well known methods. Thus, for example, with appropriate linkers, carboxylic acids are readily converted into useful reactive groups such as maleimides, aldehydes, and active disulfides, e.g. orthopyridyl disulfides (OPPS).

B. Monoderivatization with Heterobifunctional Oxyamines or Hydrazines

In a further embodiment, a heterobifunctional reagent comprising, at one terminus, a highly nucleophilic amine such as an oxyamine or hydrazine is selectively reacted with the reductive end of a carbohydrate polymer, preferably the aldehyde end of an aldose. The other terminus of the reagent bears a different functional group (i.e., not an oxyamine or hydrazine) that is either protected or is otherwise unreactive under the conditions of the reaction. Such reactions produce oxyimine or hydrazone linkages, as shown in the scheme below, to the carbohydrate moiety, with a distinct functional group, indicated by G¹, where L¹is a linker as described below, at the new terminus. Because of the presence of the heterogroup, X (which may also be sulfur) adjacent the C═N bond, these linkages are generally stable except to certain acid-catalyzed hydrolytic procedures. If more stability is desired, the product may be further converted in a reduction step, as also shown in the scheme below.

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Accordingly, the invention provides a monofunctional water-soluble carbohydrate-based reagent having the structure

POLY¹-C^a(H)_x(R¹) custom-character N(R³)_x—X-L¹-G¹ (IV)

where:

POLY¹is a water-soluble carbohydrate polymer having a terminal anomeric carbon atom, where C^ais said terminal anomeric carbon atom;

custom-character represents a double bond when x=0 and a single bond when x=1;

R¹is H or hydroxymethyl;

X is oxygen or NR², where R²is hydrogen, methyl, lower alkyl, cycloalkyl, or aryl, and is preferably H or methyl, and more preferably H;

R³is H or methyl, and is typically H;

L¹is a linker group, and

G¹is a functional group, in reactive or protected form, not selected from oxyamine and hydrazine.

In selected embodiments, X is oxygen (an oxyamine reagent) or NR², e.g. NH₂(a hydrazine reagent). X may also be sulfur.

A particularly useful embodiment is that in which G¹is a carboxyl group. For example, the reaction of O-(carboxymethyl)hydroxylamine with dextran gives dextran-O-(carboxymethyl)oxyimine, designated herein as (2), as described in Example 6. In this case, L¹is an alkylene (methylene) linker.

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In another example, a reagent containing an oxyamine group connected by an oligo(ethylene glycol)-alkylene linker to a butanoic acid group can be used to provide a butanoic acid having an extended linker to the polysaccharide, as shown in Example 8 below. The dextran reagent is designated herein as (7). Such reagents can be purified to low polydispersities by ion exchange chromatography.

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In further embodiments, additional heterobifunctional reagents having linkers based on oligomers, e.g. tetraethylene glycol, attached to having highly nucleophilic amines, such as hydrazines or oxyamines, are used to prepare a variety of polysaccharide reagents. These reagents include an optionally protected functional group that may ultimately be activated for reaction with a drug moiety. For example, preparation of a protected aldehyde-terminated dextran reagent, oxyimine-linked dextran butyraldehyde (16), is described in Example 13.

The hydroxy-imine moiety in these reagents may rearrange to an amino ketone moiety, as shown in the scheme below.

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C. Linker Moieties

As described above, the reagents disclosed herein may include a linker moiety, designated L¹. A linker may be used to connect polymer segments making up the component POLY to each other.

A linker is typically but is not necessarily linear in nature. The overall length of the linker will typically range between 1 to about 40 atoms, where by length is meant the number of atoms in a single chain, not counting substituents. For instance, —CH₂— counts as one atom with respect to overall linker length, and —CH₂CH(CH₃)O— counts as 3 atoms in length. Preferably, a linker will have a length of about 1 to about 20 atoms, or, more preferably, from about 2 to about 15 atoms; e.g. 3 to 8 atoms.

Illustrative linkers are those corresponding to either of the following structures: —(CH₂)_c-D_e-(CH₂)_f— or —(CH₂)_p-M_r-C(O)—K_s—(CH₂)_q—; where c is 0 to 8; “D” is O, NH, or S; e is 0 or 1; f is 0 to 8; p is 0 to 8; “M” is —NH or 0; “K” is NH or 0; q is 0 to 8, and r and s are each independently 0 or 1.

Other exemplary linker moieties include, but are not limited to, the following: —O—, —S—, —C(O)—, —S(O₂)—, —S(O)—, —NH—S(O₂)—, —S(O₂)—NH—, —CH═CH—, —O—CH═CH—, —C(O)—NH—, —NH—C(O)—NH—, —O—C(O)—NH—, —C(S)—, —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—, —CH₂—O—, —O—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—, —CH₂—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—CH₂—, —CH₂—CH₂—CH₂—CH₂—O—, —S—CH₂—, —CH₂—S—, —CH₂—S—CH₂—, —CH₂—CH₂—S—, —S—CH₂—CH₂—CH₂—, —CH₂—S—CH₂—CH₂—, —CH₂—CH₂—S—CH₂—, —CH₂—CH₂—CH₂—S—, —S—CH₂—CH₂—CH₂—CH₂—, —CH₂—S—CH₂—CH₂—CH₂—, —CH₂—CH₂—S—CH₂—CH₂—, —CH₂—CH₂—CH₂—S—CH₂—, —CH₂—CH₂—CH₂—CH₂—S—, —C(O)—NH—CH₂—, —C(O)—NH—CH₂—CH₂—, —CH₂—C(O)—NH—CH₂—, —CH₂—CH₂—C(O)—NH—, —C(O)—NH—CH₂—CH₂—CH₂—, —CH₂—C(O)—NH—CH₂—CH₂—, —CH₂—CH₂—C(O)—NH—CH₂—, —CH₂—CH₂—CH₂—C(O)—NH—, —C(O)—NH—CH₂—CH₂—CH₂—CH₂—, —CH₂—C(O)—NH—CH₂—CH₂—CH₂—, —CH₂—CH₂—C(O)—NH—CH₂—CH₂—, —CH₂—CH₂—CH₂—C(O)—NH—CH₂—, —CH₂—CH₂—CH₂—C(O)—NH—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—C(O)—NH—, —NH—C(O)—CH₂—C(O)—NH—, —NH—C(O)—CH₂—CH₂—C(O)—NH—, —NH—C(O)—CH₂—CH₂—CH₂—C(O)—NH—, —NH—C(O)—CH₂—CH₂—CH₂—CH₂—C(O)—NH—, —NH—C(O)—CH═CH—C(O)—NH—, —C(O)—O—CH₂—, —CH₂—C(O)—O—CH₂—, —CH₂—CH₂—C(O)—O—CH₂—, —C(O)—O—CH₂—CH₂—, —NH—C(O)—CH₂—, —CH₂—NH—C(O)—CH₂—, —CH₂—CH₂—NH—C(O)—CH₂—, —NH—C(O)—CH₂—CH₂—, —CH₂—NH—C(O)—CH₂—CH₂—, —CH₂—CH₂—NH—C(O)—CH₂—CH₂—, —C(O)—NH—CH₂—, —C(O)—NH—CH₂—CH₂—, —O—C(O)—NH—CH₂—, —O—C(O)—NH—CH₂—CH₂—, —NH—CH₂—, —NH—CH₂—CH₂—, —CH₂—NH—CH₂—, —CH₂—CH₂—NH—CH₂—, —C(O)—CH₂—, —C(O)—CH₂—CH₂—, —CH₂—C(O)—CH₂—, —CH₂—CH₂—C(O)—CH₂—, —CH₂—CH₂—C(O)—CH₂—CH₂—, —CH₂—CH₂—C(O)—, —CH₂—CH₂—CH₂—C(O)—NH—CH₂—CH₂—NH—, —CH₂—CH₂—CH₂—C(O)—NH—CH₂—CH₂—NH—C(O)—, —CH₂—CH₂—CH₂—C(O)—NH—CH₂—CH₂—NH—C(O)—CH₂—, —CH₂—CH₂—CH₂—C(O)—NH—CH₂—CH₂—NH—C(O)—CH₂—CH₂—, bivalent cycloalkyl, and amino acids.

Also included are —N(R⁶)—, where R⁶is H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl; and —NH—C(O)—O—(CH₂)_h—(OCH₂CH₂)_j— or —O—C(O)—NH—(CH₂)_h—(OCH₂CH₂)_j—, where (h) is zero to six, and (j) is zero to 20. Other specific spacer moieties have the following structures: —C(O)—NH—(CH₂)_1-6—NH—C(O)—, —NH—C(O)—NH—(CH₂)_1-6—NH—C(O)—, and —O—C(O)—NH—(CH₂)_1-6—NH—C(O)—, wherein the subscript values following each methylene indicate the number of methylenes contained in the structure, e.g., (CH₂)_1-6means that the structure can contain 1, 2, 3, 4, 5 or 6 methylenes.

A linker may include combinations of two or more of any of the foregoing.

In the reagents and/or conjugates of structures I-V herein, the linker preferably includes a carbon atom attached to the atom X (generally oxygen or nitrogen), which may be part of, for example, an alkyl or alkylene group, or a carbonyl carbon. A linker can comprise a single functional group such as an amide, an ester, a urethane (carbamate), or a urea, preferably containing contain methylene or other alkylene groups flanking one or both sides of the functional group. Alternatively, a linker may contain a combination of functional groups, which can be the same or different. A linker can be an alkylene chain, optionally containing one or more oxygen or sulfur atoms (i.e., an ether or thioether linkage). Also included are alkylene chains containing a nitrogen atom (i.e. an amine linkage.)

Preferably, the linker is hydrolytically stable, and may contain one or more of the following functional groups: amide, urethane, ether, thioether, or urea. However, hydrolytically degradable linkages, such as carboxylate ester, phosphate ester, orthoester, anhydride, imine, acetal, ketal, oligonucleotide, or peptide, may also be present.

Additionally, any of the above spacer moieties may further include an ethylene oxide oligomer chain comprising 1 to 20 ethylene oxide monomer units (i.e., —(CH₂CH₂O)_1-20). That is, the ethylene oxide oligomer chain can occur before or after the spacer moiety, and optionally in between any two atoms of a spacer moiety comprised of two or more atoms.

D. Functional Groups

As described above, the reagents of structures I-IV include a functional group G¹which is useful for forming a conjugate of the polymer, e.g., with a pharmacologically active agent, surface, solid support, or the like. The functional group typically comprises an electrophilic or nucleophilic group that provides for covalent attachment of a desired agent to the carbohydrate polymer.

Preferred nucleophilic groups include amine, hydroxy, and thiol, particularly amine.

Examples of electrophilic functional groups include carboxylic acid, carboxylic ester, particularly imide esters, orthoester, carbonate, isocyanate, isothiocyanate, aldehyde, ketone, thione, alkenyl, acrylate, methacrylate, acrylamide, sulfone, maleimide, disulfide, iodo, epoxy, sulfonate, thiosulfonate, silane, alkoxysilane, halosilane, and phosphoramidate. More specific examples of these groups include succinimidyl ester or carbonate, imidazoyl ester or carbonate, benzotriazole ester or carbonate, vinyl sulfone, chloroethylsulfone, vinylpyridine, pyridyl disulfide, iodoacetamide, glyoxal, dione, mesylate, tosylate, and tresylate (2,2,2-trifluoroethanesulfonate).

Also included are sulfur analogs of several of these groups, such as thione, thione hydrate, thioketal, etc., as well as hydrates or protected derivatives of any of the above moieties (e.g. aldehyde hydrate, hemiacetal, acetal, ketone hydrate, hemiketal, ketal, thioketal, thioacetal). Another useful conjugation reagent is 2-thiazolidine thione.

The term “carboxylic acid derivative” encompasses various functional groups that include a carbonyl group with an attached heteroatom, such as ester, thioester, anhydride, amide, acid halide, nitrile, carbamate, carbonate, isocyanate, and isothiocyanate. An “activated derivative” of a carboxylic acid refers to a carboxylic acid derivative which reacts readily with nucleophiles, generally much more readily than the underivatized carboxylic acid. Activated carboxylic acids include, for example, acid halides (such as acid chlorides), anhydrides, carbonates, and esters. Such esters (referred to as active or activated esters) include imide esters, of the general form —(CO)O—N[(CO)—]₂; for example, N-hydroxysuccinimidyl (NHS) esters or N-hydroxyphthalimidyl esters. Also preferred are imidazolyl esters and benzotriazole esters. Particularly preferred are activated propionic acid or butanoic acid esters, as described in co-owned U.S. Pat. No. 5,672,662. These include groups of the form —(CH₂)_2-3C(═O)O-Q, where Q is preferably selected from N-succinimide, N-sulfosuccinimide, N-phthalimide, N-glutarimide, N-tetrahydrophthalimide, N-norbornene-2,3-dicarboximide, benzotriazole, 7-azabenzotriazole, and imidazole.

Other preferred electrophilic groups include succinimidyl carbonate, maleimide, benzotriazole carbonate, glycidyl ether, imidazoyl carbonate, p-nitrophenyl carbonate, acrylate, tresylate, aldehyde, and orthopyridyl disulfide.

These electrophilic groups are subject to reaction with nucleophiles, e.g. hydroxy, thio, or amino groups, to produce various bond types. For example, carboxylic acids and activated derivatives thereof, which include orthoesters, succinimidyl esters, imidazolyl esters, and benzotriazole esters, react with the above types of nucleophiles to form esters, thioesters, and amides, respectively, of which amides are the most hydrolytically stable. Carbonates, including succinimidyl, imidazolyl, and benzotriazole carbonates, will react with hydroxyl or amino groups to form further carbonates or carbamates, respectively. Isocyanates (R—N═C═O) react with hydroxyl or amino groups to form, respectively, carbamate (RNH—C(O)—OR′) or urea (RNH—C(O)—NHR′) linkages. Phosphoramidites can be reacted with hydroxyl reagents, followed by oxidation, to form phosphate esters (as in conventional oligonucleotide synthesis).

Aldehydes, ketones, glyoxals, diones and their hydrates or alcohol adducts (i.e. aldehyde hydrate, hemiacetal, acetal, ketone hydrate, hemiketal, and ketal) are preferably reacted with amines, followed by reduction of the resulting imine, if desired, to give an amine linkage (reductive amination). Alternatively, these groups can be reacted with hydroxyl containing groups, to form further acetals, ketals, etc. In this cases, the linkages formed are subject to hydrolytic degradation, which may be desirable, as discussed further below.

Several of the electrophilic functional groups include electrophilic double bonds to which nucleophilic groups, such a thiols, can be added, to form, for example, thioether bonds. These groups include maleimides, vinyl sulfones, vinyl pyridine, acrylates, methacrylates, and acrylamides. Other groups comprise leaving groups which can be displaced by a nucleophile; these include chloroethyl sulfone, pyridyl disulfides (which include a cleavable S—S bond), iodoacetamide, mesylate, tosylate, thiosulfonate, and tresylate. Epoxides react by ring opening by a nucleophile, to form, for example, an ether or amine bond. Silanes, including halosilanes and alkoxysilanes, react with hydroxy- or oxide-containing compounds, or surfaces such as glass, to form siloxanes.

III. Conjugation Method

In accordance with the invention, methods of forming stable conjugates of monoderivatized carbohydrate polymers with biologically active molecules (e.g. drugs) are provided. Accordingly, the invention provides a method of conjugating a monoderivatized carbohydrate polymer with a target compound, the method comprising: reacting a reagent of structure(s) I, II or IV, having a terminal functional group G¹, or a reagent as described in section IIA above, having a terminal carboxylic acid or carboxylic acid derivative, with a biologically active molecule having a corresponding functional group, which is reactive with G¹or with said carboxylic acid or carboxylic acid derivative, to form a stable covalent bond between the reagent and the biologically active molecule.

Functional groups and corresponding functional group with which they are reactive are known in the art and include those described in section HD above. In one embodiment, the functional group on the biologically active molecule is an amine, as is common in protein conjugations.

In general, preferred embodiments of the method employ preferred embodiments of the reagents as described herein.

A. Reaction Conditions for Conjugation

Suitable solvents for carrying out the conjugation reaction include buffers such as aqueous sodium phosphate, sodium acetate, sodium carbonate, phosphate buffered saline (PBS), sodium borate, and N-(2-hydroxyethyl) piperazine-N′-(2-ethanesulfonic acid) (HEPES). For conjugation to a protein, the polymeric reagent is typically added to the protein-containing solution at an equimolar amount or at a molar excess relative to target protein. Molar excesses of carbohydrate reagent relative to target protein are typically in the range of about 2 to 50, preferably in the range of 2 to 20, and most preferably in the range of 2 to 5. The conjugation reaction is typically carried out at temperatures at or below about room temperature (25° C.), although temperatures may range from about −15° C. to about 100° C., more preferably from about 4° C. to 37° C., for approximately one to 24 hours. Exemplary conjugation reactions are described in Examples 14 and 16-18 below.

Conditions for conjugation to a small molecule, e.g. amphotericin B or other amine-containing molecules as discussed below, will vary according to the small molecule being modified. Typically, however, the conjugation is conducted using a slight molar excess of polymeric reagent relative to small molecule, e.g., about 1.2-1.5, to about a 5 to 10-fold molar excess. In some instances, depending upon the molecule, the small molecule drug may actually be used in excess, such as when the carbohydrate-small molecule conjugate precipitates in the reaction solvent, e.g., ether, while the unreacted drug remains in solution.

The exact reaction time is determined by monitoring the progress of the reaction over time. Progress of the reaction is typically monitored by withdrawing aliquots from the reaction mixture at various time points and analyzing the reaction mixture by SDS-PAGE or MALDI-TOF mass spectrometry or any other suitable analytical method.

B. Characterization and Optional Separation of Conjugates

The strategy for purification of the final conjugate reaction mixture will depend upon a number of factors, such as the molecular weight of the polymer employed, the particular protein, and the residual activity and in vivo properties of the conjugate species.

Conjugates having different molecular weights can be isolated using gel filtration chromatography. Gel filtration columns suitable for carrying out this type of separation include Superdex® and Sephadex® columns available from Amersham Biosciences. Selection of a particular column will depend upon the desired fractionation range desired. Elution is generally carried out using a non-amine based buffer, such as phosphate, acetate, or the like. The collected fractions may be analyzed by a number of different methods, for example, (i) OD at 280 nm for protein content, (ii) BSA protein analysis, (iii) iodine testing for PEG content, or (iv) by running an SDS PAGE gel, followed by staining with barium iodide.

Carbohydrate polymers having carboxylic acid termini, prepared as described herein, can be purified by ion exchange chromatography, as demonstrated in the Examples below. This process can produce reagents having low polydispersities, an important feature for drug delivery.

Separation of positional isomers (i.e. conjugates having polymers attached to different locations on a protein), generally not achievable by molecular weight-based methods, can often be carried out by reverse phase chromatography using e.g. an RP-HPLC C18 column (Amersham Biosciences or Vydac).

C. Conjugation to Proteins: Random and N-Terminal Selective

Generally, the polymeric reagents of the invention can be used to selectively target the modification of the N-terminus of a protein, under conditions that differentiate the reactivity of the α-amine at the N-terminal amino acid. Reaction conditions for preparing an N-terminally modified protein or peptide include (i) dissolving the protein or peptide to be modified in a non-amine-containing buffer (e.g., at a pH range from about 4 to about 6.5, preferably from about 5 to 6.5, most preferably at a pH of about 5 to 5.5), (ii) adding to the protein or peptide solution a polymeric reagent (α-hydroxy aldehyde or ketone) of the invention, and (iii) allowing the protein or peptide and polymeric reagent to react to form the conjugate.

Reaction under conditions of higher pH can be used for random attachment of a polymeric reagent (α-hydroxy aldehyde or ketone). More specifically, to covalently attach a polymeric reagent to any number of lysine residues that are surface accessible, a protein or peptide (such as those exemplary biomolecules provided below) is typically reacted with a polymeric reagent of the invention in a non amine-containing buffer at mild pH, generally ranging from about 5 to 8, more preferably from about 6.5 to 8. Non-amine containing buffers are preferred, since the amino-groups in the buffer can compete with protein amino groups for coupling to the polymeric reagent. A suitable non-amine containing buffer is selected having an appropriate pK for the desired pH range for conducting the conjugation chemistry. The coupling reaction generally takes anywhere from minutes to several hours (e.g., from 5 minutes to 24 hours or more), and on average, coupling is achieved between about 0.2 and 4 hours.

The degree of modification, that is, the number of polymeric reagents that are covalently attached at available sites on the target molecule, can be increased by increasing, either independently or simultaneously, any one or more of: molar ratio of polymeric reagent to protein or peptide, temperature, reaction time, and pH.

IV. Polymeric Conjugates

In accordance with the invention, polymeric conjugates, comprising a reagent as disclosed herein conjugated to a biologically active molecule (e.g. drug), preferably a single such molecule, are provided. (In some cases, multiple carbohydrate polymers may be attached to a single biologically active molecule.) The conjugates are prepared by reaction of a reagent of structure(s) I, II or IV, having a terminal functional group G¹, or a reagent as described in section IIA above, having a terminal carboxylic acid or carboxylic acid derivative, with a biologically active molecule having a corresponding functional group, which is reactive with G¹or with said carboxylic acid or carboxylic acid derivative, to form a stable covalent bond between the reagent and the biologically active molecule.

Conjugates formed using reagents of structure IV thereby typically have the structure

POLY¹-C^a(H)_x(R¹) custom-character N(H)_x—X-L¹-G²-B

where

POLY¹is a water-soluble carbohydrate polymer having a terminal anomeric carbon atom, where Ca is said terminal anomeric carbon atom;

custom-character represents a double bond when x=0 and a single bond when x=1;

R¹is H or hydroxymethyl;

X is oxygen or NR², where R²is hydrogen, methyl, lower alkyl, cycloalkyl, or aryl;

L¹is a linker group, and

G²is a covalent bond comprising a residue or converted form of functional group G¹, following reaction with a corresponding functional group on biomolecule B.

Conjugates of dextran with several proteins (lysozyme, protegrin-1, C-peptide, and insulin), in accordance with the invention, is described in Examples 14 and 16-18 below. Biological activity of the dextran-insulin conjugate (designated 20b) in vitro and in vivo is described in Examples 19 and 20, respectively. Conjugation of chitosan with a single stranded RNA is described in Example 23.

V. The Conjugated Biologically Active Agent

The biologically active agent conjugated to a polymeric reagent of the invention may fall into one of a number of structural classes, including but not limited to small molecules (including difficulty soluble small molecules), peptides, polypeptides, proteins, polysaccharides, steroids, nucleotides, oligonucleotides, polynucleotides, fats, electrolytes, and the like. In one embodiment, the molecule either possesses a native amino group or is modified to contain at least one reactive amino group. As noted above, the working Examples below describe conjugates of the proteins lysozyme, protegrin-1, C-peptide, and insulin.

The agent may be a therapeutic substance selected from, for example, hypnotics and sedatives, psychic energizers, tranquilizers, respiratory drugs, anticonvulsants, muscle relaxants, antiparkinson agents (dopamine antagonists), analgesics, anti-inflammatories, antianxiety drugs (anxiolytics), appetite suppressants, antimigraine agents, muscle contractants, anti-infectives (antibiotics, antivirals, antifungals, vaccines) antiarthritics, antimalarials, antiemetics, anepileptics, bronchodilators, cytokines, growth factors, anti-cancer agents, antithrombotic agents, antihypertensives, cardiovascular drugs, antiarrhythmics, antioxicants, anti-asthma agents, hormonal agents including contraceptives, sympathomimetics, diuretics, lipid regulating agents, antiandrogenic agents, antiparasitics, anticoagulants, neoplastics, antineoplastics, hypoglycemics, nutritional agents and supplements, growth supplements, antienteritis agents, vaccines, antibodies, diagnostic agents, and contrasting agents.

Specific examples of active agents suitable for covalent attachment to a polymer of the invention include aspariginase, amdoxovir (DAPD), antide, becaplermin, calcitonins, cyanovirin, denileukin diftitox, erythropoietin (EPO), EPO agonists (e.g., peptides from about 10-40 amino acids in length and comprising a particular core sequence as described in WO 96/40749), dornase α, erythropoiesis stimulating protein (NESP), coagulation factors such as Factor V, Factor VII, Factor VIIa, Factor VIII, Factor IX, Factor X, Factor XII, Factor XIII, von Willebrand factor; ceredase, cerezyme, α-glucosidase, collagen, cyclosporin, alpha defensins, beta defensins, exedin-4, granulocyte colony stimulating factor (GCSF), thrombopoietin (TPO), α-1 proteinase inhibitor, elcatonin, granulocyte macrophage colony stimulating factor (GMCSF), fibrinogen, filgrastim, growth hormones human growth hormone (hGH), growth hormone releasing hormone (GHRH), GRO-beta, GRO-beta antibody, bone morphogenic proteins such as bone morphogenic protein-2, bone morphogenic protein-6, OP-1; acidic fibroblast growth factor, basic fibroblast growth factor, CD-40 ligand, heparin, human serum albumin, low molecular weight heparin (LMWH), interferons such as interferon alpha, interferon beta, interferon gamma, interferon omega, interferon tau, consensus interferon; interleukins and interleukin receptors such as interleukin-1 receptor, interleukin-2, interleukin-2 fusion proteins, interleukin-1 receptor antagonist, interleukin-3, interleukin-4, interleukin-4 receptor, interleukin-6, interleukin-8, interleukin-12, interleukin-13 receptor, interleukin-17 receptor; lactoferrin and lactoferrin fragments, luteinizing hormone releasing hormone (LHRH), insulin, pro-insulin, insulin analogues (e.g., mono-acylated insulin as described in U.S. Pat. No. 5,922,675), amylin, C-peptide, somatostatin, somatostatin analogs including octreotide, vasopressin, follicle stimulating hormone (FSH), influenza vaccine, insulin-like growth factor (IGF), insulintropin, macrophage colony stimulating factor (M-CSF), plasminogen activators such as alteplase, urokinase, reteplase, streptokinase, pamiteplase, lanoteplase, and teneteplase; nerve growth factor (NGF), osteoprotegerin, platelet-derived growth factor, tissue growth factors, transforming growth factor-1, vascular endothelial growth factor, leukemia inhibiting factor, keratinocyte growth factor (KGF), glial growth factor (GGF), T Cell receptors, CD molecules/antigens, tumor necrosis factor (TNF), monocyte chemoattractant protein-1, endothelial growth factors, parathyroid hormone (PTH), glucagon-like peptide, somatotropin, thymosin alpha 1, thymosin alpha 1 IIb/IIIa inhibitor, thymosin beta 10, thymosin beta 9, thymosin beta 4, alpha-1 antitrypsin, phosphodiesterase (PDE) compounds, VLA-4 (very late antigen-4), VLA-4 inhibitors, bisphosponates, respiratory syncytial virus antibody, cystic fibrosis transmembrane regulator (CFTR) gene, deoxyreibonuclease (Dnase), bactericidal/permeability increasing protein (BPI), and anti-CMV antibody. Exemplary monoclonal antibodies include etanercept (a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kD TNF receptor linked to the Fc portion of IgG1), abciximab, afeliomomab, basiliximab, daclizumab, infliximab, ibritumomab tiuexetan, mitumomab, muromonab-CD3, iodine 131 tositumomab conjugate, olizumab, rituximab, and trastuzumab (herceptin).

Additional agents suitable for covalent attachment to a polymer of the invention include but are not limited to amifostine, amiodarone, aminocaproic acid, aminohippurate sodium, aminoglutethimide, aminolevulinic acid, aminosalicylic acid, amsacrine, anagrelide, anastrozole, asparaginase, anthracyclines, bexarotene, bicalutamide, bleomycin, buserelin, busulfan, cabergoline, capecitabine, carboplatin, carmustine, chlorambucin, cilastatin sodium, cisplatin, cladribine, clodronate, cyclophosphamide, cyproterone, cytarabine, camptothecins, 13-cis retinoic acid, all trans retinoic acid; dacarbazine, dactinomycin, daunorubicin, deferoxamine, dexamethasone, diclofenac, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estramustine, etoposide, exemestane, fexofenadine, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, epinephrine, L-Dopa, hydroxyurea, idarubicin, ifosfamide, imatinib, irinotecan, itraconazole, goserelin, letrozole, leucovorin, levamisole, lisinopril, lovothyroxine sodium, lomustine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, metaraminol bitartrate, methotrexate, metoclopramide, mexiletine, mitomycin, mitotane, mitoxantrone, naloxone, nicotine, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, pilcamycin, porfimer, prednisone, procarbazine, prochlorperazine, ondansetron, raltitrexed, sirolimus, streptozocin, tacrolimus, tamoxifen, temozolomide, teniposide, testosterone, tetrahydrocannabinol, thalidomide, thioguanine, thiotepa, topotecan, tretinoin, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, dolasetron, granisetron; formoterol, fluticasone, leuprolide, midazolam, alprazolam, amphotericin B, podophylotoxins, nucleoside antivirals, aroyl hydrazones. sumatriptan; macrolides such as erythromycin, oleandomycin, troleandomycin, roxithromycin, clarithromycin, davercin, azithromycin, flurithromycin, dirithromycin, josamycin, spiromycin, midecamycin, leucomycin, miocamycin, rokitamycin, andazithromycin, and swinolide A; fluoroquinolones such as ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, alatrofloxacin, moxifloxicin, norfloxacin, enoxacin, grepafloxacin, gatifloxacin, lomefloxacin, sparfloxacin, temafloxacin, pefloxacin, amifloxacin, fleroxacin, tosufloxacin, prulifloxacin, irloxacin, pazufloxacin, clinafloxacin, and sitafloxacin; aminoglycosides such as gentamicin, netilmicin, paramecin, tobramycin, amikacin, kanamycin, neomycin, streptomycin, vancomycin, teicoplanin, rampolanin, mideplanin, colistin, daptomycin, gramicidin, colistimethate; polymixins such as polymixin B, capreomycin, bacitracin, penems; penicillins including penicllinase-sensitive agents such as penicillin G and penicillin V; penicllinase-resistant agents such as methicillin, oxacillin, cloxacillin, dicloxacillin, floxacillin, and nafcillin; gram negative microorganism active agents such as ampicillin, amoxicillin, and hetacillin, cillin, and galampicillin; antipseudomonal penicillins such as carbenicillin, ticarcillin, azlocillin, mezlocillin, and piperacillin; cephalosporins such as cefpodoxime, cefprozil, ceftbuten, ceflizoxime, ceftriaxone, cephalothin, cephapirin, cephalexin, cephradrine, cefoxitin, cefamandole, cefazolin, cephaloridine, cefaclor, cefadroxil, cephaloglycin, cefuroxime, ceforamide, cefotaxime, cefatrizine, cephacetrile, cefepime, cefixime, cefonicid, cefoperazone, cefotetan, cefinetazole, ceftazidime, loracarbef, and moxalactam; monobactams such as aztreonam; and carbapenems such as imipenem, meropenem, pentamidine isethiouate, albuterol sulfate, lidocaine, metaproterenol sulfate, beclomethasone diprepionate, triamcinolone acetamide, budesonide acetonide, fluticasone, ipratropium bromide, flunisolide, cromolyn sodium, and ergotamine tartrate; taxanes such as paclitaxel; SN-38, and tyrphostines.

Preferred small molecules for coupling to a polymeric reagent of the invention are those having at least one amino group. Preferred molecules include aminohippurate sodium, amphotericin B, doxorubicin, aminocaproic acid, aminolevulinic acid, aminosalicylic acid, metaraminol bitartrate, pamidronate disodium, daunorubicin, levothyroxine sodium, lisinopril, cilastatin sodium, mexiletine, cephalexin, deferoxamine, and amifostine.

Preferred peptides or proteins for coupling to a polymeric reagent of the invention include EPO, IFN-alpha, IFN-beta, IFN-gamma, consensus IFN, Factor VII, Factor VIII, Factor IX, IL-2, remicade (infliximab), Rituxan (rituximab), Enbrel (etanercept), Synagis (palivizumab), Reopro (abciximab), Herceptin (trastuzimab), tPA, Cerizyme (imiglucerase), Hepatitus-B vaccine, rDNAse, alpha-1 proteinase inhibitor, GCSF, GMCSF, hGH, insulin, FSH, an PTH.

TABLE 1

This table lists the SEQ ID NOs., names, sequences, and known or suspected therapeutic

activities of various peptides described herein. The SEQ ID NOs. 1-301 describe sequences

that are required to be provided with the Sequence Listing and are therefore appended with

the instant Specification. In some instances, these peptides contain features that are

either inconsistent with or not amenable to inclusion in the Sequence Listing. For example,

a sequence with less than four-amino acids; a sequence with a D-amino acid; or certain

modification that cannot be described in the Sequence Listing presently, and therefore are

not provided in the Sequence Listing. However, for the ease of use and description, a SEQ

ID NO. has been provided to these peptides (i.e., SEQ ID NOs: 302-469).

SEQ

ID

Therapeutic

NO:
Name
Family
Sequence and/or other Identifying Information
Activity

1
carperitide
ANP
SLRRSSCFGGRMDRIGAQSGLGCNSFRY;
Cardiostimulant

human alpha-atrial natriuretic peptide;
Respiratory

Atriopeptin-28 (human);

2
alpha-neo-
Endorphin
H-Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro-Lys-OH
Analgesic,

endorphin

other

3
A-3847
Insulin
gi|386828|gb|AAA59172.1| insulin [Homo sapiens]
Antidiabetic

MALWMRLLPLLALLALWGPDPAAAFVNQHLCGSHL

VEALYLVCGERGFFYTPKTRREAEDLQVGQVELGGG

PGAGSLQPLALEGSLQKRGIVEQCCTSICSLYQLENYCN

4
A-4114
Insulin
MALWMRLLPLLALLALWGPDPAAAFVNQHLCGSHLV
Antidiabetic

EALYLVCGERGFFYTPKTRREAEDLQVGQVELGG

5
A-68552

GPGAGSLQPLALEGSLQKRGIVEQCCTSICSLYQLENYCN
Anorectic/

Antiobesity

302
A-75998

[Ac-D-2Nal1-D-4ClPhe2-D-3Pal3-NMeTyr5-D-
Releasing

and

Lys(Nic)6-Lys(Isp)8-D-Ala10]GnRH;
hormone

303

N-acetyl-D-2-naphthylalanyl-D-4-
Reproductive/

chlorophenylalanyl-D-3-pyridylalanyl-seryl-N-
gonadal,

methyltyrosyl-D-N(epsilon)-nicotinyllysyl-
general

leucyl-N(epsilon)-isopropyllysyl-prolyl-

alaninamide acetate

6
AN-1792
beta-
gi|8176533|gb|AAB26264.2| beta-amyloid peptide
Cognition

amyloid
precursor; beta APP [Homo sapiens]
enhancer

peptide
GSGLTNIKTEEISEVKMDAEFRHDSGYEVHHQKLVFFA

EDVGSNKGAIIGLMVGGVVIATVIIITLVMLK

KQYTSNHHGVVE

7
AAMP-1

MESESESGAAADTPPLETLSFHGDEEIIEVVELDPGPPD
Anticoagulant

PDDLAQEMEDVDFEEEEEEEGNEEGWVLEPQEGVVG
Anti-

SMEGPDDSEVTFALHSASVFCVSLDPKTNTLAVTGGE
inflammatory

DDKAFVWRLSDGELLFECAGHKDSVTCAGFSHDSTLV
Immunological

ATGDMSGLLKVWQVDTKEEVWSFEAGDLEWMEWH
Anticancer,

PRAPVLLAGTADGNTWMWKVPNGDCKTFQGPNCPAT
other

CGRVLPDGKRAVVGYEDGTIRIWDLKQGSPIHVLKGT
Vulnerary

EGHQGPLTCVAANQDGSLILTGSVDCQAKLVSATTGK

VVGVFRPETVASQPSLGEGEESESNSVESLGFCSVMPL

AAVGYLDGTLAIYDLATQTLRHQCQHQSGIVQLLWEA

GTAVVYTCSLDGIVRLWDARTGRLLTDYRGHTAEILDF

ALSKDASLVVTTSGDHKAKVFCVQRPDR

8
Exenatide
GLP-1
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS
Antidiabetic

Anorectic/

Antiobesity

9
AC-625

Acetyl-ATQRLANELVRLQTYPRTNVGSNTY-NH₂
Anti-

hypertensive,

renin system

Symptomatic

antidiabetic

10
ACTH

gi|80861463|ref|NP_001030333.1|
Adrenal and

proopiomelanocortin preproprotein
pituitary

[Homo sapiens]
disorders

MPRSCCSRSGALLLALLLQASMEVRGWCLESSQCQDL

TTESNLLECIRACKPDLSAETPMFPGNGDEQPLTENPR

KYVMGHFRWDRFGRRNSSSSGSSGAGQKREDVSAGE

DCGPLPEGGPEPRSDGAKPGPREGKRSYSMEHFRWGK

PVGKKRRPVKVYPNGAEDESAEAFPLEFKRELTGQRL

REGDGPDGPADDGAGAQADLEHSLLVAAEKKDEGPY

RMEHFRWGSPPKDKRYGGFMTSEKSQTPLVTLFKNAII

KNAYKKGE

11
AIDS

gi|288842|emb|CAA78890.1| V3 loop [Human
Therapeutic

therapeutic

immunodeficiency virus type 1]
vaccine

vaccine

CTRPSNNTRKSIPVGPGKALYATGAIIGNIRQAHC

12
AIDS

gi|5081475|gb|AAD39400.1|AF128998_1 gag
Antiviral,

therapy

[Human immunodeficiency virus type 1]
anti-HIV

MGARASVLSGGKLDKWEKIRLRPGGKKTYQLKHIVW

ASRELERFAVNPGLLETGGGCKQILVQLQPSLQTGSEE

LKSLYNAVATLYCVHQGIEVRDTKEALDKIEEEQNKSK

KKAQQAAADTGNSSQVSQNYPIVQNLQGQMVHQAIS

PRTLNAWVKVIEEKAFSPEVIPMFSALSEGATPQDLNT

MLNTVGGHQAAMQMLKETINEEAAEWDRLHPAHAG

PNAPGQMREPRGSDIAGTTSTLQEQIGWMTSNPPVPV

GEIYKRWIILGLNKIVRMYSPVSILDIRQGPKEPFRDYV

DRFYKTLRAEQASQDVKNWMTETLLVQNANPDCKTI

LKALGPAATLEEMMTACQGVGGPSHKARILAEAMSQ

VTSPANIMMQRGNFRNQRKTIKCFNCGKEGHLARHC

RAPRKKGCWKCGREGHQMKDCTERQANFLGKIWPS

HKGRPGNFLQSRPEPTAPPEESFRFGEETTTPPQKQEPL

PSQKQETIDKDLYPLASLKSLFGNDPSLQ

13
Allotrap-2702

Allotrap 1258; Allotrap 2702; Allotrap E;
Immunosuppres-

and

Allotrap G; RDP58; peptide Bc-1nl;
sant

14

NLRIALR/RLAIRLN

15
Alzheimer's

H-DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVV-OH;
Imaging agent

and
imaging agent

or H-DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA-

16

OH

17
AM-425

gi|4504991|ref|NP_002300.1| leukemia inhibitory
Antiarthritic,

factor (cholinergic differentiation factor)
immunological

[Homo sapiens]

MKVLAAGVVPLLLVLHWKHGAGSPLPITPVNATCAIR

HPCHNNLMNQIRSQLAQLNGSANALFILYYTAQGEPFP

NNLDKLCGPNVTDFPPFHANGTEKAKLVELYRIVVYL

GTSLGNITRDQKILNPSALSLHSKLNATADILRGLLSNV

LCRLCSKYHVGHVDVTYGPDTSGKDVFQKKKLGCQL

LGKYKQIIAVLAQAF

304
AN-238

L-Threoninamide, N-[5-[2-[(2S,4S)-
Somatostatin

l,2,3,4,6,ll-hexahydro-2,5,12-trihydroxy-7-
Anticancer,

methoxy-6,11-dioxo-4-[[2,3,6-trideoxy-3-
hormonal

(2,3-dihydro-1H-pyrrol-1-yl)-alpha-L-lyxo-

hexopyranosyl]oxy]-2-naphthacenyl]-2-

oxoethoxy]-1,5-dioxopentyl]-D-phenylalanyl-L-

cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-

valyl-L-cysteinyl-, cyclic (2-7)-disulfide

305
AV-9

[D-Arg]9-NH₂
Antiviral, other

8
AZM-134
GLP-1
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS
Anorectic/

Antiobesity

Antidiabetic

18
Addressin

gi|109633022|ref|NP_570116.2| mucosal vascular
Recombinant,

addressin cell adhesion molecule 1 isoform a
other

precursor [Homo sapiens]
Anti-

MDFGLALLLAGLLGLLLGQSLQVKPLQVEPPEPVVAV
inflammatory

ALGASRQLTCRLACADRGASVQWRGLDTSLGAVQSD

TGRSVLTVRNASLSAAGTRVCVGSCGGRTFQHTVQLL

VYAFPDQLTVSPAALVPGDPEVACTAHKVTPVDPNALS

FSLLVGGQELEGAQALGPEVQEEEEEPQGDEDVLFRV

TERWRLPPLGTPVPPALYCQATMRLPGLELSHRQAIPV

LHSPTSPEPPDTTSPESPDTTSPESPDTTSQEPPDTTSPE

PPDKTSPEPAPQQGSTHTPRSPGSTRTRRPEISQAGPTQ

GEVIPTGSSKPAGDQLPAALWTSSAVLGLLLLALPTYH

LWKRCRHLAEDDTHPPASLRLLPQVSAWAGLRGTGQVGISPS

306
ambamustine

L-Methionine, N-[3-[bis(2-chloroethyl)amino]-
Anticancer,

N-(4-fluoro-L-phenylalanyl)-L-phenylalanyl]-,
alkylating

ethyl ester
Anticancer,

antimetabolite

19
amylin

DTTVSEPAPSCVTLYQSWRYSQADNGCAETVTVKVV
Antidiabetic

antagonists

YEDDTEGLCYAVAPGQITTVGDGYIGSHGHARYLARCL

20
anaritide
ANP
gi|178638|gb|AAA35529.1| atrial natriuretic
Antihyperten-

analogues

peptide
sive,

MSSFSTTTVSFLLLLAFQLLGQTRANPMYNAVSNADL
diuretic

MDFKNLLDHLEEKMPLEDEVVPPQVLSDPNEEAGAA

LSPLPEVPPWTGEVSPAQRDGGALGRGPWDSSDRSAL

LKSKLRALLTAPRSLRRSSCFGGRMDRIGAQSGLGCNSFRY

21-
anti-

As diclosed in U.S. Pat. No. 5,470,831:
Anti-

28
inflammatory

Thr-Thr-Ser-Gln-Val-Arg-Pro-Arg
inflammatory

peptides

Val-Lys-Thr-Thr-Ser-Gln-Val-Arg-Pro-Arg.
Immunosuppres-

Ser-Gln-Val-Arg-Pro-Arg
sant Multiple

Val-Arg-Pro-Arg
sclerosis

Thr-Thr-Ser-Gln-Val-Arg-Pro-Arg-His-Ile-Thr.
treatment

Thr-Thr-Ser-Gln-Val
Antiarthritic,

Thr-Ser-Gln-Val-Arg
other

Thr-Thr-Ser-Gly-Ile-His-Pro-Lys
Stomatological

Dermatological

307
antiflammins

L-Leucine, N-[N-[N-[N-[N2-[N2-[N-(N-L-histidyl-
Anti-

L-alpha-aspartyl)-L-methionyl]-L-asparaginyl]-
inflammatory

L-lysyl]-L-valyl]-L-leucyl]-L-alpha-aspartyl]-

308
antifungal

tripeptides of N3-4-methoxyfumanyl and di- and
Antifungal

tripeptides

tripeptides of N3-D-trans 2,3-epoxysuccinamoyl-

L-2,3-diaminopropanoic acid

29
Gastrimmune

G17-DT; G17DT (vaccine); Gastrimmune; Glu-Gly-
Anticancer,

Pro-Trp-Leu-Glu-Glu-Glu-Glu -diphtheria toxoid;
immunological

anti-gastrin 17 immunogen; gastrin 17 vaccine;

gastrin-17-diphtheria toxoid conjugate

30
antithrombin

gi|312673|emb|CAA51292.1| Hirudin [Hirudinaria
Antithrombotic

polypeptides

manillensis]
Anticoagulant

MFSLKLFVVFLAVCICVSQAVSYTDCTESGQNYCLCVGGNL

CGGGKHCEMDGSGNKCVDGEGTPKPKSQTEGDFEEIPDEDILN

31
antiviral

NH₂-Tyr-Ala-Gly-Ala-Val-Val-Asn-Asp-Leu-COOH
Antiviral, other

peptides

32
apolipoprotein

gi|671882|emb|CAA28583.1| apolipoprotein [Homo
Hypolipaemic/

sapiens]
Anti-

MKLLAATVLLLTICSLEGALVRRQAKEPCVESLVSQYF
atherosclerosis

QTVTDYGKDLMEKVKSPELQAEAKSYFEKSKE

QLTPLIKKAGTELVNFLSYFVELGTHPATQ

33
arthritis

gi|46369603|gb|AAS89650.1| secreted antigen
Recombinant,

antigen

85A precursor [Mycobacterium bovis BCG]
other

MQLVDRVRGAVTGMSRRLVVGAVGAALVSGLVGAVG
Antiarthritic,

GTATAGAFSRPGLPVEYLQVPSPSMGRDIKVQFQSGG
immunological

ANSPALYLLDGLRAQDDFSGWDINTPAFEWYDQSGLS
Immunosuppres-

VVMPVGGQSSFYSDWYQPACGKAGCQTYKWETFLTS
sant

ELPGWLQANRHVKPTGSAVVGLSMAASSALTLAIYHP

QQFVYAGAMSGLLDPSQAMGPTLIGLAMGDAGGYK

ASDMWGPKEDPAWQRNDPLLNVGKLIANNTRVWVY

CGNGKPSDLGGNNLPAKFLEGFVRTSNIKFQDAYNAG

GGHNGVFDFPDSGTHSWEYWGAQLNAMKPDLQRAL

GATPNTGPAPQGA

309
Avorelin

5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-
Releasing

seryl-L-tyrosyl-2-methyl-D-tryptophyl-L-
hormone

leucyl-L-arginyl-N-ethyl-L-prolinamide
Anticancer,

hormonal

Menstruation

disorders

310
B-956

N-[8(R)-Amino-2(S)-benzyl-5(S)-isopropyl-9-
Anticancer,

sulfanyl-3(Z),6(E)-nonadienoyl]-L-methionine
other

311
BCH-2687

L-Tyrosyl-D-arginyl-L-phenylalanyl-L-
Analgesic,

phenylalaninamide
other

34
BCH-2763

L-Leucine, D-phenylalanyl-L-prolyl-5-
Antithrombotic

aminopentanoyl-5-aminopentanoyl-L-alpha-
Anticoagulant

aspartyl-L-phenylalanyl-L-alpha-glutamyl-L-

prolyl-L-isoleucyl-L-prolyl-; BCH-2763; Phe-

Pro-(NH(CH₂)₄CO)₂-Asp-Phe-Glu-Pro-Ile-Pro-Leu;

phenylalanyl-prolyl-(NH(CH₂)₄CO)₂-aspartyl-

phenylalanyl-glutamyl-prolyl-isoleucyl-

prolyl-leucine

312
frakefamide

L-phenylalaninamide, L-tyrosyl-D-alanyl-4-
Analgesic, other

fluoro-L-phenylalanyl-

313
BIM-22015

Glycinamide, D-alanyl-L-glutaminyl-L-tyrosyl-
ACTH

L-phenylalanyl-L-arginyl-L-tryptophyl-
Neurological

35
BIM-26028

Pyroglutaminyl-glutaminyl-arginyl-leucyl-
Releasing

glycyl-asparaginyl-glutaminyl-tryptyl-alanyl-
hormone

valyl-glycyl-histidinyl-leucyl-leucyl-NH₂
Respiratory

Anorectic/

Antiobesity

Anticancer,

hormonal

314
BIM-44002

L-Tyrosinamide, L-phenylalanyl-L-norleucyl-L-
Hormone

histidyl-L-asparaginyl-L-leucyl-D-tryptophyl-
Osteoporosis

L-lysyl-L-histidyl-L-leucyl-L-seryl-L-seryl-
treatment

L-norleucyl-L-alpha-glutamyl-L-arginyl-L-

valyl-L-.alpha.-glutamyl-L-tryptophyl-L-

leucyl-L-arginyl-L-lysyl-L-lysyl-L-leucyl-L-

glutaminyy-L-alpha-aspartyl-L-valyl-L-

histidyl-L-asparaginyl-

36
BIO-1211

L-Proline, N-((4-((((2-
Antiasthma

methylphenyl)aminocarbonyl)amino)phenyl)acetyl)-
GI inflammatory/

L-leucyl-Lalpha-aspartyl-L-valyl-; BIO-1211; N-
bowel disorders

((4-((((2-
Multiple

methylphenyl)amino)carbonyl)amino)phenyl)acetyl)-
sclerosis

leucyl-aspartyl-valyl-proline
treatment

37
BPC-15

BPC 15; BPC-15; BPC-157; booly protection
Anti-

compound 15; L-Valine, glycyl-L-alpha-glutamyl-
inflammatory

L-prolyl-L-prolyl-L-prolylglycyl-L-lysyl-L-

prolyl-L-alanyl-L-alpha-aspartyl-L-alpha-

aspartyl-L-alanylglycyl-L-leucyl-

315
bivalirudin

L-Leucine, D-phenylalanyl-L-prolyl-L-arginyl-L-
Anticoagulant

prolylglycylglycylglycylglycyl-L-
Antianginal

asparaginylglycl-L-alpha-aspartyl-L-

phenylalanyl-L-alpha-glutamyl-L-alpha-glutamyl-

L-isoleucyl-L-prolyl-L-alpha-glutamyl-L-

tyrosyl-; D-phenylalanyl-L-prolyl-L-arginyl-L-

prolyl-glycylglycyl-glycyl-glycyl-L-asparagyl-

glycyl-L-aspartyl-L-phenylalanyl-L-glutamyl-L-

glutamyl-L-isoleucyl-Lprolyl-L-glutamyl-L-

glutamyl-L-tyrosyl-L-leucine trifluoroacetate

(salt) hydrate

38
bombesin

5-oxoPro-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-
Anticancer,

antagonist

Gly-His-Leu-MetNH₂[CAS], Bombesin 14; Bombesin
other

Dihydrochloride; Dihydrochloride, Bombesin

39
brain
BNP
SPKMVQGSGCFGRKMDRISSSSGLGCKVLRRH
COPD treatment,

natriuretic

cardiac

peptide

41
C-peptide
C-peptide
Glu-Ala-Glu-Asp-Leu-Gln-Val-Gly-Gln-Val-Glu-Leu-
Symptomatic

analogues

Gly-Gly-Gly-Pro-Gly-Ala-Gly-Ser-Leu-Gln-Pro-Leu-
antidiabetic

Ala-Leu-Glu-Gly-Ser-Leu-Gln
Ophthalmological

Neurological

316
C5a

Me-Phe-Lys-Pro-D-Cha-L-Cha-D-Phe
Anti-

antagonist

inflammatory

42
CBT-101

L-Cysteinamide, L-asparaginyl-L-leucylglycyl-L-
Antiglaucoma

valyl-S-[(acetylamino)methyl]-, monoacetate

43
CCK(27-32)

Tyr(SO₃)-Met-Gly-Trp-Met-Asp; CBZ-CCK
Analgesic,

(27-32)-NH₂; cholecystokinin (27-32) amide,
obesity, other

benzoyloxycarbonyl-, D-Trp

44
CD4

CD4 (81-92), D-Ile; CD4 (81-92), D-Tyr; CD4
Antiviral,

(81-92), D-Tyr,D-Cys,D-Glu(5); CD4(81-92);
anti-HIV

TYICEVEDQKEE; Thr-Tyr-Ile-Cys-Glu-Val-Glu-Asp-

Gln-Lys-Glu-Glu; threonyl-tyrosyl-isoleucyl-

cysteinyl-glutamyl-valyl-glutamyl-aspartyl-

glutaminyl-lysyl-glutamyl-glutamic acid

317
CEE-04-420

Lys-D-Pro-Thr and Lys-D-Pro-Val
Analgesic, other

45
CEP-079

gi|108796063|ref|NP_001007140.2| insulin-like
Ophthalmological

growth factor 2 isoform 1 precursor [Homo

sapiens]

MGIPMGKSMLVLLTFLAFASCCIAAYRPSETLCGGELV

DTLQFVCGDRGFYFSRPASRVSRRSRGIVEEC

CFRSCDLALLETYCATPAKSERDVSTPPTVLPDNFPRY

PVGKFFQYDTWKQSTQRLRRGLPALLRARRGH

VLAKELEAFREAKRHRPLIALPTQDPAHGGAPPEMASNRK

318
mifamurtide

L-Alaninamide, N-(N-acetylmuramoyl)-L-alanyl-D-
Anticancer,

alpha-glutaminyl-N-[4-hydroxy-10-oxo-7-[(1-
immunological

oxohexadecyl)oxy]-3,5,9-trioxa-4-

phosphapentacos-1-yl]-, P-oxide, monosodium

salt, (R)-

46
CGRP
CGRP
ACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVGSKAF-NH₂
Hormone

analogues

Cardiovascular

47
rusalatide

gi|4503635|ref|NP_000497.1| coagulation factor
Musculoskeletal

acetate

II preproprotein [Homo sapiens]
Vulnerary

MAHVRGLQLPGCLALAALCSLVHSQHVFLAPQQARS
Symptomatic

LLQRVRRANTFLEEVRKGNLERECVEETCSYEEAFEA
antidiabetic

LESSTATDVFWAKYTACETARTPRDKLAACLEGNCAE
Cardiovascular

GLGTNYRGHVNITRSGIECQLWRSRYPHKPEINSTTHP
Anti-infective,

GADLQENFCRNPDSSTTGPWCYTTDPTVRRQECSIPV
other

CGQDQVTVAMTPRSEGSSVNLSPPLEQCVPDRGQQYQ
Ophthalmological

GRLAVTTHGLPCLAWASAQAKALSKHQDFNSAVQLVE

NFCRNPDGDEEGVWCYVAGKPGDFGYCDLNYCEEAV

EEETGDGLDEDSDRAIEGRTATSEYQTFFNPRTFGSGE

ADCGLRPLFEKKSLEDKTERELLESYIDGRIVEGSDAEI

GMSPWQVMLFRKSPQELLCGASLISDRWVLTAAHCLL

YPPWDKNFTENDLLVRIGKHSRTRYERNIEKISMLEKI

YIHPRYNWRENLDRDIALMKLKKPVAFSDYIHPVCLP

DRETAASLLQAGYKGRVTGWGNLKETWTANVGKGQ

PSVLQVVNLPIVERPVCKDSTRIRITDNMFCAGYKPDE

GKRGDACEGDSGGPFVMKSPFNNRWYQMGIVSWGE

GCDRDGKYGFYTHVFRLKKWIQKVIDQFGE

48
CKS-17

L-Leucine, L-leucyl-L-glutaminyl-L-asparaginyl-
Immunosuppres-

L-arginyl-L-arginylglycyl-L-leucyl-L-alpha-
sant

aspartyl-L-leucyl-L-leucyl-L-phenylalanyl-L-
Anticancer,

leucyl-L-lysyl-L-alpha-glutamylglycylglycyl-;
immunological

CKS-17; CKS-17 peptide

10
corticorelin
cortico-
gi|80861463|ref|NP_001030333.1|
Neuroprotective

acetate
tropin
proopiomelanocortin preproprotein [Homo sapiens]
Antiasthma

MPRSCCSRSGALLLALLLQASMEVRGWCLESSQCQDL
Anti-

TTESNLLECIRACKPDLSAETPMFPGNGDEQPLTENPR
inflammatory

KYVMGHFRWDRFGRRNSSSSGSSGAGQKREDVSAGE

DCGPLPEGGPEPRSDGAKPGPREGKRSYSMEHFRWGK

PVGKKRRPVKVYPNGAEDESAEAFPLEFKRELTGQRL

REGDGPDGPADDGAGAQADLEHSLLVAAEKKDEGPY

RMEHFRWGSPPKDKRYGGFMTSEKSQTPLVTLFKNAII

KNAYKKGE

49
CT-112

L-Arginine, L-threonyl-L-threonyl-L-seryl-L-
Antiarthritic,

glutaminyl-L-valyl-L-arginyl-L-prolyl-; 5-(3-
immunological

ethoxy-4-pentyloxyphenyl)-2,4-thiazolidinedione

50
CTAP-III

phenylalanyl-cysteinyl-tyrosyl-tryptophyl-
Vulnerary

arginyl-threonyl-penicillaminyl-threoninamide;
Antiarthritic,

rCTAP-III-Leu-21 (des 1-15); somatostatin analog
other

CTAP
Musculoskeletal

Recombinant,

other

51
CVFM

Cys-Val-Phe-Met
Anticancer,

other

52
calcitonin
calcitonin
CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAP (human)
Formulation,

and

H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-
oral, other

53

Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-
Hormone

Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH₂ (salmon)
Osteoporosis

treatment

54
calciseptine

sp|P22947|TXCAS_DENPO Calciseptin
Anti-

OS = Dendroaspis polylepis polylepis PE = 1
hypertensive,

SV = 1
other

RICYIHKASLPRATKTCVENTCYKMFIRTQREYISERGCGCPTAMWPY

QTECCKGDRCNK

52
calcitonin
calcitonin
CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAP (human)
Hormone

and
analogues

H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-
Osteoporosis

53

Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-
treatment

Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH₂ (salmon)

55
calphobindin I

gi|186680508|ref|NM_001154.3| Homo sapiens
Ophthalmol-

annexin A5(ANXA5),
ogical,

MAQVLRGTVTDFPGFDERADAETLRKAMKGLGTDEE
Vulnerary

SILTLLTSRSNAQRQEISAAFKTLFGRDLLDDLKSELTG

KFEKLIVALMKPSRLYDAYELKHALKGAGTNEKVLTEI

IASRTPEELRAIKQVYEEEYGSSLEDDVVGDTSGYYQR

MLVVLLQANRDPDAGIDEAQVEQDAQALFQAGELK

WGTDEEKFITIFGTRSVSHLRKVFDKYMTISGFQIEETI

DRETSGNLEQLLLAVVKSIRSIPAYLAETLYYAMKGAG

TDDHTLIRVMVSRSEIDLFNIRKEFRKNFATSLYSMIKG

DTSGDYKKALLLLCGEDD

319
cargutocin

1,6-Dicarbaoxytocin, 1-butanoic acid-7-glycine-
Labour inducer

320
casokefamide

L-Tyrosinamide, L-tyrosyl-D-alanyl-L-
Antidiarrhoeal

phenylalanyl-D-alanyl-

56
cekropin-P

sp|P14661|CECP1_PIG Cecropin-P1 OS = Sus scrofa
Antibacterial,

PE = 1 SV = 1
other

SWLSKTAKKLENSAKKRISEGIAIAIQGGPR

57
tasidotin

N,N-Dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-
Anticancer,

hydrochloride

L-propyl-L-proline-tert-butylamide
other

58
ceruletide

Pyr-Gln-Asp-Tyr(SO3H)-Thr-Gly-Trp-Met-Asp-Phe-
Analgesic, other

diethylamine

C(O)-NH₂
Gastroprokinetic

321
cetrorelix

D-Alaninamide, N-acetyl-3-(2-naphthalenyl)-D-
Fertility

acetate

alanyl-4-chloro-D-phenylalanyl-3-(3-pyridinyl)-
enhancer

D-alanyl-L-seryl-L-tyrosyl-N5-(aminocarbonyl)-
Prostate

D-ol-L-leucyl-L-arginyl-L-prolyl-
disorders

Menstruation

disorders

Anticancer,

hormonal

59
corti
corti
SQEPPISLDLTFHLLREVLEMTKADQLAQQAHSNRKLLDIA
Releasing

coliberin
coliberin

hormone

322
D-22213

L-Histidinamide, N2-[(2,3,4,9-tetrahydro-1H-
Anticancer,

pyrido[3,4-b]indol-3-yl)carbonyl]-L-glutaminyl-
other

L-tryptophyl-L-alanyl-L-valylglycyl-N-[1-[[[1-

(aminocarbonyl)-3-methylbutyl]amino]methyl]-3-

methylbutyl]-, [1(R),6[S-(R*,R*)]]-, monoacetate

323
DAP

L-AP-L-Ala and L-Ala-L-Ala-DL-AP;
Antibacterial,

inhibitors

other

60
DP-640
insulin
L-Tyrosinamide, β-alanyl-L-arginylglycyl-L-
Insulin

phenylalanyl-L-phenylalanyl-, diacetate (salt)
Antidiabetic

61
DP-107

L-Leucine, L-methionyl-L-threonyl-L-leucyl-L-
Antiviral,

threonyl-L-valyl-L-glutaminyl-L-alanyl-L-
anti-HIV

arginyl-L-glutaminyl-L-leucyl-L-leucyl-L-seryl-

L-glutaminyl-L-isoleucyl-L-valyl-L-glutaminyl-L-

glutaminyl-L-glutaminyl-L-asparaginyl-L-

asparaginyl-L-leucyl-L-leucyl-L-arginyl-L-

alanyl-L-isoleucyl-L-.alpha.-glutamyl-L-alanyl-

L-glutaminyl-L-glutaminyl-L-histidyl-L-leucyl-L-

leucyl-L-glutaminyl-L-leucyl-L-threonyl-L-valyl-

L-tryptophylglycyl-L-isoleucyl-L-lysyl-L-

glutaminyl-

62
DU-728

Arg-Gly-Asp-Ser
Antithrombotic

63
Dynorphin A

H-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-
Analgesic, other

Leu-Lys-Trp-Asp-Asn-Gln-OH
Neuroprotective

Dependence

treatment

64
defensins

gi|181535|gb|AAA52304.1| defensin precursor
Antibiotic,

MRTLAILAAILLVALQAQAEPLQARADEVAAAPEQIAA
other

DIPEVVVSLAWDESLAPKHPGSRKNMDCYCRIPACIA
Antifungal

GERRYGTCIYQGRLWAFCC
Vulnerary

324
detirelix

D-Alaninamide, N-acetyl-3-(2-naphthalenyl)-D-
Releasing

alanyl-4-chloro-D-phenylalanyl-D-tryptophyl-L-
hormone

seryl-L-tyrosyl-N6-[bis(ethylamino)methylene]-D-
Abortifacient

lysyl-L-leucyl-L-arginyl-L-prolyl-
Male

contraceptive

65
disagregin

gi|545738|gb|AAB30092.1| disagregin = fibrinogen
Antithrombotic

receptor antagonist [Ornithodoros moubata =
Cardiovascular

tick, salivary gland, Peptide, 60 aa]

SDDKCQGRPMYGCREDDDSVFGWTYDSNHGQCWKG

SYCKHRRQPSNYFASQQECRNTCGA

66
E-2078

D-Leucinamide, N-methyl-L-tyrosylglycylglycyl-L-
Analgesic, other

and

phenylalanyl-L-leucyl-L-arginyl-N2-methyl-L-

65

arginyl-N-ethyl-

SDDKCQGRPMYGCREDDDSVFGWTYDSNHGQCWKG

SYCKHRRQPSNYFASQQECRNTCGA

ELS-1

Arg-Lys-Glu
Immunostimulant,

other

67
ecallantide

Glu-Ala-Met-His-Ser-Phe-Cys-Ala-Phe-Lys-Ala-Asp-
Angioedema,

Asp-Gly-Pro-Cys-Arg-Ala-Ala-His-Pro-Arg-Trp-Phe-
Anti-

Phe-Asn-Ile-Phe-Thr-Arg-Gln-Cys-Glu-Glu-Phe-Ile-
inflammatory,

Tyr-Gly-Gly-Cys-Glu-Gly-Asn-Gln-Asn-Arg-Phe-Glu-
Haemostatic,

Ser-Leu-Glu-Glu-Cys-Lys-Lys-Met-Cys-Thr-Arg-Asp
Antiarthritic,

other

325
ES-1005

bis-(1-naphthyl)methylacetyl-His-Sta-Leu-E-Lys
Anti-

diHCl
hypertensive,

renin system

326
efegatran

L-prolinamide, N-methyl-D-phenylalanyl-n-(4-
Antithrombotic

((aminoiminomethyl)amino)-1-formylbutyl), (S)-
Antianginal

68
elafin

gi|999146|gb|AAB34627.1| elafin [Homo sapiens]
Respiratory

and
derivatives

MRASSFLIVVVFLIAGTLVLE
COPD treatment

69

H-Ala-Gln-Glu-Pro-Val-Lys-Gly-Pro-Val-Ser-Thr-
Antiarthritic,

Lys-Pro-Gly-Ser-Cys-Pro-Ile-Ile-Leu-Ile-Arg-Cys-
other

Ala-Met-Leu-Asn-Pro-Pro-Asn-Arg-Cys-Leu-Lys-Asp-

Thr-Asp-Cys-Pro-Gly-Ile-Lys-Lys-Cys-Cys-Glu-Gly-

Ser-Cys-Gly-Met-Ala-Cys-Phe-Val-Pro-Gln-OH

(Disufide bonds between Cys16-Cys45, Cys23-Cys49,

Cys32-Cys44, Cys38-Cys53)

70
elcatonin
calcitonin
Ser-Asn-Leu-Ser-Thr-Asn-Val-Leu-Gly-Lys-Leu-Ser-
Hormone

and

Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-
Osteoporosis

52

Asn-Val-Gly-Ala-Gly-Thr-Pro-NH₂
treatment

CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAP (human)
Analgesic, other

71
eledoisin

5-oxo-L-Pro-L-Pro-L-Ser-L-Lys-L-Asp-L-Ala-L-Phe-
Ophthalmological

L-Ala-L-isoleucylglycyl-L-Leu-L-methionin-amide

3
encapsulated
insulin
gi|386828|gb|AAA59172.1| insulin [Homo sapiens]
Formulation,

insulin

MALWMRLLPLLALLALWGPDPAAAFVNQHLCGSHLVE
optimized,

ALYLVCGERGFFYTPKTRREAEDLQVGQVELGGGPGA
nanoparticles

GSLQPLALEGSLQKRGIVEQCCTSICSLYQLENYCN
Insulin

Antidiabetic

72
endorphin, β-

YGGFMTSEKSQTPLVTLFKNAIIKNAYKKGE
Analgesic, other

72
endorphin,

YGGFMTSEKSQTPLVTLFKNAIIKNAYKKGE
Analgesic, other

pancreatic

73
endothelial

gi|189701|gb|AAA60043.1| endothelial cell
Cardiovascular

cell

growth factor

growth factor

MAALMTPGTGAPPAPGDFSGEGSQGLPDPSPEPKQLP

ELIRMKRDGGRLSEADIRGFVAAVVNGSAQGAQIGAM

LMAIRLRGMDLEETSVLTQALAQSGQQLEWPEAWRQ

QLVDKHSTGGVGDKVSLVLAPALAACGCKVPMISGR

GLGHTGGTLDKLESIPGFNVIQSPEQMQVLLDQAGCCI

VGQSEQLVPADGILYAARDVTATVDSLPLITASILSKKL

VEGLSALVVDVKFGGAAVFPNQEQARELAKTLVGVG

ASLGLRVAAALTAMDKPLGRCVGHALEVEEALLCMD

GAGPPDLRDLVTTLGGALLWLSGHAGTQAQGAARVA

AALDDGSALGRFERMLAAQGVDPGLARALCSGSPAE

RRQLLPRAREQEELLAPADGTVELVRALPLALVLHEL

GAGRSRAGEPLRLGVGAELLVDVGQRLRRGTPWLRV

HRDGPALSGPQSRALQEALVLSDRAPFAAPSPFAELVL

PPQQ

74
eptifibatide

MAP-HAR-GLY-ASP-TRP-PRO-CYS-NH₂
Antianginal

Cardiovascular

327
examorelin
GHRP
L-Lysinamide, L-histidyl-2-methyl-D-tryptophyl-
Releasing

L-alanyl-L-tryptophyl-D-phenylalanyl-
hormone

Vulnerary

Cardiovascular

75
FG-005

SMR1-QHNPR
Male sexual

dysfunction

328
FR-113680

L-Phenylalaninamide, N-acetyl-L-threonyl-1-
Antiasthma

formyl-D-tryptophyl-N-methyl-N-(phenylmethyl)-

76
fibronectin-

Gly-Arg-Gly-Asp-Ser
Anticancer,

related

other

peptide

329
G-4120

L-Cysteine, N-(mercaptoacetyl)-D-tyrosyl-L-
Antithrombotic

arginylglycyl-L-alpha-aspartyl-, cyclic (1-5)-

sulfide, S-oxide

330
EP-51216

2S)-6-amino-2-[[(2S)-2-[[(2R)-2-[[(2R)-2-(4-
GH Releasing

aminobutanoylamino)-3-(2-methyl 1H-indol-3-
hormone

yl)propanoyl]amino]-3-(2-methyl-1H-indol-3-
Vulnerary,

yl)propanoyl]amino]-3-(2-methyl-1H-indol-3-
endocrine

yl)propanoyl]amino]hexanamide

8
GLP-1 +
GLP-1
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS
Antidiabetic

exendin-4

77
GM-1986

YYWIGIR
Anti-

inflammatory

78
GnRH-
GnRH
gi|133908612|ref]NP_001076580.1| gonadotropin-
Antiprolactin

associated

releasing hormone 1 precursor [Homo sapiens]
Menstruation

peptide

MKPIQKLLAGLILLTWCVEGCSSQHWSYGLRPGGKRD
disorders

AENLIDSFQEIVKEVGQLAETQRFECTTHQPRSPLRDL
Fertility

KGALESLIEEETGQKKI
enhancer

79
GRF1-44

gi|11034841|ref|NP_066567.1| growth hormone
Musculoskeletal

releasing hormone preproprotein [Homo sapiens]

MPLWVFFFVILTLSNSSHCSPPPPLTLRMRRYADAIFTNSYRKV

80
GRF
GHRF
gi|337133|gb|AAA52609.1| growth hormone
Idiopathic

releasing factor
growth hormone

MPLWVFFFVILTLSNSSHCSPPPPLTLRMRRYADAIFTN
deficiency;

SYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL
cachexia

GRQVDSMWAEQKQMELESILVALLQKHRNSQG

331
GYKI-14451

L-Prolinamide, N-[(1,1-dimethylethoxy)carbonyl]-
Antithrombotic

D-phenylalanyl-N-[4-[(aminoiminomethyl)amino]-1-

formylbutyl]-, (S)-

81
galanin

gi|1247490|emb|CAA01907.1) galanin [Homo
Releasing

sapiens]
hormone

MARGSALLLASLLLAAALSASAGLWSPAKEKRGWTL

NSAGYLLGPHAVGNHRSFSDKNGLTSKRELRPEDDMK

PGSFDRSIPENNIMRTIIEFLSFLHLKEAGALDRLLDLPA

AASSEDIERS

82
gastrin

(benzyloxycarbonyl)-L-Glu-L-Ala-L-Tyr-Gly-L-
Antiulcer

antagonists

Tyr-L-Met-L-aspartic acid amide

332
glaspimod

N2,N2′-[2,7-Bis(pyroglutamyl-glutamyl-
Immunomodulator,

aspartylamino)-octanediolyl]bis(lysine)
anti-infective

Immunostimulant,

other Radio/

chemoprotective

83
glicentin

gi|125987831|sp|P01275.3|GLUC_HUMAN Glucagon
Insulin

precursor [Contains: Glicentin; Glicentin-
Antiulcer

related polypeptide (GRPP); Oxyntomodulin (OXY)
Antidiabetic

(OXM); Glucagon; Glucagon-like peptide 1

(GLP-1); Glucagon-like peptide 1(7-37)

(GLP-1(7-37)); Glucagon-like peptide 1(7-36)

(GLP-1(7-36)); Glucagon-like peptide 2 (GLP-2)]

MKSIYFVAGLFVMLVQGSWQRSLQDTEEKSRSFSASQ

ADPLSDPDQMNEDKRHSQGTFTSDYSKYLDSRRAQD

FVQWLMNTKRNRNNIAKRHDEFERHAEGTFTSDVSS

YLEGQAAKEFIAWLVKGRGRRDFPEEVAIVEELGRRH

ADGSFSDEMNTILDNLAARDFINWLIQTKITDRK

84
glucagon

H₂N-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-
hypoglycemia

Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-
Diagnostic

Gln-Trp-Leu-Met-Asn-Thr-COOH

84
glucagon
glucagon
His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-
Hypoglycemia

Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-

Trp-Leu-Met-Asn-Thr

85
gonadorelin
gonadorelin
gi|121522|sp|P01148.1|GON1_HUMAN
Female

analogues

Progonadoliberin-1 precursor (Progonadoliberin
contraceptive;

I) [Contains: Gonadoliberin-1 (Gonadoliberin I)
enometiosis,

(Luteinizing hormone-releasing hormone I)
uterine ,

(LH-RH I) (Gonadotropin-releasing hormone I)
leiomyoma

(GnRH-I) (Luliberin I)(Gonadorelin); GnRH-
precocious

associated peptide 1 (GnRH-associated
puberty,

peptide I)]
prostate

MKPIQKLLAGLILLTWCVEGCSSQHWSYGLRPGGKRD
and breast

AENLIDSFQEIVKEVGQLAETQRFECTTHQPRSPLRDL
cancer

KGALESLIEEETGQKKI

333
gonadorelin

[Ac-DNAL1(2),4FDPhe2,D-Trp3,D-Arg6]-LHRH
Female

antagonist

contraceptive;

enometiosis,

uterine

leiomyoma,

precocious

puberty,

prostate

and breast

cancer

86
gonadorelin
gonadorelin
5-oxo-L-His-L-Trp-L-Ser-L-Tyr-Gly-L-Leu-L-Arg-
Female

L-Pro-glycinamide
contraceptive;

enometiosis,

uterine

leiomyoma,

precocious

puberty,

prostate

and breast

cancer

334
goralatide

L-Proline, 1-[N2-[N-(N-acetyl-L-seryl)-L-α-
Haematological

aspartyl]-L-lysyl]-
Immunological

Radio/

chemoprotective

335
H-142

L-Lysine, N2-[N-[N-[N-[4-methyl-2-[[N-[N-[1-(N-
Anti-

L-prolyl-L-histidyl)-L-prolyl]-L-phenylalanyl]-
hypertensive,

L-histidyl]amino]pentyl]-L-valyl]-L-isoleucyl]-
renin system

L-histidyl]-, (S)-

336
I5B2

L-Tyrosinamide, N-methyl-L-valyl-N-[2-(4-
Anti-

hydroxyphenyl)-1-phosphonoethyl]-
hypertensive,

renin system

87
iseganan

L-Argininamide, L-arginylglycylglycyl-L-leucyl-
Antibacterial,

hydrochloride

L-cysteinyl-L-tyrosyl-L-cysteinyl-L-
other

arginylglycyl-L-arginyl-L-
Antifungal

phenylalanyl-L-cysteinyl-L-valyl-L-cysteinyl-L-
Antiviral, other

valylglycyl-, cyclic (5-14), (7-12)-

bis(disulfide) hydrochloride

88
netamiftide

L-Tryptophanamide, 4-fluoro-L-phenylalanyl-(4R)-
Antidepressant

4-hydroxy-L-prolyl-L-arginylglycyl-,
Anxiolytic

bis(trifluoroacetate) (salt)

337
icrocaptide

L-Arginine, glycyl-N2-ethyl-L-lysyl-L-prolyl-
Cardiovascular

Septic shock

treatment

338
icatibant

L-Arginine, D-arginyl-L-arginyl-L-prolyl-trans-
Cardiovascular

4-hydroxy-L-prolylglycyl-3-(2-thienyl)-L-alanyl-
Hepatoprotective

L-seryl-D-1,2,3,4-tetrahydro-3-
Vulnerary

isoquinolinecarbany-L-(2α,3aβ,7aβ)-octahydro-1H-

indole-2-carbonyl-

339
AG-1776

3-[2(S)-Hydroxy-3(S)-(3-hydroxy-2-
Antiviral,

methylbenzamido)-4-phenylbutanoyl]-5,5-dimethyl-
anti-HIV

N-(2-methylbenzyl)thiazolidine-4(R)-carboxamide

340
pralmorelin

L-Lysinamide, D-alanyl-3-(2-naphthalenyl)-D-
Diagnostic

alanyl-L-alanyl-L-tryptophyl-D-phenylalanyl-
Releasing

hormone

89
katacalcin
calcitonin
gi|115478|sp|P01258.1|CALC_HUMAN Calcitonin
Osteoporosis

precursor [Contains: Calcitonin; Katacalcin
treatment

(Calcitonin carboxyl-terminal peptide) (CCP)
Hormone

(PDN-21)]
Recombinant,

MGFQKFSPFLALSILVLLQAGSLHAAPFRSALESSPADP
other

ATLSEDEARLLLAALVQDYVQMKASELEQEQEREGSS

LDSPRSKRCGNLSTCMLGTYTQDFNKFHTFPQTAIGV

GAPGKKRDMSSDLERDHRPHVSMPQAN

341
ketomethyl-

N-[N-[3-benzoylamino-4-phenyl-2-oxobutyl]-N-
Anti-

ureas

methylaminocarbonyl]proline
hypertensive,

renin system

90
L-346670

N-L-arginyl-8-L-methionine-21a-L-phenylalanine-
Anti-

21b-L-arginine-21c-L-tyrosine-
hypertensive,

diuretic

91
L-364210

N-isovaleryl-L-histidyl-L-prolyl-L-phenylalanyl-
Anti-

L-histidyl-(3S,4S)-4-amino-5-cyclohexyl-3-
hypertensive,

hydroxypentanoic acid)-L-leucyl-L-
renin system

phenylalanylamide

342
L-659837

L-Phenylalanine, N-[2-(3-amino-2-oxo-1-
Analgesic,

pyrrolidinyl)-4-methyl-1-oxopentyl]-L-methionyl-
other

L-glutaminyl-L-tryptophyl-, cyclic (4-1)-

peptide, [S-(R*,S*)]-

343
L-693549

5(S)-(tert-butoxycarbonylamino)-4(S)-hydroxy-N-
Antiviral,

[2(R)-hydroxyindan-1(S)-yl]-2(R)-[4-(3-
anti-HIV

hydroxypropyl)benzyl]-6-phenylhexamide

344
L-709049

L-Alaninamide, N-acetyl-L-tyrosyl-L-valyl-N-(2-
Anti-

carboxy-1-formylethyl)-, (S)-
inflammatory

92
LDV-

4-((N′-2-methylphenyl)ureido)phenylalanyl-leucyl-
Anticancer,

containing

alpha-aspartyl-valyl-prolyl-alanyl-alanyl-lysine
other

peptides

Lys-Phe

L-Phenylalanine, N-L-lysyl-
Haematological

Antisickling

93
lagatide

D-Alaninamide, L-prolyl-L-valyl-L-threonyl-L-
Antidiarrhoeal

lysyl-L-prolyl-L-glutaminyl-

94
laminin A

seryl-isoleucyl-lysyl-valyl-alanyl-valinamide
Anticancer,

peptide

other

Neurological

95
laminin

tyrosyl-isoleucyl-glycyl-serylarginine
Anticancer,

other

345
lanreotide
somatostatin
L-Threoninamide, 3-(2-naphthalenyl)-D-alanyl-L-
Acromegaly

cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-
Anticancer,

valyl-L-cysteinyl-, cyclic (2-7)-disulfide;
hormonal

L-Threoninamide, 3-(1-naphthalenyl)-D-alanyl-L-
Cardiovascular

cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-
Antidiarrhoeal

valyl-L-cysteinyl-, cyclic (2-7)-disulfide

346
leuprolide

Luteinizing hormone-releasing factor (pig),
Formulation,

acetate

6-D-leucine-9-(N-ethyl-L-prolinamide)-10-
implant

deglycinamide-
Anticancer,

hormonal

Menstruation

disorders

347
MCI-826

Butanoic acid, 2,2-diethyl-4-[[3-[2-[4-(1-
Antiasthma

methylethyl)-2-thiazolyl]ethenyl]phenyl]amino]-

4-oxo-, (E)-

96
omiganan

L-lysinamide, L-isoleucyl-L-leucyl-L-arginyl-L-
Peptide

pentahydro-

tryptophyl-L-prolyl-L-tryptophyl-L-tryptophyl-
antibiotic

chloride

L-prolyl-L-tryptophyl-L-arginyl-L-arginyl,

pentahydrochloride

97-
MBP

gi|68509940|ref|NP_001020272.1| Golli-mbp
Multiple

100

isoform 1 [Homo sapiens]
sclerosis

MGNHAGKRELNAEKASTNSETNRGESEKKRNLGELS

RTTSEDNEVFGEADANQNNGTSSQDTAVTDSKRTADP

KNAWQDAHPADPGSRPHLIRLFSRDAPGREDNTFKDR

PSESDELQTIQEDSAATSESLDVMASQKRPSQRHGSKY

LATASTMDHARHGFLPRHRDTGILDSIGRFFGGDRGAP

KRGSGKDSHHPARTAHYGSLPQKSHGRTQDENPVVHF

FKNIVTPRTPPPSQGKGRGLSLSRFSWGAEGQRPGFGY

GGRASDYKSAHKGFKGVDAQGTLSKIFKLGGRDSRS

GSPMARR

gi|68509938|ref|NP_001020271.1| Golli-mbp

isoform 2 [Homo sapiens]

MGNHAGKRELNAEKASTNSETNRGESEKKRNLGELS

RTTSEDNEVFGEADANQNNGTSSQDTAVTDSKRTADP

KNAWQDAHPADPGSRPHLIRLFSRDAPGREDNTFKDR

PSESDELQTIQEDSAATSESLDVMASQKRPSQRHGSKY

LATASTMDHARHGFLPRHRDTGILDSIGRFFGGDRGAP

KRGSGKVSSEE

gi|68509930|ref|NP_001020252.1| myelin basic

protein isoform 1 [Homo sapiens]

MASQKRPSQRHGSKYLATASTMDHARHGFLPRHRDT

GILDSIGRFFGGDRGAPKRGSGKVPWLKPGRSPLPSHA

RSQPGLCNMYKDSHHPARTAHYGSLPQKSHGRTQDE

NPVVHFFKNIVTPRTPPPSQGKGRGLSLSRFSWGAEGQ

RPGFGYGGRASDYKSAHKGFKGVDAQGTLSKIFKLG

GRDSRSGSPMARR

gi|4505123|ref|NP_002376.1| myelin basic

protein isoform 2 [Homo sapiens]

MASQKRPSQRHGSKYLATASTM

348
MDL-104238

N-[4-(4-morpholinylcarbonyl)benzoyl]-L-valyl-
Anti-

N′-[3,3,4,4,4-pentafluoro-1-(1-methylethyl)-
inflammatory

2-oxobutyl]-L-2-azetamide

349
MDL-28050

D-Glutamic acid, N-[N-[N-[N-[N-[1-[N-[1-[N-
Antithrombotic

[N-(3-carboxy-1-oxopropyl)-L-tyrosyl]-L-alpha-
Anticoagulant

glutamyl]-L-prolyl]-L-isoleucyl]-L-prolyl]-L-

alpha-glutamyl]-L-alpha-glutamyl]-L-alanyl]-3-

cyclohexyl-L-alanyl]-

101
MMP

FN 439; FN-439; H2N-C6H4-CO-Gly-Pro-Leu-Ala-
Antiarthritic,

inhibitors

NHOH; MMP-inhibitor I; p-NH₂-Bz-Gly-Pro-D-Leu-
Anticancer,

D-Ala-NHOH
Anti-

inflammatory

350
MR-988

N-pivaloyl-leucyl-gamma-aminobutyric acid
Antiepileptic

351
mertiatide

Glycine, N-[N-[N-(mercaptoacetyl)glycyl]glycyl]-
Diagnostic

352
metkephamide

L-Methioninamide, L-tyrosyl-D-alanylglycyl-L-
Analgesic, other

353
murabutide

D-Glutamine, N2-[N-(N-acetylmuramoyl)-L-
Immunomodulator,

alanyl]-, butyl ester
anti-infective

Anticancer,

immunological

Immunostimu-

lant, other

354
muramyl

D-alpha-Glutamine, N2-[N-(N-acetylmuramoyl)-L-
Immunomodulator,

dipeptide

alanyl]-
anti-infective

derivatives

Anticancer,

immunological

Immunostimu-

lant, other

355
NPY24-36

N-acetyl[Leu-28Leu-31]NPY24-36
Antihypotensive

102
NAGA

Asn-Ala-Gly-Ala
Analgesic, other

356
tiplimotide

L-Proline, D-alanyl-L-lysyl-L-prolyl-L-valyl-L-
Multiple

valyl-L-histidyl-L-leucyl-L-phenylalanyl-L-
sclerosis

alanyl-L-asparaginyl-L-isoleucyl-L-valyl-L-
treatment

threonyl-L-prolyl-L-arginyl-L-threonyl-

103
opebecan

gi|157276599|ref|NP_001716.2| bactericidal/
Recombinant,

permeability-increasing protein precursor
other

[Homo sapiens]
Antibacterial,

MRENMARGPCNAPRWASLMVLVAIGTAVTAAVNPGV
other GI

VVRISQKGLDYASQQGTAALQKELKRIKIPDYSDSFKI
inflammatory/

KHLGKGHYSFYSMDIREFQLPSSQISMVPNVGLKFSIS
bowel

NANIKISGKWKAQKRFLKMSGNFDLSIEGMSISADLK
disorders

LGSNPTSGKPTITCSSCSSHINSVHVHISKSKVGWLIQL
Vulnerary

FHKKIESALRNKMNSQVCEKVTNSVSSELQPYFQTLP
Anti-

VMTKIDSVAGINYGLVAPPATTAETLDVQMKGEFYSEN
inflammatory

HHNPPPFAPPVMEFPAAHDRMVYLGLSDYFFNTAGLV
Symptomatic

YQEAGVLKMTLRDDMIPKESKFRLTTKFFGTFLPEVA
antidiabetic

KKFPNMKIQIHVSASTPPHLSVQPTGLTFYPAVDVQAF
Ophthalmological

AVLPNSSLASLFLIGMHTTGSMEVSAESNRLVGELKLD

RLLLELKHSNIGPFPVELLQDIMNYIVPILVLPRVNEKL

QKGFPLPTPARVQLYNVVLQPHQNFLLFGADVVYK

104
liraglutide
GLP-1
Glycine, L-histidyl-L-alanyl-L-alpha-
Antidiabetic

and

glutamylglycyl-L-threonyl-L-phenylalanyl-L-
Anorectic/

105

threonyl-L-seryl-L-alpha-aspartyl-L-valyl-L-
Antiobesity

seryl-L-seryl-L-tyrosyl-L-leucyl-L-alpha-

glutamylglycyl-L-glutaminyl-L-alanyl-L-alanyl-

N6-[N-(1-oxohexadecyl)-L-gamma-glutamyl]-

L-lysyl-L-alpha-glutamyl-L-phenylalanyl-L-

isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-

valyl-L-arginylglycyl-L-arginyl-

SFKIKHLGKGHYSFYSMDIREFQLPSSQISMVPNVGLK

FSISNANIKISGKWKAQKRFLKMSGNFDLSIE

106
Nona CCK

GMSISADLKLGSNPTSGKPTITCSSCSSHINSVHVHISK
Diagnostic

SKVGWLIQLFHKKIESALRNKMNSQVCEKVT
Neuroleptic

Anorectic/

Antiobesity

Antidepressant

107
NP-06

Cysteinyl-leucyl-glycyl-valyl-glycyl-seryl-
Antiviral,

and

cysteinyl-asparaginyl-aspartyl-phenylalanyl-
anti-HIV

108

alanyl-glycyl-cysteinyl-glycyl-tyrosyl-alanyl-

isoleucyl-valyl-cysteinyl-phenylalanyl-

tryptophanS-3.1-S-3.13:S-3.7-S-3.19-

bis(disulfide)N-2.1-C-4.9-lactam

NSVSSELQPYFQTLPVMTKIDSVAGINYGLVAPPATTAE

TLDVQMKGEFYSENHHNPPPFAPPVMEFPAA

109
NPC-18545

Bradykinin, N2-D-arginyl-3-(trans-4-hydroxy-L-
Anti-

proline)-7-(D-1,2,3,4-tetrahydro-3-
inflammatory

isoquinolinecarboxylic acid)-8-[L-

(2alpha,3aβ,7a.beta.)-octahydro-1H-indole-2-

carboxylic acid]-

HDRMVYLGLSDYFFNTAGLVYQEAGVLKMTLRDDMI

PKESKFRLTTKFFGTFLPEVAKKFPNMKIQIHVS

110
Nva-FMDP

Nva-N3-4-methoxyfumaroyl-L-2,3-diaminopropanoic
Antifungal

acid

ASTPPHLSVQPTGLTFYPAVDVQAFAVLPNSSLASLFLI

GMHTTGSMEVSAESNRLVGELKLDRLLLELK

111
nacartocin

6-Carbaoxytocin, 1-(3-mercaptopropanoic acid)-
Hormone

2-(4-ethyl-L-phenylalanine)-
Labour inducer

HSNIGPFPVELLQDIMNYIVPILVLPRVNEKLQKGFPLP
Anti-

TPARVQLYNVVLQPHQNFLLFGADVVYK
hypertensive,

diuretic

112
natural

U.S. Pat. No. 5,288,708
Antiulcer

peptide

Partial N terminal sequence: H₂N-Gly-Glu-Pro-
Hepatoprotective

Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-
Vulnerary

Val- . . . -COOH
Anti-

inflammatory

Antiparkinsonian

Urological

39
nesiritide
BNP
SPKMVQGSGCFGRKMDRISSSSGLGCKVLRRH
Cardiostimulant

citrate

Vasodilator,

coronary

113-
neurotrophic

U.S. Pat. No. 5,545,719:
Cognition

141
factors

AspLeuGlnValPheVal; GlyGluLysLysAsp;
enhancer

AlaThrHisGluSer;
Neuroprotective

CysLeuProValSerGly; LeuProValSerGlySer;

ProCysHisAlaProPro; GlyGlyHisAspLeuGluSerGly;

AspAspLeuGlnValPhe 15 ProLeuThrSerGly 15

LeuIleHisPheGluGluGlyVal 15 (2) INFORMATION FOR

SEQ ID NO: 11: (i) SEQUENCE CHARACTERISTICS: (A)

LENGTH: 7 amino acids (B) TYPE: amino acid (D)

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v)

FRAGMENT TYPE: internal (xi) SEQUENCE

DESCRIPTION: SEQ ID NO: ll: GlyGluPheSerTyrAspSer

15 (2) INFORMATION FOR SEQ ID NO: 12: (i)

SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino

acids (B) TYPE: amino acid (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE:

internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:

12: HisAlaProProLeuThrSer 15 (2) INFORMATION FOR

SEQ ID NO: 13: (i) SEQUENCE CHARACTERISTICS: (A)

LENGTH: 7 amino acids (B) TYPE: amino acid (D)

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v)

FRAGMENT TYPE: internal (xi) SEQUENCE

DESCRIPTION: SEQ ID NO: 13: AspLeuGluSerGlyGluPhe

15 (2) INFORMATION FOR SEQ ID NO: 14: (i)

SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino

acids (B) TYPE: amino acid (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE:

internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:

14: GlyGluPheSerValCysAspSer 15 (2) INFORMATION

FOR SEQ ID NO: 15: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 10 amino acids (B) TYPE: amino acid

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide

(v) FRAGMENT TYPE: internal (xi) SEQUENCE

DESCRIPTION: SEQ ID NO: 15:

LysLysGlyGluPheSerValAlaAspSer 1510 (2)

INFORMATION FOR SEQ ID NO: 16: (i) SEQUENCE

CHARACTERISTICS: (A) LENGTH: 9 amino acids (B)

TYPE: amino acid (D) TOPOLOGY: linear (ii)

MOLECULE TYPE: peptide (v) FRAGMENT TYPE:

internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:

16: LysLysGlyGluPheTyrCysSerArg 15 (2)

INFORMATION FOR SEQ ID NO: 17: (i) SEQUENCE

CHARACTERISTICS: (A) LENGTH: 13 amino acids (B)

TYPE: amino acid (D) TOPOLOGY: linear (ii)

MOLECULE TYPE: peptide (v) FRAGMENT TYPE:

internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:

17: GlyLeuArgValArgValTrpAsnGlyLysPheProLys 1510

(2) INFORMATION FOR SEQ ID NO: 18: (i) SEQUENCE

CHARACTERISTICS: (A) LENGTH: 16 amino acids (B)

TYPE: amino acid (D) TOPOLOGY: linear (ii)

MOLECULE TYPE: peptide (v) FRAGMENT TYPE:

internal (xi) SEQUENCE DESCRIPTION: SEQ ID

NO: 18:

GlyValAlaPheGluGluAlaProAspAspHisSerPhePheLeuPhe

151015 (2) INFORMATION FOR SEQ ID NO: 19: (i)

SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino

acids (B) TYPE: amino acid (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE:

internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:

19: GlyGlyHisAspLeuSerGly 15 (2) INFORMATION FOR

SEQ ID NO: 20: (i) SEQUENCE CHARACTERISTICS: (A)

LENGTH: 8 amino acids (B) TYPE: amino acid (D)

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v)

FRAGMENT TYPE: internal (xi) SEQUENCE

DESCRIPTION: SEQ ID NO: 20:

GlyGlyHisAspLeuGluSerGly 15 (2) INFORMATION FOR

SEQ ID NO: 21: (i) SEQUENCE CHARACTERISTICS: (A)

LENGTH: 14 amino acids (B) TYPE: amino acid (D)

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v)

FRAGMENT TYPE: internal (xi) SEQUENCE

DESCRIPTION: SEQ ID NO: 21:

GlyGlyHisAspLeuGluSerGlyGluPheSerTyrAspSer 1510

(2) INFORMATION FOR SEQ ID NO: 22: (i) SEQUENCE

CHARACTERISTICS: (A) LENGTH: 14 amino acids (B)

TYPE: amino acid (D) TOPOLOGY: linear (ii)

MOLECULE TYPE: peptide (v) FRAGMENT TYPE:

internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:

22: GlyGlySerAspLeuSerGlyGluPheSerValCysAspSer

1510 (2) INFORMATION FOR SEQ ID NO: 23: (i)

SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino

acids (B) TYPE: amino acid (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE:

internal (xi) SEQUENCE DESCRIPTION: SEQ ID

NO: 23:

GlyGlySerAspLeuSerGlyGlyGluPheSerValCysAspSer

151015 (2) INFORMATION FOR SEQ ID NO: 24: (i)

SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino

acids (B) TYPE: amino acid (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (v) FRAGMENT TYPE:

internal (xi) SEQUENCE DESCRIPTION: SEQ ID

NO: 24:

GlyGlySerAspLeuSerGlyGlyGluPheSerValAlaAspSer

151015 (2) INFORMATION FOR SEQ ID NO: 25: (i)

SEQUENCE CHARACTERISTICS: (A) LENGTH: 14

amino acids (B) TYPE: amino acid (D) TOPOLOGY:

linear (ii) MOLECULE TYPE: peptide (v) FRAGMENT

TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ

ID NO: 25:

GlyGlySerAspLeuSerGlyGluPheSerValAlaAspSer 1510

(2) INFORMATION FOR SEQ ID NO: 26: (i) SEQUENCE

CHARACTERISTICS: (A) LENGTH: 6 amino acids (B)

TYPE: amino acid (D) TOPOLOGY: linear (ii)

MOLECULE TYPE: peptide (v) FRAGMENT TYPE:

internal (xi) SEQUENCE DESCRIPTION: SEQ ID

NO: 26:

GluThrLeuGlnPheArg 15 (2) INFORMATION FOR SEQ ID

NO: 27: (i) SEQUENCE CHARACTERISTICS: (A)

LENGTH: 8 amino acids (B) TYPE: amino acid (D)

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v)

FRAGMENT TYPE: internal (xi) SEQUENCE

DESCRIPTION: SEQ ID NO: 27:

LysLysGluThrLeuGlnPheArg 15 (2) INFORMATION FOR

SEQ ID NO: 28: (i) SEQUENCE CHARACTERISTICS: (A)

LENGTH: 8 amino acids (B) TYPE: amino acid (D)

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (v)

FRAGMENT TYPE: internal (xi) SEQUENCE

DESCRIPTION: SEQ ID NO: 28:

GluThrLeuGlnPheArgLysLys 15 (2) INFORMATION FOR

SEQ ID NO: 29: (i) SEQUENCE CHARACTERISTICS: (A)

LENGTH: 9 amino acids (B) TYPE: amino acid (D)

TOPOLOGY: linear (ii)MOLECULETYPE: peptide(v)

FRAGMENT TYPE: internal (xi) SEQUENCE

DESCRIPTION: SEQ ID NO: 29:

LysAlaSerThrThrThrAsnTyrThr 15

357
nifalatide

L-Prolinamide, L-tyrosyl-4-(methylsulfinyl)-D-2-
Antidiarrhoeal

aminobutanoylglycyl-4-nitro-L-phenylalanyl-
Analgesic, other

358
Org-2766

L-Phenylalanine, 4-(methylsulfonyl)-L-2-
ACTH

aminobutanoyl-L-alpha-glutamyl-L-histidyl-L-
Symptomatic

phenylalanyl-D-lysyl-
antidiabetic

Radio/

chemoprotective

Neurological

359
Org-30035

L-Phenylalanine, glycylglycyl-L-phenylalanyl-4-
Neuroleptic

(methylsulfonyl)-L-2-aminobutanoyl-D-lysyl-
Anxiolytic

360
octreotide
somatostatin
L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-
Acromegaly

phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-
Antidiarrhoeal

[2-hydroxy-1-(hydroxymethyl)propyl]-, cyclic
Anticancer,

(2-7)-disulfide, [R-(R*,R*)]-; L-Cysteinamide,
hormonal

D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-

tryptophyl-L-lysyl-L-threonyl-N-(2-hydroxy-

1-(hydroxymethyl)propyl)-, cyclic (2-7)-

disulfide, (R-(R*,R*))-

142
osteogenic

Glycine, L-alanyl-L-leucyl-L-lysyl-L-arginyl-L-
Osteoporosis

growth

glutaminylglycyl-L-arginyl-L-threonyl-L-leucyl-
treatment

peptide

L-tyrosylglycyl-L-phenylalanylglycyl-

143
P-113

Angiotensin II, 1-(N-methylglycine)-5-L-valine-
Stomatological

8-L-alanine-[CAS]; (Sar(1), Ala(8))ANGII;
Antibacterial,

(Sar1,Val5,Ala8)Angiotensin II; 1 Sar 8 Ala
other

Angiotensin II; 1 Sarcosine 8 Alanine
Antifungal

Angiotensin II; 1-Sar-8-Ala Angiotensin II;

1-Sar-8-Ala-angiotensin II; 1-Sarcosine-8-

Alanine Angiotensin II; Acetate, Hydrated

Saralasin; Angiotensin II, 1-Sar-8-Ala;

Angiotensin II, 1-Sarcosine-8-Alanine; Anhydrous

Saralasin Acetate; Hydrated Saralasin Acetate;

P-113; P-113 Acetate; Sar Arg Val Tyr Val His

Pro Ala; Sar-Arg-Val-Tyr-Val-His-Pro-Ala;

Saralasin Acetate; Saralasin Acetate, Anhydrous;

Saralasin Acetate, Hydrated; angiotensin II,

Sar(1)-Ala(8)-; angiotensin II, sarcosyl(1)-

alanine(8)-

361
PACAP 27

Pituitary adenylate cyclase-activating peptide-27
Antiviral,

anti-HIV

362
PAPP

N-(dibenzyloxyphosphophionyl)-L-alanyl-L-prolyl-
Antihyperten-

L-proline
sive, other

363
PD-83176

CBZ-his-tyr(OBn)-ser(OBn)-trp-D-ala-NH₂
Anticancer,

other

364
PD-122264

N-[(1,1-dimethylethoxy)carbonyl]-alpha-
Anorectic/

methyltryptophyl-L-phenylalaninamide
Antiobesity

Analgesic, other

365
PD-132002

DL-Serinamide, N-(4-morpholinylsulfonyl)-L-
Antihyperten-

phenylalanyl-N-[1-(cyclohexylmethyl)-2,3-
sive, renin

dihydroxy-5-methylhexyl]-O-methyl-3-oxo-,
system

[1S-(1R*,2S*,3R*)]-

144
Penetratin

U.S. Pat. Nos. 5,888,762 and 6,080,762;
Formulation

PCT Pub. Nos. WO/2000/29427 and WO/2000/01417:
technology

NH2-Arg Lys Arg Gly Arg Gln Thr Tyr Thr Arg Tyr

Gln Thr Leu Glu Leu Glu Lys Glu Phe His Phe Asn

Arg Tyr Leu Thr Arg Arg Arg Arg lle Glu lle Ala

His Ala Leu Cys Leu Thr Glu Arg Gln lle Lys lle

Trp Phe Gln Asn Arg Arg Met Lys Trp Lys Lys Glu

Asn-COOH.

366
PL-030

Glycinamide, L-tyrosyl-L-prolyl-N-methyl-L-
Analgesic, other

phenylalanyl-D-prolyl-

367
POL-443

Z-prolyl-leucyl-tryptophan
Antihyperten-

sive, renin

system

368
POL-509

L-Tryptophan, N-[N-(5-oxo-L-prolyl)-L-leucyl]-,
Immunostimulant,

methyl ester-
other

369
PPA

D-phenylalanine-L-proline-L-arginylchloromethane
Anticoagulant

Diagnostic

Antithrombotic

145
PR-39

L-Prolinamide, L-arginyl-L-arginyl-L-arginyl-L-
Antibacterial,

prolyl-L-arginyl-L-prolyl-L-prolyl-L-tyrosyl-L-
other

leucyl-L-prolyl-L-arginyl-L-prolyl-L-arginyl-L-

prolyl-L-prolyl-L-prolyl-L-phenylalanyl-L-

phenylalanyl-L-prolyl-L-prolyl-L-arginyl-L-

leucyl-L-prolyl-L-prolyl-L-arginyl-L-isoleucyl-

L-prolyl-L-prolylglycyl-L-phenylalanyl-L-prolyl-

L-prolyl-L-arginyl-L-phenylalanyl-L-prolyl-L-

prolyl-L-arginyl-L-phenylalanyl-

146
tigapotide

L-Threonine, L-alpha-glutamyl-L-tryptophyl-L-
Anticancer,

triflutate

glutaminyl-L-threonyl-L-alpha-aspartyl-L-
other

asparaginyl-S-[(acetylamino)methyl]-L-cysteinyl-

L-alpha-glutamyl-L-threonyl-S-

[(acetylamino)methyl]-L-cysteinyl-L-threonyl-S-

[(acetylamino)methyl]-L-cysteinyl-L-tyrosyl-L-

alpha-glutamyl-, mono(trifluoroacetate)

370
PT-14

L-Lysinamide, N-acetyl-L-norleucyl-L-alpha-
Male sexual

aspartyl-L-histidyl-D-phenylalanyl-L-arginyl-L-
dysfunction

tryptophyl-, cyclic (2-7)-peptide
Female sexual

dysfunction

147
PT-5
somatostatin
gi|21619156|gb|AAH32625.1| Somatostatin
Anticancer,

[Homo sapiens]
other

MLSCRLQCALAALSIVLALGCVTGAPSDPRLRQFLQK

SLAAAAGKQELAKYFLAELLSEPNQTENDALEPEDLS

QAAEQDEMRLELQRSANSNPAMAPRERKAGCKNFFW

KTFTSC

148
semparatide
PTHrP
gi|131542|sp|P12272.1|PTHR_HUMAN Parathyroid
Hormone

hormone-related protein precursor (PTH-rP)
Osteoporosis

(PTHrP) [Contains: PTHrP[1-36]; PTHrP[38-94];
treatment

Osteostatin (PTHrP[107-139])]

MQRRLVQQWSVAVFLLSYAVPSCGRSVEGLSRRLKRA

VSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTAEIRATS

EVSPNSKPSPNTKNHPVFGSDDEGRYLTQETNKVETY

KEQPLKTPGKKKKGKPGKRKEQEKKKRRTRSAWLDS

GVTGSGLEGDHLSDTSTTSLELDSRRH

149
parathyroid
PTH
SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF
Osteoporosis

hormone

treatment

fragments

150
enfuvirtide

L-Phenylalaninamide, N-acetyl-L-tyrosyl-L-
Antiviral,

threonyl-L-seryl-L-leucyl-L-isoleucyl-L-
anti-HIV

histidyl-L-seryl-L-leucyl-L-isoleucyl-L-

alpha-glutamyl-L-alpha-glutamyl-L-seryl-L-

glutaminyl-L-asparaginyl-L-glutaminyl-L-

glutaminyl-L-alpha-glutamyl-L-lysyl-L-

asparaginyl-L-alpha-glutamyl-L-glutaminyl-

L-alpha-glutamyl-L-leucyl-L-leucyl-L-alpha-

glutamyl-L-leucyl-L-alpha-aspartyl-L-lysyl-

L-tryptophyl-L-alanyl-L-seryl-L-leucyl-L-

tryptophyl-L-asparaginyl-L-tryptophyl-

151
pentapeptide

Ala-Arg-Pro-Ala-Lys
Vasodilator,

6A

coronary

371
pentigetide

L-Arginine, N2-[1-[N-(N-L-alpha-aspartyl-L-
Antiallergic,

seryl)-L-alpha-aspartyl]-L-prolyl]-
non-asthma

Ophthalmological

Antiasthma

372
peptide

N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-
Ophthalmologic

analogues

triiodo-5-(2-methoxyacetamido)-N1-
Antiarthritic,

methylisophthalamide
other

Antiulcer

Antihyperten-

sive, other

Multiple

sclerosis

treatment

COPD treatment

373
peptide G

[Arg(6), D-Trp(7,9), MePhe(8)]substance P
Anticancer,

other

374
peptide T

D-Ala1-peptide T
Antiviral,

analogue

anti-HIV

375
peptide T

L-Threonine, N-[N-[N2-[N-[N-[N-(N-L-alanyl-L-
Analgesic, other

seryl)-L-threonyl]-L-threonyl]-L-threonyl]-L-
Antiviral, other

asparaginyl]-L-tyrosyl]-
Antiarthritic,

other GI

inflammatory/

bowel disorders

Anti-

inflammatory

152
pramlintide

1,2-Dithia-5,8,11,14,17-pentaazacycloeicosane,
Antidiabetic

cyclic peptide derivative U.S. Pat. No.
Anorectic/

5,998,367 gi|10066209|gb|AAE39671.1| Sequence 1
Antiobesity

from U.S. Pat. No. 5,998,367

KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY;

376
pranlukast

Benzamide, N-[4-oxo-2-(1H-tetrazol-5-yl)-4H-1-
Antiasthma

benzopyran-8-yl]-4-(4-phenylbutoxy)-; 8-(4(4-
Antiallergic,

phenylbutoxy)benzoyl)amino-2-(tetrazol-5′-yl)-
non-asthma

4-oxo-4H-1-benzopyran

3
proinsulin
proinsulin
gi|59036749|gb|AAW83741.1| proinsulin
Antidiabetic

[Homo sapiens]

MALWMRLLPLLALLALWGPDPAAAFVNQHLCGSHLV

EALYLVCGERGFFYTPKTRREAEDLQVGQVELGGGPG

AGSLQPLALEGSLQKRGIVEQCCTSICSLYQLENYCN

377
protirelin
TRH
L-Prolinamide, 5-oxo-L-prolyl-L-histidyl-;
Releasing

2-Nle-3-Prot-protirelin; TRH, Nle(2)-Prot(3)-;
hormone

pyroglutamyl-norleucyl-proline thioamide
Diagnostic

378
protirelin
TRH
prolinamide, 5-oxo-L-prolyl-L-histidyL-
Releasing

hormone

Cognition

enhancer

153
Ro-25-1553

L-Threoninamide, N-acetyl-L-histidyl-L-seryl-L-
Antiasthma

alpha-aspartyl-L-alanyl-L-valyl-L-phenylalanyl-
Anti-

L-threonyl-L-alpha-glutamyl-L-asparaginyl-L-
inflammatory

tyrosyl-L-threonyl-L-lysyl-L-leucyl-L-arginyl-L-

lysyl-L-glutaminyl-L-norleucyl-L-alanyl-L-

alanyl-L-lysyl-L-lysyl-L-tyrosyl-L-leucyl-L-

asparaginyl-L-alpha-aspartyl-L-leucyl-L-lysyl-L-

lysylglycylglycyl-, (25-21)-lactam

379
RWJ-51438

N-methylphenylalanyl-N-(4-
Antithrombotic

((aminoiminomethyl)amino)-1-((6-carboxy-2-

benzothiazolyl)carbonyl)butyl)prolinamide

380
TRH
TRH
L-Prolinamide, 5-oxo-L-prolyl-L-histidyl-3,3-
Diagnostic

dimethyl-; pyroGlu-His-Pro-NH₂ (or 5-oxo-L-
Thyroid hormone

prolyl-L-histidyl-L-prolinamide)

154
renin

Boc-Leu-Lys-Arg-Met-Pro-OMe
Antihyperten-

inhibitors

sive,

381
romurtide

L-Lysine, N2-[N2-[N-(N-acetylmuramoyl)-L-
Radio/

alanyl]-D-alpha-glutaminyl]-N6-(1-oxooctadecyl)-;
chemoprotective

L-Lysine, N2-(N2-(N-(N-acetylmuramoyl)-L-alanyl)-
Immunostimu-

D-alpha-glutaminyl)-N6-(1-oxooctadecyl)-
lant, other

382
S-17162

L-Tryptophan, N-[(2,3-
Urological

dihydroxypropoxy)hydroxyphosphinyl]-L-leucyl-,

disodium salt

383
S-2441

L-Argininamide, D-prolyl-L-phenylalanyl-N-
Antimigraine

heptyl-
Antigout

Septic shock

treatment

384
SDZ-CO-611
somatostatin
L-Cysteinamide, N-(1-deoxy-4-O-.alpha.-D-
Somatostatin

glucopyranosyl-D-fructopyranos-1-yl)-D-

phenylalanyl-L-cysteinyl-L-phenylalanyl-D-

tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-

(hydroxymethyl)propyl]-, cyclic (2.fwdarw.7)-

disulfide, [R-(R*,R*)]-

385
SK&F-101926

L-Argininamide, O-ethyl-N-[(1-
Antihyperten-

mercaptocyclohexyl)acetyl]-D-tyrosyl-L-
sive, diuretic

phenylalanyl-L-valyl-L-asparaginyl-L-

386
SK&F-110679

His-D-Trp-Ala-Trp-D-Phe-LysNH₂
Releasing

hormone

Vulnerary

387
edotreotide

[N-[2-[4,7-Bis[(carboxy-kappaO)methyl]-10-
Anticancer,

(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl-
hormonal

kappaN1,kappaN4,kappaN10]acetyl]-D-phenylalanyl-

L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-

threonyl-L-cysteinyl-L-threoninol cyclic (2-7)-

disulfidato(3-)]yttrium

155
SP-1

pGlu-Glu-Asp-Cys-Lys
Anticancer,

other

156
SPAAT

L-Lysine, L-methionyl-L-phenylalanyl-L-leucyl-L-
COPD treatment

alpha-glutamyl-L-alanyl-L-isoleucyl-L-prolyl-L-

methionyl-L-seryl-L-isoleucyl-L-prolyl-L-prolyl-

L-alpha-glutamyl-L-valyl-L-lysyl-L-phenylalanyl-

L-asparaginyl-L-lysyl-L-prolyl-L-phenylalanyl-L-

valyl-L-phenylalanyl-L-leucyl-L-methionyl-L-

isoleucyl-L-alpha-glutamyl-L-glutaminyl-L-

asparaginyl-L-threonyl-L-lysyl-L-seryl-L-prolyl-

L-leucyl-L-phenylalanyl-L-methionylglycyl-L-

lysyl-L-valyl-L-valyl-L-asparaginyl-L-prolyl-L-

threonyl-L-glutaminyl-

388
SR-41476

Z-Tyr-Val-Sta-Ala-Sta-OMe
Antiviral,

anti-HIV

389
SR-42128

1-[N-(3-methyl-1-oxobutyl)-L-phenylalanine]-2-L-
Antihyperten-

norleucine-
sive, renin

system

157
SR-42654

isoval-phe-norleu-sta-ala-sta-lys
Antihyperten-

sive, renin

system

147
SRIF-A
somatostatin
gi|21619156|gb|AAH32625.1| Somatostatin
Somatostatin

[Homo sapiens]
Haemostatic

MLSCRLQCALAALSIVLALGCVTGAPSDPRLRQFLQK
Alimentary/

SLAAAAGKQELAKYFLAELLSEPNQTENDALEPEDLS
Metabolic,

QAAEQDEMRLELQRSANSNPAMAPRERKAGCKNFFWKTFTSC
other

8-D-tryptophan-14-D-cysteinesomatostatin (sheep)

158
calcitonin
calcitonin
CSNLSTCVLGKLSQELHKLQTYPRTNTGSGTP
Osteoporosis

treatment

390
salmon
calcitonin
11,18-Arg-14-Lys-salmon calcitonin; 11,18-
Osteoporosis

calcitonin

arginyl-14-lysine-salmon calcitonin; Arg-Lys-
treatment

Arg-CT; calcitonin, salmon, arginyl(11,18)-

lysine(14)-

159
sermorelin

Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-
Idiopathic

Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-
growth hormone

Leu-Gln-Asp-Ile-Met-Ser-Arg-NH₂
deficiency

Imaging agent

391
saralasin

1-Sar-8-Ala-angiotensin; Angiotensin II, 1-(N-
Antihyperten-

acetate

methylglycine)-5-L-valine-8-L-alanine-
sive, renin

system

160
secretin

His-Ser-Asp-Gly-Thr-Phe-OMe; histidyl-seryl-
Haemostatic;

aspartyl-glycyl-threonyl-phenylalanine-O-methyl-
pancreatic

dysfunction

(diagnostic),

asthma, COPD,

others

159
sermorelin

Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-
Releasing

acetate

Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-
hormone

Asp-Ile-Met-Ser-Arg-NH₂
Diagnostic

161
sinapultide

L-Lysine, L-lysyl-L-leucyl-L-leucyl-L-leucyl-L-
Lung Surfactant

leucyl-L-lysyl-L-leucyl-L-leucyl-L-leucyl-L-

leucyl-L-lysyl-L-leucyl-L-leucyl-L-leucyl-L-

leucyl-L-lysyl-L-leucyl-L-leucyl-L-leucyl-L-

leucyl-

162
sleep inducing

Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu
Hypnotic/

peptide

Sedative

Dependence

treatment

163
somatoliberin

gi|11034841|ref|NP_066567.1| growth hormone
Growth hormone

releasing hormone preproprotein [Homo sapiens]
Releasing

MPLWVFFFVILTLSNSSHCSPPPPLTLRMRRYADAIFT
hormone

NSYRKVLGQLSARKLLQDIMSRQQGESNQERGARAR

LGRQVDSMWAEQKQMELESILVALLQKHSRNSQG

164
PTR-3173
somatostatin
Cyclic[(R)-βMeNphe-Phe-DTrp-Lys-Thr-Phe],
Acoegaly

MPLWVFFFVILTLSNSSHCSPPPPLTLRMRRYADAIFTN
Symptomatic

SYRKVLGQLSARKLLQDIMSRQQGESNQERG
antidiabetic

Ophthalmological

Urological

Anticancer,

hormonal

165
somatostatin
somatostatin
des-(Ala1,Gly2)-(D-Trp8,D-Asu(3,14))-
Acromegaly

analogue

somatostatin,
Antidiabetic

ARARLGRQVDSMWAEQKQMELESILVALLQKHSRNSQG
Diagnostic

392
somatostatin
somatostatin
cyclo-(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe)-
Acromegaly

analogues

somatostatin
Antidiabetic

393
somatostatin
somatostatin
3,14-Dicarbasomatostatin, 1-de-L-alanine-
Acromegaly

2-deglycine-3-butanoic acid-11-L-tyrosine-

394
somatostatin
somatostatin
3,14-Dicarbasomatostatin, 1-de-L-alanine-
Acromegaly

2-deglycine-3-butanoic acid-11-L-tyrosine-

395
syndyphalin

Glycinamide, L-tyrosyl-4-(methylsulfinyl)-
Analgesic, other

D-2-aminobutanoyl-N-methyl-N-(2-phenylethyl)-

166
synthetic

gi|109948285|ref|NP_001035971.1| poly(A)
Antiulcer

peptide BPC

binding protein, cytoplasmic 1-like 2B [Homo
Hepatoprotective

sapiens]
Vulnerary

MASLYVGDLHPEVTEAMLYEKFSPAGPILSIRICRDKIT
Anti-

RRSLGYAYVNYQQPVDAKRALETLNFDVIKG
inflammatory

RPVRIMWSQRDPSLRKSGVGNVFIKNLGKTIDNKALY
Antiparkinsonian

NIFSAFGNILSCKVACDEKGPKGYGFVHFQKQE
Musculoskeletal

SAERAIDVMNGMFLNYRKIFVGRFKSHKEREAERGA

WARQSTSADVKDFEEDTDEEATLR

167
T22

L-Argininamide, L-arginyl-L-arginyl-L-
Antiviral,

tryptophyl-L-cysteinyl-L-tyrosyl-L-arginyl-
anti-HIV

L-lysyl-L-cysteinyl-L-tyrosyl-L-lysylglycyl-

L-tyrosyl-L-cysteinyl-L-tyrosyl-L-arginyl-L-

lysyl-L-cysteinyl-, cyclic (4-17), (8-13)-

bis(disulfide)

396
Tc-99m

Technetium-99Tc, (cyclo(L-homocysteinyl-N-
Imaging agent

depreotide

methyl-L-phenylalanyl-L-tyrosyl-D-tryptophyl-

L-lysyl-L-valyl)(1-1′)-thioether with

3-((mercaptoacetyl)amino)-L-alanyl-L-lysyl-

L-cysteinyl-L-lysinamidato(3-))oxo-, (SP-5-24)-

397
Tc-99m-P280

13,13′-[Oxybis[methylene(2,5-dioxo-1,3-
Imaging agent

pyrrolidinediyl)]]bis[N-(mercaptoacetyl)-D-
Antithrombotic

tyrosyl-S-(3-aminopropyl)-L-cysteinylglycyl-L-

alpha-aspartyl-L-cysteinylglycylglycyl-S-

[(acetylamino)mehtyl]-L-cysteinylglycyl-S-

[(acetylamino)methyl-L-cysteinylglycylglycyl-L-

cysteinamide], cyclic (1 → 5), (1′ → 5′),

-bis(sulfide)

398
TEI-1345

(7E)-8-(2-naphthyl)-5,6-trans-5,6-methano-7-
Anti-

octenyl 3-(3,4-dimethoxyphenyl)-2-propenoate
inflammatory

168
THF

Leu-Glu-Asp-Gly-Pro-Lys-Phe-Leu; leucyl-
Immunomodulator,

glutamyl-aspartyl-glycyl-proly-lysyl-
anti-infective,

phenylalanyl-leucine
Immunostimulant,

anti-AIDS

169
Theradigm-

Dipalmitoyl-Lys-Ser-Ser-Gln-Tyr-Ile-Lys-Ala-Asn-
Immunomodulator,

HBV

Ser-Lys-Phe-Ile-Gly-Ile-Thr-Glu-Ala-Ala-Ala-Phe-
anti-infective,

Leu-Pro-Ser-Asp-Phe-Phe-Pro-Ser-Val-OH
Immunostimulant

80
tesamorelin
GHRF
gi|337133|gb|AAA52609.1| growth hormone
Musculoskeletal,

acetate

releasing factor
COPD, Hypnotic/

MPLWVFFFVILTLSNSSHCSPPPPLTLRMRRYADAIFTN
Sedative,

SYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL
Immunostimulant,

GRQVDSMWAEQKQMELESILVALLQKHRNSQG
Antidiabetic,

(3E)-Hex-3-enoylsomatoliberin (human) acetate
Anabolic,

salt)
Symptomatic

antidiabetic,

Vulnerary

170
TP-9201

L-Cysteinamide, N-acetyl-L-cysteinyl-L-
Neuroprotective,

asparaginyl-L-prolyl-L-arginylglycyl-L-alpha-
Antithrombotic,

aspartyl-O-methyl-L-tyrosyl-L-arginyl-,
Antianginal,

cyclic (1-9)-disulfide
Cardiovascular

399
TRH analogues
TRH
pyroGlu-His-Pro-NH₂ (or 5-oxo-L-prolyl-L-
Cognition

histidyl-L-prolinamide)
enhancer

400
TT-235

[β,β-(3-Thiapentamethylene)-β-sulfanylpropionic
Labour

acid, D-Trp2,Pen6,Arg8]-oxytocin acetate
inhibitor

401
tabilautide

L-Lysinamide, 6-carboxy-N6-[N-[N-(1-
Immunomodulator,

oxododecyl)-L-alanyl]-D-gamma-glutamyl]-,
anti-infective

(S)-
Radio/

chemoprotective

Immunostimulant,

other

171
terlipressin

N-[N-(N-glycylglycyl)glycyl]-8-L-lysine-;
Haemostatic;

and

Gly-Gly-Gly-8-Lys-vasopressin; N-(alpha)-
GI bleeding

172

glycyl-glycyl-glycyl-8-lysine vasopressin;

Gly-Gly-Gly-c[Cys-Tyr-Phe-Gln-Asn-Cys]-

Pro-Lys-Gly-NH₂; N-(N-(N-

glycylglycyl)glycyl)-8-L-lysinevasopressin

171
terlipressin

N-[N-(N-glycylglycyl)glycyl]-8-L-lysine-;
Haemostatic;

and

Gly-Gly-Gly-8-Lys-vasopressin; N-(alpha)-
GI bleeding

172

glycyl-glycyl-glycyl-8-lysine vasopressin;

Gly-Gly-Gly-c[Cys-Tyr-Phe-Gln-Asn-Cys]-

Pro-Lys-Gly-NH₂;

402
teverelix

D-Alaninamide, N-acetyl-3-(2-naphthalenyl)-
Anticancer,

D-alanyl-4-chloro-D-phenylalanyl-3-(3-
hormonal

pyridinyl)-D-alanyl-L-seryl-L-tyrosyl-N6-
Prostate

(aminocarbonyl)-D-lysyl-L-leucyl-N6-(1-
disorders

methylethyl)-L-lysyl-L-prolyl-
Menstruation

disorders

Fertility

enhancer Male

contraceptive

403
thymopentin

L-Tyrosine, N-[N-[N-(N2-L-arginyl-L-lysyl)-
Immunostimu-

L-alpha-aspartyl]-L-valyl]-; L-Tyrosine, N-
lant, other

(N-(N-(N2-L-arginyl-L-lysyl)-L-alpha-
Immunomodu-

aspartyl)-L-valyl)-
lator, anti-

infective

404
triletide

L-Histidine, N-[N-(N-acetyl-L-phenylalanyl)-L-
Antiulcer

phenylalanyl]-, methylester

405
tuftsin

L-Arginine, N2-[1-(N2-L-threonyl-L-lysyl)-L-
Anticancer,

prolyl]-
immunological

Immunostimulant,

other

173
Uroguanylin

Guanylin (rat reduced), 1-L-glutamine-2-L-
Alimentary/

glutamic acid-3-L-aspartic acid-6-L-leucine-8-
Metabolic, other

L-isoleucine-9-L-asparagine-10-L-valine-
Antidiarrhoeal

Diagnostic

174
VIC

gi|6681267|ref|NP_031929.1| endothelin 3
Gastroprokinetic

[Mus musculus]

MEPGLWLLLGLTVTSAAGLVPCPQSGDSGRASVSQGP

PEAGSERGCEETVAGPGERIVSPTVALPAQPESAGQER

APGRSGKQEDKGLPAHHRPRRCTCFTYKDKECVYYC

HLDIIWINTPEQTVPYGLSNYRESLRGKRSLGPVPESSQ

PSPWTRLRCTCMGADDKACAHFCARTRDVTSYSGRA

ERPAAEEMRETGGPRQRLMSRTDKAHRP

175
VIP

gi|5803023|ref|NP_006807.1| lectin, mannose-
Antiasthma

derivative

binding 2 [Homo sapiens]
Vasodilator,

MAAEGWIWRWGWGRRCLGRPGLLGPGPGPTTPLFLL
peripheral

LLLGSVTADITDGNSEHLKREHSLIKPYQGVGSSSMPL

WDFQGSTMLTSQYVRLTPDERSKEGSIWNHQPCFLKD

WEMHVHFKVHGTGKKNLHGDGIALWYTRDRLVPGP

VFGSKDNFHGLAIFLDTYPNDETTERVFPYISVMVNNG

SLSYDHSKDGRWTELAGCTADFRNRDHDTFLAVRYSR

GRLTVMTDLEDKNEWKNCIDITGVRLPTGYYFGASAG

TGDLSDNHDIISMKLFQLMVEHTPDEESIDWTKIEPSV

NFLKSPKDNVDDPTGNFRSGPLTGWRVFLLLLCALLGI

VVCAVVGAVVFQKRQERNKRFY

147
vapreotide,
somatostatin
gi|21619156|gb|AAH32625.1| Somatostatin [Homo
Formulation,

immediate-

sapiens]
modified-

release

MLSCRLQCALAALSIVLALGCVTGAPSDPRLRQFLQK
release,

SLAAAAGKQELAKYFLAELLSEPNQTENDALEPEDLS
immediate

QAAEQDEMRLELQRSANSNPAMAPRERKAGCKNFFW
Somatostatin

KTFTSC
Haemostatic

L-Tryptophanamide, D-phenylalanyl-L-cysteinyl-
Anticancer,

L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-
hormonal

cysteinyl-, cyclic (2-7)-disulfide-
Antidiarrhoeal

GI inflammatory/

bowel disorders

406
Pharmaprojects

L-Proline, 1-[N-[N-[1-[4-(4-hydroxyphenyl)-
Vasodilator,

No. 1269

1-oxobutyl]-L-prolyl]-.alpha.-methyl-DL-
renal

phenylalanyl]glycyl]-

407
Pharmaprojects

N(a)-((3S)-1-oxo-1,2,3,4-
Neuroleptic

No. 1583

tetrahydroisoquinoline-3-carbonyl)-L-histidyl-
Antiparkinsonian

L-prol inamide

408
Pharmaprojects

D-2-phenylglycyl-D-2-phenylglycine
Anticancer,

No. 1626

immunological

Immunostimulant,

other

409
Pharmaprojects

N-acyl-D-glutamyl-1-meso-diaminopimelyl-1-
Immunomodulator,

No. 1779

lysine tripeptide derivatives
anti-infective

Immunostimulant,

other

176
Pharmaprojects

Thr-Asp-Ser-Phe-Val-Gly-Leu-Methionylamide
Antihyperten-

No. 1876

sive, other

410
Pharmaprojects

L-leucyl-D-methionyl-glucyl-N-(2-adamantyl)-L-
Antihyperten-

No. 1913

phenylalanylamide
sive, renin

system

177
Pharmaprojects

Lys-Pro-Gly-Glu-Pro-Gly-Pro-Lys
Anticoagulant

No. 1939

178-
Pharmaprojects

U.S. Pat. No. 4,461,724 and European Patent No.
Antiulcer

182,
No. 2063

EP0078228: GSHK; ASHK; A_DSHK; LSHK; TSHK; YSHK;
Antithrombotic

178,

GSHKCH₃COOH•H₂O; SAR-SHK; PSHK; (PYR)ESHK; WSHK;

183-

GSHK•2TosOH

185

and

178

411
Pharmaprojects

N-methyl-D-Phe-Pro-Arg-H
Antithrombotic

No. 2363

186
Pharmaprojects

N-3-(4-hydroxyphenyl)propionyl-Pro-Hyp-Gly-Ala-
Antiarrhythmic

No. 2388

Gly

412
Pharmaprojects

Glp-lys-NH₂-L-mandelate
Anticancer,

No. 2425

immunological

Immunostimulant,

other

413
Pharmaprojects

D-1-Tiq-Pro-Arg-H-sulfate
Antithrombotic

No. 3341

414
Pharmaprojects

(2R,4S,5S,1′S)-5-(t-butoxycarbonyl)amino-4-
Antiviral,

No. 3415

hydroxy-N-[1′-isopropyl-1′-(4-
anti-HIV

isopropylcarbonylimidazol-2-yl)]methyl-6-phenyl-

2-phenylmethyl-hexanamide

415
Pharmaprojects

Piv-1-Ser-Leu-GABA, and Piv-Ser-Leu-GABA
Neurological

No. 4004

416
Pharmaprojects

(1R,4aR,8aR)-1,2,3,4,5,6,7,8-perhydroisoquinolin-
Antithrombotic

No. 4323

1-carbonyl-(L)-prolinyl-(L)-arinine aldehyde
Anticoagulant

187,
Pharmaprojects

H-Trp-Ala-Ser-Gly-L-Asn-OH & H-Trp-D-Ala-Ser-Gly-
Hypnotic/

and
No. 491

Asp(OH)₂
Sedative

417

Antidepressant

Neuroprotective

188
Pharmaprojects

H₂N-Asp-Ala-Asp-Pro-Arg-Gln-Tyr-Ala-COOH
Anti-

No. 4975

inflammatory

418
Pharmaprojects

2-Amino-N-{1-(R)-benzyloxymethyl-2-[4-
Osteoporosis

No. 5200

(morpholine-4-carbonyl)-4-phenyl-piperidin-1-yl]-
treatment

2-oxo-ethyl}-isobutyramide

419
Pharmaprojects

4-chloro-phenylcarbamoyl-thienylalanyl-leucyl-
Anti-

No. 5356

phenylalanine
inflammatory

Anti-infective,

other

420
DMP-444

synthetic cyclic pentapeptide (cyclo(D-Val-
Imaging agent

NMeArg-Gly-Asp-Mamb))with a tethered

hydrazinonicotinyl (HYNIC) chelator for

radiolabelling with 99mTc

189
RIP-3

MSCVKLWPSGAPAPLVSIEELENQELVGKGGFGTVFR
Anticancer,

AQHRKWGYDVAVKIVNSKAISREVKAMASLDNEFVL
other

RLEGVIEKVNWDQDPKPALVTKFMENGSLSGLLQSQC

PRPWPLLCRLLKEVVLGMFYLHDQNPVLLHRDLKPS

NVLLDPELHVKLADFGLSTFQGGSQSGTGSGEPGGTL

GYLAPELFVNVNRKASTASDVYSFGILMWAVLAGREV

ELPTEPSLVYEAVCNRQNRPSLAELPQAGPETPGLEGL

KELMQLCWSSEPKDRPSFQECLPKTDEVFQMVENNM

NAAVSTVKDFLSQLRSSNRRFSIPESGQGGTEMDGFRR

TIENQHSRNDVMVSEWLNKLNLEEPPSSVPKKCPSLT

KRSRAQEEQVPQAWTAGTSSDSMAQPPQTPETSTFRN

QMPSPTSTGTPSPGPRGNQGAERQGMNWSCRTPEPNP

VTGRPLVNIYNCSGVQVGDNNYLTMQQTTALPTWGL

APSGKGRGLQHPPPVGSQEGPKDPEAWSRPQGWYNHSGK

421
Pharmaprojects

N-(N-acetyl-1-isoleucyl-L-tyrosyl)-(−)-1-amino-
Antihyperten-

No. 955

2-(4-hydroxyphenyl)ethylphosphonic acid
sive, other

422
leuprolide

6-D-leucine-9-(N-ethyl-L-prolinamide)-10-
Formulation,

deglycinamide-
modified-

release,

Anticancer

190
edratide

L-glycyl-L-tyrosyl-L-tyrosyl-L-tryptophyl-L-
Immunosuppres-

seryl-L-tryptophyl-L-isoleucyl-L-arginyl-L-
sant

glutaminyl-Lprolyl-L-prolyl-L-glycyl-L-lysyl-

L-glycyl-L-glutamyl-L-glutamyl-L-tryptophyl-

L-isoleucyl-L-glycine

423
Prosaptide

H-Thr-D-Ala-Leu-Ile-Asp-Asn-Asn-Ala-Thr-Glu-
Symptomatic

TX14(A)

Glu-Ile-Leu-Tyr-OH
antidiabetic

Neurological

Analgesic, other

8
GLP-1
GLP-1
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS
Antidiabetic

160
secretin

His-Ser-Asp-Gly-Thr-Phe-OMe; histidyl-seryl-
Hormone,

aspartyl-glycyl-threonyl-phenylalanine-O-methyl-
Diagnostic, GI

inflammatory/

bowel

disorders,

Neurological,

Neuroleptic

147
BIM-23190
somatostatin
gi|21619156|gb|AAH32625.1| Somatostatin
Acromegaly

[Homo sapiens]
Antidiabetic

MLSCRLQCALAALSIVLALGCVTGAPSDPRLRQFLQK

SLAAAAGKQELAKYFLAELLSEPNQTENDALEPEDLS

QAAEQDEMRLELQRSANSNPAMAPRERKAGCKNFFW

KTFTSC

L-Threoninamide, N-[[4-(2-hydroxyethyl)-1-

piperazinyl]acetyl]-D-phenylalanyl-L-cysteinyl-

L-tyrosyl-D-tryptophyl-L-lysyl-(2S)-2-

aminobutanoyl-L-cysteinyl-,cyclic (2-7)-disulfide

191
β-amyloid
beta-amyloid
gi|8176533|gb|AAB26264.2| beta-amyloid peptide
Cognition

peptides
peptide
precursor; beta APP [Homo sapiens]
enhancer

GSGLTNIKTEEISEVKMDAEFRHDSGYEVHHQKLVFFA

EDVGSNKGAIIGLMVGGVVIATVIIITLVMLK

KQYTSNHHGVVE

425
oglufanide

L-tryptophan, L-alpha-glutamyl-, disodium salt
Immunomodula-

disodium

tor, anti-

infective

Anticancer,

immunological

192
HAV peptide

leucyl-arginyl-alanyl-histidyl-alanyl-valyl-
Neurological

matrix

aspartyl-valyl-asparaginyl-glycinamide

149
PTH 1-34
PTH
SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF
Hormone

leuprorelin

6-D-leucine-9-(N-ethyl-L-prolinamide)-10-
Anticancer

deglycinamide-

193
TRP-2

H-Leu-Leu-Pro-Gly-Gly-Arg-Pro-Tyr-Arg-OH
Anticancer,

immunological

426
golotimod

(2R)-2-amino-5-[[(1S)-1-carboxy-2-(1H-indol-3-
Immunostimulant,

yl)ethyl]amino]-5-oxopentanoic acid
other

Immunomodulator,

anti-infective

Anticancer,

immunological

Stomatological

194
angiotensin-
Angiotensin
gi|28710|emb|CAA77513.1| angiotensin II
Vulnerary

II
II
[Homo sapiens]
Symptomatic

MILNSSTEDGIKRIQDDCPKAGRHNYIFVMIPTLYSIIFV
antidiabetic

VGIFGNSLVVIVIYFYMKLKTVASVFLLNLALADLCFL

LTLPLWAVYTAMEYRWPFGNYLCKIASASVSFNLYASV

FLLTCLSIDRYLAIVHPMKSRLRRTMLVAKVTCIIIWLL

AGLASLPAIIHRNVFFIENTNITVCAFHYESQNSTLPIGL

GLTKNILGFLFPFLIILTSYTLIWKALKKAYEIQKNKPR

NDDIFKIIMAIVLFFFFSWIPHQIFTFLDVLIQLGIIRDCR

IADIVDTAMPITICIAYFNNCLNPLFYGFLGKKFKRYFL

QLLKYIPPKAKSHSNLSTKMSTLSYRPSDNVSSSTKKP

APCFEVE

195
omiganan

L-lysinamide, L-isoleucyl-L-leucyl-L-arginyl-L-
Formulation,

tryptophyl-L-prolyl-L-tryptophyl-L-tryptophyl-
dermal, topical

L-prolyl-L-tryptophyl-L-arginyl-L-arginyl,
Peptide

pentahydrochloride
antibiotic

Antiacne

427
leuprorelin

6-D-leucine-9-(N-ethyl-L-prolinamide)-10-
Transmucosal,

deglycinamide-
nasal,

Menstruation

disorders,

Anticancer,

hormonal,

Fertility

enhancer

428
delmitide

D-Tyrosinamide, D-arginyl-D-norleucyl-D-
GI

acetate

norleucyl-D-norleucyl-D-arginyl-D-norleucyl-D-
inflammatory/

norleucyl-D-norleucylglycyl-, monoacetate
bowel disorders,

Radio/

chemoprotective,

Antipsoriasis,

Antipruritic/

inflamm, aller-

gic, Multiple

sclerosis

treatment,

Alimentary/

Metabolic,

other,

Antiviral,

anti-HIV,

Antiasthma, COPD

treatment,

Respiratory

Stomatological

196
cat PAD

MRGALLVLALLVTQALGVKMAETCPIFYDVFFAVANG
Antiasthma

NELLLDLSLTKVNATEPERTAMKKIQDCYVENGLISRV
Antiallergic,

LDGLVMTTISSSKDCMGEAVQNTVEDLKLNTLGR
non-asthma

429
NOV-002

bis-(gamma-L-glutamyl)-L-cysteinyl-bis-glycin
Anticancer,

disodium salt
immunological

Radio/

chemosensitizer

Antidote

430
GPG-NH2

glycyl-prolyl-glycine amide
Antiviral,

anti-HIV

431
ABT-510

NAc-Sar-Gly-ValDalloleThrNValleArgProNHE
Anticancer,

other

8
CJC-1131
GLP-1
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS
Antidiabetic

432
desmopressin

Vasopressin, 1-(3-mercaptopropanoic acid)-8-D-
Formulation,

arginine-
oral,

Hormone,

Antidiabetic,

Urological

197
metastin

MNSLVSWQLLLFLCATHFGEPLEKVASVGNSRPTGQQ
Anticancer,

LESLGLLAPGEQSLPCTERKPAATARLSRRGTSLSPPPE
other

SSGSPQQPGLSAPHSRQIPAPQGAVLVQREKDLPNYNW

NSFGLRFGKREAAPGNHGRSAGRG

433
leuprorelin

5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-
Anticancer

L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-

prolinamide acetate (salt)

434
SGS-111

N-phenylacetylprolylglycine ethyl ester
Cognition

enhancer

Neuroprotective

435
taltobulin

(4S)-4-[[(2S)-3,3-dimethyl-2-[[(2S)-3-methyl-2-
Anticancer,

(methylamino)-3-
other

phenylbutanoyl]amino]butanoyl]methylamino]-2,5-

dimethylhex-2-enoic acid

436
leuprolide

6-D-leucine-9-(N-ethyl-L-prolinamide)-10-
inhalable,

deglycinamide-
systemic,

Anticancer,

Menstruation

disorders

103
XOMA-629

gi|157276599|ref|NP_001716.2| bactericidal/
Antiacne

permeability-increasing protein precursor
Anti-infective,

[Homo sapiens]
other

MRENMARGPCNAPRWASLMVLVAIGTAVTAAVNPGV

VVRISQKGLDYASQQGTAALQKELKRIKIPDYSDSFKI

KHLGKGHYSFYSMDIREFQLPSSQISMVPNVGLKFSIS

NANIKISGKWKAQKRFLKMSGNFDLSIEGMSISADLK

LGSNPTSGKPTITCSSCSSHINSVHVHISKSKVGWLIQL

FHKKIESALRNKMNSQVCEKVTNSVSSELQPYFQTLP

VMTKIDSVAGINYGLVAPPATTAETLDVQMKGEFYSEN

HHNPPPFAPPVMEFPAAHDRMVYLGLSDYFFNTAGLV

YQEAGVLKMTLRDDMIPKESKFRLTTKFFGTFLPEVA

KKFPNMKIQIHVSASTPPHLSVQPTGLTFYPAVDVQAF

AVLPNSSLASLFLIGMHTTGSMEVSAESNRLVGELKLD

RLLLELKHSNIGPFPVELLQDIMNYIVPILVLPRVNEKL

QKGFPLPTPARVQLYNVVLQPHQNFLLFGADVVYK

198
synthetic

gi|8393713|ref|NP_058651.1| Sep (O-phosphoserine)
Antianaemic

erythropoiesis

tRNA: Sec (selenocysteine) tRNA synthase isoform
Radio/

pro

1 [Homo sapiens]
chemoprotective

MSTSYGCFWRRFIHGIGRSGDISAVQPKAAGSSLLNKI

TNSLVLDIIKLAGVHTVANCFVVPMATGMSLTLCFLTL

RHKRPKAKYIIWPRIDQKSCFKSMITAGFEPVVIENVLE

GDELRTDLKAVEAKVQELGPDCILCIHSTTSCFAPRVP

DRLEELAVICANYDIPHIVNNAYGVQSSKCMHLIQQG

ARVGRIDAFVQSLDKNFMVPVGGAIIAGFNDSFIQEIS

KMYPGRASASPSLDVLITLLSLGSNGYKKLLKERKEM

FSYLSNQIKKLSEAYNERLLHTPHNPISLAMTLKTLDE

HRDKAVTQLGSMLFTKQVSGARVVPLGSMQTVSGYT

FRGFMSHTNNYPCAYLNAASAIGMKMQDVDLFINRL

DRCLKAVRKERSKESDDNYDKTEDVDIEEMALKLDN

VLLDTYQDASS

191
β-amyloid
beta-
gi|8176533|gb|AAB26264.2| beta-amyloid peptide
Cognition

amyloid
precursor; beta APP [Homo sapiens]
enhancer

vaccine
peptide
GSGLTNIKTEEISEVKMDAEFRHDSGYEVHHQKLVFFA

EDVGSNKGAIIGLMVGGVVIATVIIITLVMLKKQYTSN

HHGVVE

437
sincalide

1-De-(5-oxo-L-proline)-2-de-L-glutamine-5-L-
Imaging agent

methioninecaerulein
Alimentary/

Metabolic

438
albiglutide

([8-glycine]human glucagon-like peptide 1-
Antidiabetic

(7-36)-peptidyl)([8-glycine]human glucagon-like
Anorectic/

peptide 1-(7-36)-peptidyl)(human serum albumin
Antiobesity

(585 residues))

199
SB-144

gi|13899257|ref|NP_113622.1| transmembrane and
Anticancer,

ubiquitin-like domain containing 1 [Homo sapiens]
other Radio/

MTLIEGVGDEVTVLFSVLACLLVLALAWVSTHTAEGG
chemosensitizer

DPLPQPSGTPTPSQPSAAMAATDSMRGEAPGAETPSLR

HRGQAAQPEPSTGFTATPPAPDSPQEPLVLRLKFLNDSE

QVARAWPHDTIGSLKRTQFPGREQQVRLIYQGQLLGD

DTQTLGSLHLPPNCVLHCHVSTRVGPPNPPCPPGSEPG

PSGLEIGSLLLPLLLLLLLLLWYCQIQYRPFFPLTATLGL

AGFTLLLSLLAFAMYRP

200
exenatide LAR

L-histidylglycyl-L-glutamylglycyl-L-threonyl-L-
Antidiabetic

phenylalanyl-L-threonyl-L-seryl-L-aspartyl-L-

leucyl-L-seryl-L-lysyl-L-glutaminyl-L-methionyl-

L-glutamyl-L-glutamyl-L-glutamyl-L-alanyl-L-

valyl-L-arginyl-L-leucyl-L-phenylalanyl-L-

isoleucyl-L-glutamyl-L-tryptophyl-L-leucyl-

L-lysyl-L-asparaginylglycylglycyl-L-prolyl-L-

seryl-L-serylglycyl-L-alanyl-L-prolyl-L-prolyl-

L-prolyl-L-serinamide

201
BA-058
PTHrP
gi|131542|sp|P12272.1|PTHR_HUMAN Parathyroid
Osteoporosis

hormone-related protein precursor (PTH-rP)
treatment

(PTHrP) [Contains: PTHrP[1-36]; PTHrP[38-94];

Osteostatin (PTHrP[107-139])]

MQRRLVQQWSVAVFLLSYAVPSCGRSVEGLSRRLKRA

VSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTAEIRATS

EVSPNSKPSPNTKNHPVRFGSDDEGRYLTQETNKVET

YKEQPLKTPGKKKKGKPGKRKEQEKKKRRTRSAWLD

SGVTGSGLEGDHLSDTSTTSLELDSRRH

8
BIM-51077
GLP-1
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS
Antidiabetic

[(aminoisobutyric acid) 8, 35]hGLP- 1(1-36)NH 2,

has the same amino acid sequence as human

GLP-1(7-36 amide) except for the replacement of

amino acids 8 and 35 with α-aminoisobutyric acid

(Aib) to reduce protease susceptibility.

202
TM-701

H-Met-Cys-Met-Pro-Cys-Phe-Thr-Thr-Asp-His-Gln-
Anticancer,

Met-Ala-Arg-Lys-Cys-Asp-Asp-Cys-Cys-Gly-Gly-Lys-
other Radio/

Gly-Arg-Gly-Lys-Cys-Tyr-Gly-Pro-Gln-Cys-Leu-Cys-
chemosensitizer

Arg-NH₂

(Disulfide bridge: 2-19, 5-28, 16-33, 20-35)

439
CZEN-002

[dNal(2′)-7,Phe-12]-α-MSH 6-13
Antifungal,

Antibacterial,

other, Antivi-

ral, anti-HIV,

Immunosuppres-

sant, Metabolic

and enzyme

disorders, Anti-

inflammatory,

Antiarthritic,

other GI

inflammatory/

bowel disorders

203
ZP-120

Ac-RYYRWKKKKKKK-NH₂
Cardiostimulant

204
CTT

H-Cys-Thr-Thr-His-Trp-Gly-Phe-Thr-Leu-Cys-OH
Formulation

technology

205
PYY3-36

gi|71361686|ref|NP_0041512| peptide YY [Homo
Anorectic/

sapiens]
Antiobesity

MVFVRRPWPALTTVLLALLVCLGALVDAYPIKPEAPRE

DASPEELNRYYASLRHYLNLVTRQRYGKRDGPDTLLS

KTFFPDGEDRPVRSRSEGPDLW

AEZS-130

EP1572 UMV1843 [Aib-DTrp-DgTrp-CHO]
Growth hormone

Anabolic

Musculoskeletal

206
AL-108

H-Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln-OH
Neuroprotective

Cognition

enhancer

Antiparkinsonian

Ophthalmological

202
TM-801

H-Met-Cys-Met-Pro-Cys-Phe-Thr-Thr-Asp-His-Gln-
Imaging agent

Met-Ala-Arg-Lys-Cys-Asp-Asp-Cys-Cys-Gly-Gly-Lys-

Gly-Arg-Gly-Lys-Cys-Tyr-Gly-Pro-Gln-Cys-Leu-Cys-

Arg-NH₂

(Disulfide bridge: 2-19, 5-28, 16-33, 20-35)

202
TM-901

H-Met-Cys-Met-Pro-Cys-Phe-Thr-Thr-Asp-His-Gln-
Anticancer,

Met-Ala-Arg-Lys-Cys-Asp-Asp-Cys-Cys-Gly-Gly-Lys-
other Imaging

Gly-Arg-Gly-Lys-Cys-Tyr-Gly-Pro-Gln-Cys-Leu-Cys-
agent

Arg-NH₂

(Disulfide bridge: 2-19, 5-28, 16-33, 20-35)

440
S-0373
TRH
pyroGlu-His-Pro-NH₂ (or 5-oxo-L-prolyl-L-
Neurological

histidyl-L-prolinamide)
Psychostimulant

Antiparkinsonian

205
PYY3-36

gi|71361686|ref|NP_004151.2| peptide YY [Homo
Formulation,

sapiens]
oral, other

MVFVRRPWPALTTVLLALLVCLGALVDAYPIKPEAPRE
Anorectic/

DASPEELNRYYASLRHYLNLVTRQRYGKRDGPDTLLS
Antiobesity

KTFFPDGEDRPVRSRSEGPDLW

207
XG-101

gi|4885433|ref|NP_005447.1| mitogen-activated
Immunological

protein kinase 8 interacting protein 1 [Homo
Cardiovascular

sapiens]
Neuroprotective

MAERESGGLGGGAASPPAASPFLGLHIASPPNFRLTHD
Immunosuppres-

ISLEEFEDEDLSEITDECGISLQCKDTLSLRPPRAGLLSA
sant

GGGGAGSRLQAEMLQMDLIDATGDTPGAEDDEEDDD

EERAARRPGAGPPKAESGQEPASRGQGQSQGQSQGPG

SGDTYRPKRPTTLNLFPQVPRSQDTLNNNSLGKKHSW

QDRVSRSSSPLKTGEQTPPHEHICLSDELPPQSGPAPTT

DRGTSTDSPCRRSTATQMAPPGGPPAAPPGGRGHSHR

DRIHYQADVRLEATEEIYLTPVQRPPDAAEPTSAFLPPT

ESRMSVSSDPDPAAYPSTAGRPHPSISEEEEGFDCLSSP

ERAEPPGGGWRGSLGEPPPPPRASLSSDTSALSYDSVK

YTLVVDEHAQLELVSLRPCFGDYSDESDSATVYDNCA

SVSSPYESAIGEEYEEAPRPQPPACLSEDSTPDEPDVHF

SKKFLNVFMSGRSRSSSAESFGLFSCIINGEEQEQTHRA

IFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNMR

TGARGVFPAYYAIEVTKEPEHMAALAKNSDWVDQFR

VKFLGSVQVPYHKGNDVLCAAMQKJATTRRLTVHFN

PPSSCVLEISVRGVKIGVKADDSQEAKGNKCSHFFQLK

NISFCGYHPKNNKYFGFITKHPADHRFACHVFVSEDST

KALAESVGRAFQQFYKQFVEYTCPTEDIYLE

208
XG-102

gi|4885433|ref|NP_005447.1| mitogen-activated
Neuroprotective

protein kinase 8 interacting protein 1 [Homo
Cardiovascular

sapiens]
Otological

MAERESGGLGGGAASPPAASPFLGLHIASPPNFRLTHD
Ophthalmological

ISLEEFEDEDLSEITDECGISLQCKDTLSLRPPRAGLLSA
Antiparkinsonian

GGGGAGSRLQAEMLQMDLIDATGDTPGAEDDEEDDD
Immunosuppres-

EERAARRPGAGPPKAESGQEPASRGQGQSQGQSQGPG
sant

SGDTYRPKRPTTLNLFPQVPRSQDTLNNNSLGKKHSW

QDRVSRSSSPLKTGEQTPPHEHICLSDELPPQSGPAPTT

DRGTSTDSPCRRSTATQMAPPGGPPAAPPGGRGHSHR

DRIHYQADVRLEATEEIYLTPVQRPPDAAEPTSAFLPPT

ESRMSVSSDPDPAAYPSTAGRPHPSISEEEEGFDCLSSP

ERAEPPGGGWRGSLGEPPPPPRASLSSDTSALSYDSVK

YTLVVDEHAQLELVSLRPCFGDYSDESDSATVYDNCA

SVSSPYESAIGEEYEEAPRPQPPACLSEDSTPDEPDVHF

SKKFLNVFMSGRSRSSSAESFGLFSCIINGEEQEQTHRA

IFRFVPRHEDELELEVDDPLLVELQAEDYWYEAYNMR

TGARGVFPAYYAIEVTKEPEHMAALAKNSDWVDQFR

VKFLGSVQVPYHKGNDVLCAAMQKIATTRRLTVHFN

PPSSCVLEISVRGVKGVKADDSQEAKGNKCSHFFQLK

NISFCGYHPKNNKYFGFITKHPADHRFACHVFVSEDST

KALAESVGRAFQQFYKQFVEYTCPTEDIYLE

441
lanreotide SR

L-Threonamide, 3-(2-naphthalenyl)-D-alanyl-L-
Formulation,

cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-
modified-

valyl-L-cysteinyl-, cyclic (2-7)-disulfide
release, other

Somatostalin

Antihyperten-

sive, other

209
OGP-(10-14)-L

H-Tyrosine-Glycine-Phenylalanine-Glycine-
Haematological

Glycine-OH
Musculoskeletal

210
WP9QY

cyclo(Tyr-Cys-Trp-Ser-Gln-Tyr-Leu-Cys-Tyr);
Antiarthritic,

cyclo(tyrosyl-cysteinyl-tryptophyl-seryl-
other Anti-

glutaminyl-tyrosyl-leucyl-cysteinyl-tyrosyl)
inflammatory

211
aviptadil

His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-
Antihyperten-

Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-
sive, other

Ser-Ile-Leu-Asn
Respiratory

Immunosuppres-

sant

212
AL-209

Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala
Neuroprotective

Cognition

enhancer

Ophthalmological

442
octreotide

L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-
Formulation,

phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-
implant

[2-hydroxy-1-(hydroxymethyl)propyl]-, cyclic
Formulation,

(2-7)-disulfide, [R-(R*,R*)]-
modified-

release, >24 hr

Somatostatin

213
CDX-110

Leu-Glu-Glu-Lys-Lys-Gly-Asn-Tyr-Val-Val-Thr-Asp-
Recombinant

His-Cys-KLH
vaccine

Anticancer,

immunological

444
desmopressin

Vasopressin, 1-(3-mercaptopropanoic acid)-8-D-
Hormone,

arginine-
Urological,

Reproductive/

gonadal, general

445
obinepitide

[34-L-glutamine]pancreatic hormone (human)
Anorectic/

Insulin

Insulin (ox), 8A-L-threonine-10A-L-isoleucine-
Antiobesity

30B-L-threonine-
solubility-

enhanced Insulin

171
terlipressin

N-(N-(N-glycylglycyl)glycyl)-8-L-
Hepatoprotec-

lysinevasopressin [CAS}; Gly-Gly-Gly-8-Lys-
tive,

vasopressin; N-(alpha)-glycyl-glycyl-glycyl-8-
Urological,

lysine vasopressin; Remestyp; TGLVP; glipressin;
Gi bleeding

glycylpressin; glypressin; terlypressin;

triglycyl lysine vasopressin; triglycyl-(8-

lysine)vasopressin; triglycylvasopressin;

vasopressin, tri-Gly-8-Lys-

214
ZT-153

Asn-Phe-Gly-Ala-Ile-Leu; NFGAIL; asparagyl-
Antidiabetic

phenylalanyl-glycyl-alanyl-isoleucyl-leucine;

islet amyloid polypeptide (22-27)

215,
FGLL

gi|42544189|ref|NP_004458.3| fibrinogen-like 1
Cognition

215

precursor [Homo sapiens]
enhancer

and

MAKVFSFILVTTALTMGREISALEDCAQEQMRLRAQV
Neurological

216

RLLETRVKQQQVKIKQLLQENEVQFLDKGDENTVIDL

GSKRQYADCSEIFNDGYKLSGFYKIKPLQSPAEFSVYC

DMSDGGGWTVIQRRSDGSENFNRGWKDYENGFGNF

VQKHGEYWLGNKNLHFLTTQEDYTLKIDLADFEKNS

RYAQYKNFKVGDEKNFYELNIGEYSGTAGDSLAGNFH

PEVQWWASHQRMKFSTWDRDHDNYEGNCAEEDQSG

WWFNRCHSANLNGVYYSGPYTAKTDNGIVWYTWHG

WWYSLKSVVMKIRPNDFIPNVI

gi|42544200|ref|NP_963846.1| fibrinogen-Like 1

precursor [Homo sapiens]

MAKVFSFILVTTALTMGREISALEDCAQEQMRLRAQV

RLLETRVKQQQVKIKQLLQENEVQFLDKGDENTVIDL

GSKRQYADCSEIFNDGYKLSGFYKIKPLQSPAEFSVYC

DMSDGGGWTVIQRRSDGSENFNRGWKDYENGFGNF

VQKHGEYWLGNKNLHFLTTQEDYTLKIDLADFEKNS

RYAQYKNFKVGDEKNFYELNIGEYSGTAGDSLAGNFH

PEVQWWASHQRMKFSTWDRDHDNYEGNCAEEDQSG

WWFNRCHSANLNGVYYSGPYTAKTDNGIVWYTWHG

WWYSLKSVVMKIRPNDFIPNVI

gi|42544198|ref|NP_671736.2| fibrinogen-like 1

precursor [Homo sapiens]

MAKVFSFILVTTALTMGREISALEDCAQEQMRLRAQV

RLLETRVKQQQVKIKQLLQENEVQFLD

217
ST-03

gi|386634|gb|AAB27460.1|01-ST-3 = heat-stable
Recombinant

enterotoxin [Vibrio cholerae, 01, Peptide, 19 aa]
growth factor

NLIDCCEICCNPACFGCLN
Musculoskeletal

Osteoporosis

treatment

446
cetrorelix

D-Alaninamide, N-acetyl-3-(2-naphthalenyl)-D-
Formulation,

acetate

alanyl-4-chloro-D-phenylalanyl-3-(3-pyridinyl)-
modified-

D-alanyl-L-seryl-L-tyrosyl-N5-(aminocarbonyl)-
release, >24 hr

D-ol-L-leucyl-L-arginyl-L-prolyl-
Menstruation

disorders

218
neurode-

alpha toxin, Naja; cobra alpha toxin; cobra
Cognition

generative

toxin alpha; toxin alpha, cobra;
enhancer

ther

gi|64054|emb|CAA26373.1| unnamed protein product

[Laticauda semifasciata]

MKTLLLTLVVVTIVCLDLGYTRICFNHQSSQPQTTKTC

SPGESSCYNKQWSDFRGTIIERGCGCPTVKPGIKLSCC

ESEVCNN

gi|4519816|dbj|BAA75752.1| short chain

neurotoxin [Laticauda semifasciata]

MKTLLLTLVVVTIVCLDLGYTRICFNHQSSQPQTTKTC

SPGESSCYNKQWSDFRGTIIERGCGCPTVKPGIKLSCC

ESEVCNN

gi|32140561|dbj|BAC78199.1| erabutoxin

a [Laticauda semifasciata]

MKTLLLTLVVVTIVCLDLGYTRICFNHQSSQPQTTKTC

SPGESSCYNKQWSDFRGTIIERGCGCPTVKPGIKLSCC

ESEVCNN

gi|32140563|dbj|BAC78200.1| erabutoxin

a [Laticauda semifasciata]

MKTLLLTLVVVTIVCLDLGYTRICFNHQSSQPQTTKTC

SPGESSCYNKQWSDFRGTIIERGCGCPTVKPGIKLSCC

ESEVCNN

219
CT-319

MSNKKIIKIIKLQIPGGKANPAPPIGPALGAAGVNIMGF
Antiviral,

CKEFNAATQDRPGDLLPVVIT
anti-HIV

VYSDKTFSFVMKQSPVSSLIKKALGLESGSKIPNRNKV

GKLTRAQITVIAEQKMKDMDVV

LLESAERMVEGTARSMGVDVE

447
Peptide T

L-Threonine, N-(N-(N2-(N-(N-(N-(N-D-alanyl-L-
Antipsoriasis

seryl)-L-threonyl)-L-threonyl)-L-threonyl)-L-
Multiple

asparaginyl)-L-tyrosyl)-[CAS]; HIV Peptide T;
sclerosis

Peptide T, HIV
treatment

Cognition

enhancer

Musculoskeletal

220
APP-018

pallidin [Mus musculus]
Hypolipaemic/

and

gi|9790039|ref|NP_062762.1|[9790039]
Anti-

221

MSVPEPPPPDGVLTGPSDSLEAGEPTPGLSDTSPDEGLI
atherosclerosis

EDFPVDDRAVEHLVGGLLSHY

LPDLQRSKRALQELTQNQVVLLDTLEQEISKFKECHS

MLDINALFTEAKHYHAKLVTIRK

EMLLLHEKTSKLKKRALKLQQKRQREELEREQQREK

EFEREKQLTAKPAKRT

envelope glycoprotein [Human immunodeficiency

virus type 1]

gi|4205319|gb|AAD11044.1|[4205319]

KLTPLCVTLNCTDLDLRNTTNNTTTEERGEMKNCSFN

ITTNIRDRYQKEYALFYKLDVIP

IKEDNTSDNTSYRLISCNTSVITQACPKIS

222
somatropin

gi|60651145|gb|AAX31661.1| somatotropin
Formulation,

[Bubalus bubalis]
transmucosal,

AFPAMSLSSLFANAVLRAQHLHQLAADTFKEFERTYI
nasal Growth

PEGQRYSIQNTQVAFCFSETIPA
hormone Anabolic

PTGKNEAQQKSDLELLRISLLLIQSWLGPLQFLSRVFT
Reproductive/

NSLVFGTSDRVYEKLKDLEEGI
gonadal, general

LALMRELEDGTPRAGQILKRTYDKFDTNMRSDDALL

KNYGLLSCFRKDLHKTETYLRVMKCRRFGEASCAF

448
heparin

6-[5-acetamido-4,6-dihydroxy-2-
Formulation,

(sulfooxymethyl)oxan-3-yl]oxy-3-[5-(6-carboxy-
transmucosal,

4,5-dihydroxy-3-sulfooxyoxan-2-yl)oxy-6-
nasal

(hydroxymethyl)-3-(sulfoamino)-4-sulfooxyoxan-
Anticoagulant

2-yl]oxy-4-hydroxy-5-sulfooxyoxane-2-carboxylic

acid

46
CGRP
CGRP
ACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVGSKAF-NH₂
Cardiovascular

Cardiostimulant

449
YM-216391

A concise total synthesis of the unusual
Anticancer,

oxazole-based cyclopeptide structure YM-216391,
other

which also establishes the stereochemistry of

the natural product i.e. 1, is described. The

unusual polyoxazole-thiazole-based cyclopeptide

1, designated YM-216391, was recently isolated

from Streptomyces nobilis. 1 It shares both a

structural and biological homology with the

potent telomerase inhibitor telomestatin 2 which

is showing promise in cancer

chemotherapy. 2 The structure of YM-216391

comprises a continuum of five azoles which have

their origins in serine, cysteine and

phenylalanine, linked via a glycine valine

isoleucine tripeptide tether. The complete

stereochemical assignment of YM-216391 has not

been established. In this communication we

describe a concise total synthesis of the

cyclopeptide, which not only confirms its unique

structure but also allows the assignment of its

stereochemistry, shown in formula 1. Thus, the

2,4-disubstituted oxazoles 3 and 4 and the

trisubstituted oxazole 5 were first elaborated

223
FGLm

LSENDEWTQDRAKP
Cognition

enhancer

Neurological

224
prohanin

NPFPTWRKRPG
Analgesic, other

225
heart failure
NP
gi|189079|gb|AAA36355.1| natriuretic peptide
Cardiostimulant

therapy

MDPQTAPSRALLLLLFLHLAFLGGRSHPLGSPGSASDL

ETSGLQEQRNHLQGKLSELQVEQTSLEPLQES

PRPTGVWKSREVATEGIRGHRKMVLYTLRAPRSPKMV

QGSGCFGRKMDRISSSSGLGCKVLRRH

450
SEN-304

D-[(chG)Y-(chG)(chG)(MeL)]-NH₂, where chG is R-
Cognition

cyclohexylglycine
enhancer Anti-

inflammatory

451
Primacoll

Synthetic growth factor
Musculoskeletal

452
Octreotide

L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-
Formulation,

phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-
modified-

[2-hydroxy-1-(hydroxymethyl)propyl]-, cyclic
release, >24 hr

(2-7)-disulfide, [R-(R*,R*)]-
Symptomatic

antidiabetic

Ophthalmological

Somatostatin

453
ALS-02

Glycine, N-(aminoiminomethyl)-N-methyl-
Neuroprotective

200
exendin-4,
GLP-1
L-histidylglycyl-L-glutamylglycyl-L-threonyl-L-
Antidiabetic

PC-DAC

phenylalanyl-L-threonyl-L-seryl-L-aspartyl-L-

leucyl-L-seryl-L-lysyl-L-glutaminyl-L-methionyl-

L-glutamyl-L-glutamyl-L-glutamyl-L-alanyl-L-

valyl-L-arginyl-L-leucyl-L-phenylalanyl-L-

isoleucyl-L-glutamyl-L-tryptophyl-L-leucyl-L-

lysyl-L-asparaginylglycylglycyl-L-prolyl-L-

seryl-L-serylglycyl-L-alanyl-L-prolyl-L-prolyl-

L-prolyl-L-serinamide

226
Exenatide

gi|1916067|gb|AAB51130.1| exendin 4 [Heloderma
Formulation,

suspectum]
transmucosal,

MKIILWLCVFGLFLATLFPISWQMPVESGLSSEDSASSE
nasal

SFASKIKRHGEGTFTSDLSKQMEEEAVRLFIEWLKNGG
Antidiabetic

PSSGAPPPSG

225
Cardeva
BNP
gi|113836|sp|P16860.1|ANFB_HUMAN Natriuretic
Cardiostimulant

peptides B precursor [Contains: Gamma-brain

natriuretic peptide; Brain natriuretic peptide

32 (BNP-32)]

MDPQTAPSRALLLLLFLHLAFLGGRSHPLGSPGSASDL

ETSGLQEQRNHLQGKLSELQVEQTSLEPLQES

PRPTGVWKSREVATEGIRGHRKMVLYTLRAPRSPKMV

QGSGCFGRKMDRISSSSGLGCKVLRRH

227
Alloferon

H-His-Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-
Immunomodulator,

His-Gly-OH
anti-infective

454
PAC-G31P

AMCF-I; Alveolar Macrophage Chemotactic Factor
Recombinant

I; Alveolar Macrophage Chemotactic Factor-I;
interleukin

Anionic Neutrophil Activating Peptide; Anionic
Respiratory

Neutrophil-Activating Peptide; CXCL8 Chemokine;
Antiasthma

CXCL8 Chemokines; CXCL8, Chemokine; Chemokine
COPD treatment

CXCL8; Chemokine, CXCL8; Chemokines, CXCL8;

Chemotactic Factor, Macrophage Derived;

Chemotactic Factor, Macrophage-Derived;

Chemotactic Factor, Neutrophil; Chemotactic

Factor, Neutrophil, Monocyte-Derived; Chemotactic

Peptide-Interleukin-8, Granulocyte; Granulocyte

Chemotactic Peptide Interleukin 8; Granulocyte

Chemotactic Peptide-Interleukin-8; IL-8; IL8;

Interleukin 8; Lymphocyte-Derived Neutrophil-

Activating Peptide; Macrophage-Derived

Chemotactic Factor; Monocyte-Derived Neutrophil

Chemotactic Factor; Monocyte-Derived Neutrophil-

Activating Peptide; Neutrophil Activating

Peptide,Lymphocyte Derived; Neutrophil

Activating Peptide, Monocyte Derived; Neutrophil

Activation Factor; Neutrophil Chemotactic

Factor; Neutrophil-Activating Peptide, Anionic;

Neutrophil-Activating Peptide

228
PAC-525

Ac-KWRRWVRWI-NH₂
Antibacterial,

other

229,
PAC-113

Lys-Phe-His-Glu-Lys-His-His-Ser-His-Arg-Gly-Tyr
Antifungal

229

histatin 10, human; histatin 11, human; histatin

and

12, human; histatin 3, human; histatin 4, human;

230

histatin 5, human; histatin 6, human; histatin

7, human; histatin 8, human; histatin 9, human;

histatin-3 (1-24), human; histatin-3 (1-25),

human; histatin-3 (12-24), human; histatin-3

(12-25), human; histatin-3 (12-32), human;

histatin-3 (13-25), human; histatin-3 (5-11),

human; histatin-3 (5-12), human; lysyl-

phenylalanyl-histidyl-glutamyl-lysyl-histidyl-

histidyl-seryl-histidyl-arginyl-glycyl-tyrosine

gi|4557653|ref|NP_000191.1| histatin 3 [Homo

sapiens]

MKFFVFALILALMLSMTGADSHAKRHHGYKRKFHEK

HHSHRGYRSNYLYDN

231
MLIF

Met-Gln-Cys-Asn-Ser
Anti-

U.S. Pat. No. 6,524,591
inflammatory

454
carfilzomib

L-Phenylalaninamide, (alphaS)-alpha-[(4-
Anticancer,

morpholinylacetyl)amino]benzenebutanoyl-L-
other

leucyl-N-[(1S)-3-methyl-1-[[(2R)-2-

methyloxiranyl]carbonyl]butyl]-

232
NAFB001

gi|63025222|ref|NP_000651.3| transforming growth
Ophthalmological

factor, beta 1 [Homo sapiens]
Hepatoprotective

MPPSGLRLLPLLLPLLWLLVLTPGRPAAGLSTCKTIDM

ELVKRKRIEAIRGQILSKLRLASPPSQGEVPP

GPLPEAVLALYNSTRDRVAGESAEPEPEPEADYYAKEV

TRVLMVETHNEIYDKFKQSTHSIYMFFNTSEL

REAVPEPVLLSRAELRLLRLKLKVEQHVELYQKYSNN

SWRYLSNRLLAPSDSPEWLSFDVTGVVRQWLSR

GGEIEGFRLSAHCSCDSRDNTLQVDINGFTTGRRGDLA

TIHGMNRPFLLLMATPLERAQHLQSSRHRRAL

DTNYCFSSTEKNCCVRQLYIDFRKDLGWKWIHEPKGY

HANFCLGPCPYIWSLDTQYSKVLALYNQHNPGA

SAAPCCVPQALEPLPIVYYVGRKPKVEQLSNMIVRSCKCS [PIR]

233
IL12-NGR

H-Cys-Asn-Gly-Arg-Cys-Gly-OH (Disulfide bridge:
Recombinant,

1-5)
other Cytokine

Anticancer,

immunological

234
enterostatin

Val-Pro-Val-Asp; Val-Pro-Asp-Pro-Arg
Anorectic/

and

Antiobesity

235

455
octreotide

L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-
Formulation,

phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-
modified-

[2-hydroxy-1-(hydroxymethyl)propyl]-, cyclic
release, >24 hr

(2-7)-disulfide, [R-(R*,R*)]-
Somatostatin

150
enfuvirtide

L-Phenylalaninamide, N-acetyl-L-tyrosyl-L-
Formulation,

threonyl-L-seryl-L-leucyl-L-isoleucyl-L-histidyl-
parenteral,

L-seryl-L-leucyl-L-isoleucyl-L-alpha-glutamyl-L-
needle-free

alpha-glutamyl-L-seryl-L-glutaminyl-L-
Antiviral, anti-

asparaginyl-L-glutaminyl-L-glutaminyl-L-alpha-
HIV

glutamyl-L-lysyl-L-asparaginyl-L-alpha-glutamyl-

L-glutaminyl-L-alpha-glutamyl-L-leucyl-L-leucyl-

L-alpha-glutamyl-L-leucyl-L-alpha-aspartyl-L-

lysyl-L-tryptophyl-L-alanyl-L-seryl-L-leucyl-L-

tryptophyl-L-asparaginyl-L-tryptophyl-

236
PR-21

gi|2213924|gb|AAB61615.1| neural cell adhesion
Neurological

molecule [Homo sapiens]
Cognition

MLQTKDLIWTLFFLGTAVSLQVDIVPSQGEISVGESKFF
enhancer

LCQVAGDAKDKDISWFSPNGEKLTPNQQRIS

VVWNDDSSSTLTIYNANIDDAGIYKCVVTGEDGSESE

ATVNVKIFQKLMFKNAPTPQEFREGEDAVIVCD

VVSSLPPTIIWKHKGRDVILKKDVRFIFLSNNYLPIPGI

KKTDEGTYRCEGRILARGEINFNDIQVIVNV

PPTIQARQNIVNATANLGQSVTLVCDAEGFPGPTMSW

TKDGEQIEQEEHDEKYLFSDDSSHLTIKKVDKN

HEAENICIAENKVGEQDATIHLKVFAKPQITYVEDQTA

MELAEQVILTVEASGDHIPYITWWTSTWQI

237
AC-163794
GIP
gi|183221|gb|AAA53192.1| gastric inhibitory
Antidiabetic

polypeptide precursor

MVATKTFALLLLSLFLAVGLGEKKEGHFSALPSLPVGS

HAKVSSPQPRGPRYAEGTFISDYSIAMDKIHQ

QDFVNWLLAQKGKKNDWKHNITQREARALELASQA

NRKEEEAVEPQSSPAKNPSDEDLLRDLLIQELLAC

LLDQTNLCRLRSR;

456
glucagon

Glucagon (1-29); Glukagon; HG Factor; HG-Factor;
Formulation,

Hyperglycemic Glycogenolytic Factor;
transdermal,

Hyperglycemic-Glycogenolytic Factor; Proglucagon
systemic

(33-61)
hypoglycemia

457
Insulin

Insulin (ox), 8A-L-threonine-10A-L-isoleucine-
Formulation,

30B-L-threonine-
oral, other

Formulation,

optimized,

nanoparticles

Antidiabetic

458
Dekafin-2

DNA Synthesis Factor; Fibroblast Growth Factor;
Anticancer,

Fibroblast Growth Regulatory Factor; Growth
other

Factor, Fibroblast; Growth Factors, Fibroblast

238
relaxin

(1) Glu-Leu-Tyr-Ser-Ala-Leu-Ala.Asn-Lys-Cys-Cys-
Recombinant

and

His-Val-Gly-Cys-Thr-Lys-Arg-Ser-Leu-Ala-Arg-Phe-
hormone Hormone

239

Cys
Labour inducer

(2) H-Asp-Ser-Trp-Met-Glu-Glu-Val-Ile-Lys-Leu-
Antihyperten-

Cys-Gly-Arg-Glu-Leu-Val-Arg-Ala-Gln-Ile-Ala-Ile-
sive, other

Cys-Gly-Met-Ser-Thr-Ser

Cys 11 of each chain form disulfide bond; cys 24

of the first chain forms disulfide bond with cys

23 of chain 2

459
rhNRG-1

Differentiation Factor, neu; GGF Protein; Glial
Recombinant,

Growth Factor; Heregulin; NDF Protein; NRG1
other

Protein; Neuregulin 1; neu Differentiation
Cardiostimulant

Factor

240
c-peptide
C-peptide
Glu-Ala-Glu-Asp-Leu-Gln-Val-Gly-Gln-Val-Glu-
Symptomatic

analogue

Leu-Gly-Gly-Gly-Pro-Gly-Ala-Gly-Ser-Leu-Gln-
antidiabetic

Pro-Leu-Ala-Leu-Glu-Gly-Ser-Leu-Gln

241
SB-101

gi|30353933|gb|AAH52287.1| CD44 protein [Homo
Recombinant,

sapiens]
other

MDKFWWHAAWGLCLVPLSLAQIDLNITCRFAGVFHV
Anticancer,

EKNGRYSISRTEAADLCKAFNSTLPTMAQMEKAL
other

SIGFETCSST

242
Britistatin

gi|66270695|gb|AAY43681.1| disintegrin isoform
Antithrombotic

D-1 [Bitis arietans]

SPPVCGNKILEQGEDCDCGSPANCQDRCCNAATCKLT

PGSQCNYGECCDQCRFKKAGTVCRIARGDWNDDYCT

GKSSDCPWNH

243
echistatin

gi|208338|gb|AAA72777.1| echistatin
Antithrombotic

MECESGPCCRNCKFLKEGTICKRARGDDLDDYCNGK

TCDCPRNPHKGPAT

244
gastrin

gi|4503923:20-101 gastrin preproprotein [Homo
diabetes

sapiens]

EASWKPRSQQPDAPLGTGANRDLELPWLEQQGPASH

HRRQLGPQGPPHLVADPSKKQGPWLEEEEEAYGWMD

FGRRSAEDEN

245
herpes

gi|9629447:1-23 envelope glycoprotein D [Human
Prophylactic

simplex

herpesvirus 1]
vaccine

vaccine

MGGAAARLGAVILFVVIVGLHGV

246
neurotensin

gi|5453816:152-163 neurotensin/neuromedin N
Analgesic, other

preproprotein [Homo sapiens]

LYENKPRRPYIL

247
nociceptin

gi|5453922|ref|NP_006219.1| prepronociceptin
Neurological

[Homo sapiens]
Cognition

MKVLLCDLLLLSLFSSVFSSCQRDCLTCQEKLHPALDS
enhancer

FDLEVCILECEEKVFPSPLWTPCTKVMARSSWQLSPAA
Analgesic, other

PEHVAAALYQPRASEMQHLRRMPRVRSLFQEQEEPEP

GMEEAGEMEQKQLQKRFGGFTGARKSARKLANQKR

FSEFMRQYLVLSMQSSQRRRTLHQNGNV

248
oxyntomodulin

sp|P01275.3|GLUC_HUMAN:53-89 Glucagon precursor
Obesity;

[Contains: Glicentin; Glicentin-related
Antiulcer

polypeptide (GRPP); Oxyntomodulin (OXY)(OXM)]

HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA

249
pancreastatin

gi|164417:256-304 chromogranin A precursor
Antidiabetic

GWPQAPAMDGAGKTGAEEAQPPEGKGAREHSRQEEE

EETAGAPQGLFRG

250
relaxin
Relaxin
gi|5902052|ref|NP_008842.1| relaxin 1
Recombinant

preproprotein [Homo sapiens]
hormone

MPRLFLFHLLEFCLLLNQFSRAVAAKWKDDVIKLCGR
Hormone

ELVRAQIAICGMSTWSKRSLSQEDAPQTPRPVAEIVPSF
Labour inducer

INKDTETIIIMLEFIANLPPELKAALSERQPSLPELQQYV

PALKDSNLSFEEFKKLIRNRQSEAADSNPSELKYLGLD

THSQKKRRPYVALFEKCCLIGCTKRSLAKYC

251
secretin

gi|11345450:28-54 secretin preproprotein
Haemostatic;

[Homo sapiens]
diagnostic of

HSDGTFTSELSRLREGARLQRLLQGLV
pancreatic

dysfunction,

asthma, COPD,

others

252
TIMP

MAPFEPLASGILLLLWLIAPSRACTCVPPHPQTAFCNSD
Recombinant,

LVIRAKFVGTPEVNQTTLYQRYEIKMTKMYKGFQALG
other Vulnerary

DAADIRFVYTPAMESVCGYFHRSHNRSEEFLIAGKLQ
Antiarthritic,

DGLLHITTCSFVAPWNSLSLAQRRGFTKTYTVGCEECT
other

VFPCLSIPCKLQSGTHCLWTDQLLQGSEKGFQSRHLAC
Stomatological

LPREPGLCTWQSLRSQIA

253
tendamistat

Asp-Thr-Thr-Val-Ser-Glu-Pro-Ala-Pro-Ser-Cys-Val-
Antidiabetic

Thr-Leu-Tyr-Gln-Ser-Trp-Arg-Tyr-Ser-Gln-Ala-Asp-

Asn-Gly-Cys-Ala-Gln-Thr-Val-Thr-Val-Lys-Val-Val-

Tyr-Glu-Asp-Asp-Thr-Glu-Gly-Leu-Cys-Tyr-Ala-Val-

Ala-Pro-Gly-Gln-Ile-Thr-Thr-Val-Gly-Asp-Gly-Tyr-

Ile-Gly-Ser-His-Gly-His-Ala-Arg-Tyr-Leu-Ala-Arg-

Cys-Leu

254
thymosin β4

gi|11056061|ref|NP_066932.1| thymosin, beta 4
Vulnerary

[Homo sapiens]
Ophthalmological

MSDKPDMAEIEKFDKSKLKKTETQEKNPLPSKETIEQEKQAGES
Symptomatic

antidiabetic

Dermatological

Cardiovascular

Septic shock

treatment

Antiasthma

255
urodilatin

Thr-Ala-Pro-Arg-Ser-Leu-Arg-Arg-Ser-Ser-Cys-Phe-
Cardiostimulant

Gly-Gly-Arg-Met-Asp-Arg-Ile-Gly-Ala-Gln-Ser-Gly-
Urological

Leu-Gly-Cys-Asn-Ser-Phe-Arg-Tyr
Antiasthma

256
Pharmaprojects

Gly-Ser-Arg-Ala-His-Ser-Ser-His-Leu-Lys
Anticancer,

No. 6236

other

Antiarrhythmic

Antiparkinsonian

Cognition

enhancer

Neuroprotective

257
ANUP-1

Glu-Leu-Lys-Cys-Tyr-Thr-Cys-Lys-Glu-Pro-Met-Thr-
Anticancer,

Ser-Ala-Ala-Cys
other

258
DMI-4983

Asp-Ala-His-Lys
Cardiovascular

460
Glypromate

Gly-Pro-Glu
Neuroprotective

259
CD-NP

Lys Met Val Gln Gly Ser Gly Cys Phe Gly Arg Lys
Cardiostimulant

Met Asp Ile Ser Ser Ser Ser Gly Leu Gly Cys Pro

Ser Leu Arg Asp Pro Arg Pro Asn Ala Pro Ser Thr

Ser Ala

260
Kisspeptin-54

GTSLSPPPESSGSPQQPGLSAPHSRQIPAPQGAVLVQRE
Cancer

KDLPNYNWNSFGLRF-NH2
metastasis,

angiogenesis

261
Kisspeptin-14

DLPNYNWNSFGLRF-NH2
Cancer

metastasis,

angiogenesis

262
Kisspeptin-13

LPNYNWNSFGLRF-NH2
Cancer

metastasis,

angiogenesis

263
Kisspeptin-10

YNWNSFGLRF-NH2
Cancer

metastasis,

angiogenesis

264
Ziconotide

CKGKGAKCSRLMYDCCTGSCRSGKC

461
Biphalin

Tyr-D-Ala-Gly-Phe-NH-NH-Phe-Gly-D-Ala-Tyr

39
Nesiritide
Brain
SPKMVQGSGCFGRKMDRISSSSGLGCKVLRRH

Netriuritic

peptide

(BNP)

40
CD-NP

GLSKGCFGLKLDRIGSMSGLGCPSLRDPRPNAPSTSA

265
Protegrin-1
Cytolytic
RGGRLCYCRRRFCVCVGR-NH2
antibiotic

266
V681

Ac-KWKSFLKTFKSAVKTVLHTALKAISS-NH2

462
V681

Ac-KWKSFLKTFKSA(AD)KTVLHTALKAISS-NH2
‘(AD)’ discloses

(V13A_D)

the D-

configuration

of Alanine

267
V681 des A12

KWKSFLKTFKSVKTVLHTALKAISS

268
V681 V13K

KWKSFLKTFKSAKKTVLHTALKAISS

269
V681 V13K,

KWKSFLKTFKSAKKKVLHTALKAISS

T15K

270
GLP-2
GLP
HADGSFSDEMNTILDNLAARDFINWLIQTKITD

271
GLP-2 (A2G)
GLP
HGDGSFSDEMNTILDNLAARDFINWLIQTKITD

272
GLP-2
GLP
HGDGSFSDEMNTILDNLAARDFINWLIQTKITDC

(A2G/C34)

273
AOD-9604
Human Growth
LRIVQCASVEGSCGFY
Musculoskel-

Hormone

etal, COPD,

Hypnotic/

Sedative,

Immunostimulant,

Antidiabetic,

Anabolic,

Symptomatic

antidiabetic,

Vulnerary

274
Ac-AOD-
Human Growth
Ac-LRIVQCAKVEGSCGFY
Musculoskeletal,

9604(S8K)
Hormone

COPD, Hypnotic/

Sedative,

Immunostimulant,

Antidiabetic,

Anabolic,

Symptomatic

antidiabetic,

Vulnerary

275
Ac-AOD-
Human Growth
Ac-LRIVQCASVEGSCGFYK
Musculoskeletal,

9604(K17)
Hormone

COPD, Hypnotic/

Sedative,

Immunostimulant,

Antidiabetic,

Anabolic,

Symptomatic

antidiabetic,

Vulnerary

276
C-peptide
Insulin
EAEDLQVGQVELGGGPGAGSLQPLALEGSLQ

463
CR845
Opioids
peripherally-selective kappa embedded image

opioid receptor agonists D-Phe-D-Phe-D-Leu-D-Lys-[□(4- aminopiperidine-4-carboxylic acid)]-OH
acute and chronic pain of visceral, inflammatory and neuropathic origin, and for the treatment of pruritis (itch)

277
Protegrin-2
Cytolytic
RGGRLCYCRRRFCICV
antibiotic

278
Protegrin-3
Cytolytic
RGGGLCYCRRRFCVCVGRG
antibiotic

279
Protegrin-4
Cytolytic
RGGRLCYCRGWICFCVGRG
antibiotic

280
Protegrin-5
Cytolytic
RGGRLCYCRPRFCVCVGRG
antibiotic

281
Preprotegrin
Cytolytic
METQRASLCLGRWSLWLLLLGLVVPSASAQALSYREA
antibiotic

VLRAVDRLNEQSSEANLYRLLELDQPPKADEDPGTPK

PVSFTVKETVCPRPTRQPPELCDFKENGRVKQCVGTV

TLDQIKDPLDITCNEVQGVRGGRLCYCRPRFCVCVGRG

248
Oxyntomodulin

HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA

276
C-peptide

EAEDLQVGQVELGGGPGAGSLQPLALEGSLQ

282
C-peptide

EGSLC

mutant

283
Human Opioid
Enkephalin
Tyr-Gly-Gly-Phe-Met

Growth Factor

284
cholecystoki-

RDY(SO3-)TGW(Nle)DF

nin

285
Dynorphin A

YGGFLRRIRPKLK

(1-13)

464
Pralmorelin

D-Ala-D-2-Nal-Ala-Trp-D-Phe-Lys-NH₂

(GHRFA)

286
Aniritide

RSSCFGGRMDRIGAQSGLGCNSFRY

287
Vessel dilator

EVVPPQVLSDPNEEAGAALSPLPEVPPWTGEVSPAQR

proANP31-67

465
Peptide G

Arg-Pro-Lys-Pro-Gln-Arg-D-Trp-MePhe-D-Trp-

Leu-Met

466
Tiplimotide

D-Ala-lys-pro-val-val-his-leu-phe-ala-asp-

ile-val-thr-pro-arg-thr-pro

288
Desirudin (63-

VVYTDCTESGQNLCLCEGSNVCGQGNKCILGSDGEK

desulfohi-

NQCVTGEGTPKPQSHNDGDFEEIPEEYLQ

rudin)

467
Examorelin

His-DTrp(2-Me)-Ala-Trp-DPhe-Lys-NH2

172
Terlipressin
Vesopressin
Gly-Gly-Gly-c[Cys-Tyr-Phe-Gln-Asn-Cys]-Pro-

Lys-Gly-NH2

289
Osteogenic

ALKRQGRTLYGFGG

Growth Factor

(WT)

290
Osteogenic

YGFGG

Growth Factor

(10-14)

291
Myelin Basic

Ac-ASQKRPSQRHG

Protein

peptide

292
Myelin Basic

Ac-ASQKRPSQRHG

Protein

peptide

Ac1-11[4Y]

293
Gonadorelin

pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly

(24-33)

CONH2

468
Bremelanotide
Alpha-MSH
Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH

294
Islet

GLHDPSHGTLPNGSG
Diabetes

Neogenesis

associated

peptide

(INGAP)

295
Urocortin II

IVLSLDVPIGLLQILLEQARARAAREQATTNARILARVGHC

296
A6 (anti-

CH3CO-NH2-KPSSPPEE-CONH2

angiogenic

peptide)

297
Obestatin

H-Phe-Asn-Ala-Pro-Phe-Asp-Val-Gly-Ile-Lys-

Leu-Ser-Gly-Val-Gln-Tyr-Gln-Gln-His-Ser-Gln-

Ala-Leu-NH2

298
ITF-1697

Gly-Lys(Et)-Pro-Arg

299
CNP (C-type

GLSKGCFGLKLDRIGSMSGLGC

netriuretic

peptide

300
Osteocalcin

YLYQWLGAPVPYPDPLEPRREVCELNPDCDELADHIG
Diabetes

FQEAYRRFYGPV

301

EAEDLQVGQVELGGGPGAGCLQPLALEGSLQ

469
D4F-APO1

Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH₂

mimetic

peptide

(-NH₂indicates amidation at the C-terminus; Ac indicates acetylation; other modifications are as described herein and in the specification; SIN indicates Sequence Identification Number)

The above exemplary biologically active agents are meant to encompass, where applicable, analogues, agonists, antagonists, inhibitors, isomers, and pharmaceutically acceptable salt forms thereof. In reference to peptides and proteins, the invention is intended to encompass synthetic, recombinant, native, glycosylated, and non-glycosylated forms, as well as biologically active fragments thereof. The above biologically active proteins are additionally meant to encompass variants having one or more amino acids substituted, deleted, or the like, as long as the resulting variant protein possesses at least a certain degree of activity of the parent (native) protein.

The reactive polymeric reagents of the invention may be attached, either covalently or non-covalently, to a number of solid entities including films, chemical separation and purification surfaces, solid supports, metal/metal oxide surfaces, such as gold, titanium, tantalum, niobium, aluminum, steel, and their oxides, and silicon oxide. Additionally, the polymers of the invention may also be used in biochemical sensors, bioelectronic switches, and gates. The polymeric reagents of the invention may also be employed as carriers for peptide synthesis, for the preparation of polymer-coated surfaces and polymer grafts, to prepare polymer-ligand conjugates for affinity partitioning, to prepare cross-linked or non-cross-linked hydrogels, and to prepare polymer-cofactor adducts for bioreactors.

VI. Pharmaceutical Compositions and Administration Methods

The invention also includes pharmaceutical preparations comprising a conjugate as provided herein in combination with a pharmaceutical excipient. Generally, the conjugate itself will be in a solid form (e.g., a precipitate), which can be combined with a suitable pharmaceutical excipient that can be in either solid or liquid form. The pharmaceutical preparations encompass all types of formulations and in particular those that are suited for injection, e.g., powders that can be reconstituted as well as suspensions and solutions.

Exemplary excipients include, without limitation, those selected from the group consisting of carbohydrates, inorganic salts, antimicrobial agents, antioxidants, surfactants, buffers, acids, bases, and combinations thereof.

A carbohydrate such as a sugar, a derivatized sugar such as an alditol, aldonic acid, an esterified sugar, and/or a sugar polymer may be present as an excipient. Specific carbohydrate excipients include, for example: monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosyl sorbitol, myoinositol, and the like.

The excipient can also include an inorganic salt or buffer such as citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic, and combinations thereof.

The preparation may also include an antimicrobial agent for preventing or deterring microbial growth. Nonlimiting examples of antimicrobial agents suitable for the present invention include benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, thimersol, and combinations thereof.

An antioxidant can be present in the preparation as well. Antioxidants are used to prevent oxidation, thereby preventing the deterioration of the conjugate or other components of the preparation. Suitable antioxidants for use in the present invention include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, and combinations thereof.

A surfactant may be present as an excipient. Exemplary surfactants include: polysorbates, such as “Tween 20” and “Tween 80,” and pluronics such as F68 and F88 (both of which are available from BASF, Mount Olive, N.J.); sorbitan esters; lipids, such as phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines (although preferably not in liposomal form), fatty acids and fatty esters; steroids, such as cholesterol; and chelating agents, such as EDTA, zinc and other such suitable cations.

Acids or bases may be present as an excipient in the preparation. Nonlimiting examples of acids that can be used include those acids selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof. Examples of suitable bases include, without limitation, bases selected from the group consisting of sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate, potassium fumerate, and combinations thereof.

The amount of the conjugate (i.e., the conjugate formed between the active agent and the polymer described herein) in the composition will vary depending on a number of factors, but will optimally be a therapeutically effective dose when the composition is stored in a unit dose container (e.g., a vial). In addition, the pharmaceutical preparation can be housed in a syringe. A therapeutically effective dose can be determined experimentally by repeated administration of increasing amounts of the conjugate in order to determine which amount produces a clinically desired endpoint.

The amount of any individual excipient in the composition will vary depending on the activity of the excipient and particular needs of the composition. Typically, the optimal amount of any individual excipient is determined through routine experimentation, i.e., by preparing compositions containing varying amounts of the excipient (ranging from low to high), examining the stability and other parameters, and then determining the range at which optimal performance is attained with no significant adverse effects. Generally, however, the excipient will be present in the composition in an amount of about 1% to about 99% by weight, preferably from about 5%-98% by weight, more preferably from about 15-95% by weight of the excipient, with concentrations less than 30% by weight most preferred.

These foregoing pharmaceutical excipients along with other excipients are described in “Remington: The Science & Practice of Pharmacy”, 19th ed., Williams & Williams, (1995), the “Physician's Desk Reference”, 52nd ed., Medical Economics, Montvale, N.J. (1998), and Kibbe, A. H., Handbook of Pharmaceutical Excipients, 3rd Edition, American Pharmaceutical Association, Washington, D.C., 2000.

The pharmaceutical preparations of the present invention are typically, although not necessarily, administered via injection and are therefore generally liquid solutions or suspensions immediately prior to administration. The conjugates can be administered injected parenterally by intravenous injection, or less preferably by intramuscular or by subcutaneous injection. Suitable formulation types for parenteral administration include ready-for-injection solutions, dry powders for combination with a solvent prior to use, suspensions ready for injection, dry insoluble compositions for combination with a vehicle prior to use, and emulsions and liquid concentrates for dilution prior to administration, among others.

The pharmaceutical preparation can also take other forms such as syrups, creams, ointments, tablets, powders, and the like. Other modes of administration are also included, such as pulmonary, rectal, transdermal, transmucosal, oral, intrathecal, subcutaneous, intra-arterial, and so forth.

The invention also provides methods for administering a conjugate as provided herein to a patient suffering from a condition that is responsive to treatment with the conjugated agent. The method comprises administering, generally via injection, a therapeutically effective amount of the conjugate (preferably provided as part of a pharmaceutical preparation). The actual dose to be administered will vary depend upon the age, weight, and general condition of the subject, as well as the severity of the condition being treated, the judgment of the health care professional, and conjugate being administered. Therapeutically effective amounts are known to those skilled in the art and/or are described in the pertinent reference texts and literature. Generally, a therapeutically effective amount will range from about 0.001 mg to 100 mg, preferably in doses from 0.01 mg/day to 75 mg/day, and more preferably in doses from 0.10 mg/day to 50 mg/day.

Optimally, cleavage of the water-soluble polymer portion, which may be desirable to facilitate clearance from the body, can be facilitated through the incorporation of one or more physiologically cleavable and/or enzymatically degradable linkages such as urethane, amide, carbonate or ester-containing linkages, as described above, into the polymer component. In this way, clearance of the conjugate (via cleavage of individual water-soluble polymer portions) can be modulated by selecting the polymer molecular size and the type of linkage that would provide the desired clearance properties. One of ordinary skill in the art can determine the proper molecular size of the polymer as well as the cleavable functional group. Clearance properties can be evaluated by preparing a series of polymer derivatives with different polymer weights and cleavable functional groups, and then obtaining clearance profiles (e.g., through periodic blood or urine sampling) by administering the polymer derivatives to a patient and taking periodic blood and/or urine sampling.

EXPERIMENTAL
Materials

Dextran obtained from Leuconostoc ssp., having a molecular weight ˜6,000, was purchased from Fluka Chemical Corp. and used for exploratory experiments. For drug delivery applications, where higher molecular weights are desired, dextran having molecular weights of 40 and 70 kDa was obtained from Pharmacosmos, located in Holbaek, Denmark. These higher molecular weight starting materials had polydispersity (PDI) values of 1.25-1.35.

Example 1
Preparation of Dextran(6K)-Monocarboxylic Acid (1a) by Mild Oxidation

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To a solution of Dextran 6 (10.0 g; Mw=6353, Mn=2,717, Mw/Mn=2.34; Fluka, product number 31388) in deionized water (12.0 ml) was added 0.1N iodine solution (2.0 ml) followed by slow addition of 1.0N sodium hydroxide solution until the solution became clear. This addition of iodine solution followed by slow addition of sodium hydroxide solution was repeated 18 times. The total amounts of added iodine solution and sodium hydroxide solution were 40.0 ml and 5.0 ml, respectively. The reaction mixture was dialyzed against deionized water using dialysis cassettes having a 3500 kD cutoff (Pierce). Water was distilled off under reduced pressure, and the wet product was dried under vacuum overnight. Yield 9.2 g. Anion exchange chromatography showed that the product contained 46.1% of dextran monocarboxylic acid (1) and 51.9% of unreacted dextran.

Example 2
Purification of Dextran (6K)-Monocarboxylic Acid (1a) by Anion Exchange Chromatography

A sample of the product from Example 1 (1.0 g; containing 46.1% of dextran acid and 51.9% of unreacted dextran) was dissolved in deionized water (100 ml) and applied to a DEAE Sepharose FF column (10 ml). The column was then washed with deionized water. The product adsorbed on the column was eluted with 10% ammonia. Ammonia and water were distilled off from the eluate under reduced pressure, and the residue was dried under vacuum, giving 0.2 g of white solid product. Anion exchange chromatography showed that the product contained 99.1% of dextran monocarboxylic acid (1a) and 0.9% of dextran.

Example 3
Preparation of Dextran(40K)-Monocarboxylic Acid (1b) by Mild Oxidation

To a solution of Dextran 40 (10.0 g; Mw=46,021, Mn=22,617, Mw/Mn=2.03; Sigma-Aldrich) in deionized water (12.0 ml) was added 0.1N iodine solution (2.0 ml) followed by slow addition of 1.0N sodium hydroxide solution until the solution became clear. This addition of iodine solution followed by slow addition of sodium hydroxide solution was repeated several times. The total amounts of added iodine solution and sodium hydroxide solution were 34.0 ml and 5.1 ml, respectively. The reaction mixture was dialyzed against deionized water using dialysis cassettes having a 3500 MW cutoff (Pierce). Water was then distilled off under reduced pressure, and the wet product was dried under vacuum overnight. Yield 9.3 g. Anion exchange chromatography showed that the product contained 36.4% of dextran-diacid, 59.3% of dextran-monoacid (1b), and 4.3% of unreacted dextran.

Example 4
Purification of Dextran(40K)-Monocarboxylic Acid (1b) by Anion Exchange Chromatography

A sample of the product from Example 3 (5.0 g) was dissolved in deionized water (250 ml) and applied to a DEAE Sepharose FF column (50 ml). The column was then washed with deionized water. The following fractions were collected:

Volume
Dextran-
Dextran-

Fraction #
(ml)
Diacid, %
Monoacid (1b), %
Dextran, %

1
25
0
0
0

2
25
0
0
100

3
25
0
0
100

4
25
0
0
100

5
25
0
36.0
64.0

6
25
4.1
81.4
14.5

7
25
8.9
79.6
11.5

8
25
14.4
80.3
5.3

9
25
12.7
82.1
5.2

10
25
15.3
80.0
4.7

11
25
0
100
0

Example 5
Preparation of Dextran(40K)-Monocarboxylic Acid (1b) by Controlled Oxidation of Dextran Monitored by Ion Exchange Chromatography

To a solution of Dextran 40 (10.0 g; Mw=46,021, Mn=22,617, Mw/Mn=2.03; Sigma-Aldrich) in deionized water (12.0 ml) was added 0.1N iodine solution (2.0 ml) followed by slow addition of 1.0N sodium hydroxide solution (˜0.25 ml) until the solution became clear. Ion exchange chromatography showed that the reaction mixture at that point contained 25.3% of dextran monoacid and 74.7% of unreacted dextran. The addition of iodine solution (2.0 ml) followed by slow addition of sodium hydroxide solution was repeated two more times. At this stage, ion exchange chromatography showed that the reaction mixture contained 50.7% of dextran monoacid and 49.3% of unreacted dextran. After addition of a fourth portion of iodine solution (2.0 ml) followed by slow addition of sodium hydroxide, ion exchange chromatography showed that the reaction mixture contained 84.9% of dextran monoacid and 15.1% of unreacted Dextran. A fifth addition of iodine solution (2.0 ml) followed by slow addition of sodium hydroxide produced a reaction mixture containing 3.1% of dextran diacid, 83.9% of dextran monoacid, and 13.0% of unreacted dextran. This final reaction mixture was diluted with deionized water (500 ml) and the obtained solution was filtered through a desalting column containing 120 ml of Amberlite IR-120 and 120 ml of Amberlite IRA-67 ion exchange resin. Water was then distilled off under reduced pressure from the filtrate, and the wet product was dried under vacuum overnight. Yield 8.5 g.

Example 6
Preparation of dextran(40K)-O-(carboxymethyl)oxyimine (2)

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To a solution of Dextran 40 (2.5 g; Mw=46,021, Mn=22,617, Mw/Mn=2.03; Sigma-Aldrich) in 0.1M sodium acetate buffer (pH=5.5) was added O-(carboxymethyl) hydroxylamine hemihydrochloride (0.1 g; Sigma-Aldrich). The pH was readjusted to 5.2 and the mixture was stirred overnight at room temperature. Ion exchange chromatography showed that the product contained 77.1% of dextran(40K)-O-(carboxymethyl)oxyimine (2) and 22.9% of unreacted dextran.

Example 7
Preparation of Tetra(Ethylene Glycol)-α-Amino-ω-Butanoic Acid, Orthoester (5)

This reagent can be used to prepare a carboxy-terminated carbohydrate derivative, as shown in Example 8 below.

A. Tetra(ethylene glycol)-monobutanoic acid, orthoester (3)

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A solution of tetra(ethylene glycol) (97.1 g, 0.5 mole) in toluene (200 ml) was azeotropically dried by distilling off toluene under reduced pressure. The dried tetra(ethylene glycol) was dissolved in anhydrous toluene (180 ml), and 1.0 M solution of potassium tert-butoxide in tert-butanol (120 ml, 0.12 moles) and 1-(3-bromopropyl)-4-methyl-3,6,7-trioxabicyclo[2,2,2]octane (25.1 g, 0.1 mole) were added. The mixture was placed under an argon atmosphere, heated to 70° C. and stirred overnight. After cooling to room temperature, the mixture was filtered and the solvents were distilled off under reduced pressure. The crude product was dissolved in 1000 ml of deionized water and the disubstituted product was removed by extraction with ethyl acetate (2×100 ml). Sodium chloride (100 g) was added and the product was extracted with dichloromethane (200, 100, and 100 ml). The extract was dried (MgSO₄) and the solvent was distilled off under reduced pressure. The crude product (3) (26.6 g) was dissolved in 300 ml of deionized water and extracted with dichloromethane (200, 100, and 50 ml). The extract was dried (MgSO₄) and the solvent was distilled off under reduced pressure. Yield: 23.4 g. NMR (d₆-DMSO): 0.74 ppm (s, —CH₃, orthoester) 1.56 ppm (m, —CH₂—CH₂-orthoester), 3.51 ppm (bm, —OCH₂CH₂O—), 3.80 ppm (s, —CH₂, orthoester), 4.58 ppm (t, —OH). Purity: ˜400%.

B. Tetra(ethylene glycol)-α-mesylate-ω-butanoic acid, orthoester (4)

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A mixture of tetra(ethylene glycol)monobutanoic acid orthoester (3) (20 g, 0.0549 moles), prepared in step A above, and toluene (200 ml) was azeotropically dried by distilling off toluene under reduced pressure. The dried tetra(ethylene glycol)monobutanoic acid orthoester was dissolved in anhydrous toluene (200 ml). Then, 40 ml of anhydrous dichloromethane and 15.4 ml of triethylamine (0.1105 moles) were added to the solution followed by the dropwise addition of 7.4 g of methanesulfonyl chloride (0.0646 moles) dissolved in dichloromethane (80 ml) while maintaining the solution temperature at 0-5° C. The solution was stirred an additional 2 h at room temperature under argon atmosphere. The resulting mixture was filtered, sodium carbonate (2 g) was added, and the mixture was stirred 1.0 h. Finally the solution was filtered and the solvents distilled off under reduced pressure.

Yield: 23.2 g. NMR (d₆-DMSO): 0.74 ppm (s, —CH₃, orthoester) 1.56 ppm (m, —CH₂—CH₂-orthoester), 3.18 ppm (s, CH₃-methanesulfonate), 3.51 ppm (bm, —OCH₂CH₂O—), 3.67 ppm (m, —CH₂—CH₂-methanesulfonate), 3.80 ppm (s, —CH₂, orthoester), 4.31 ppm (m, —CH₂-methanesulfonate). Purity: ˜100%.

C. Tetra(ethylene glycol)-α-amine-ω-butanoic acid, orthoester (5)

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A mixture of tetra(ethylene glycol)-α-mesylate-ω-butanoic acid orthoester (4) (23.2 g), prepared in step B above, ethyl alcohol (100 ml), and concentrated ammonia (1000 ml) was stirred for 88 h at room temperature. The reaction mixture was extracted with dichloromethane (600, 400, and 400 ml), the extract was dried (MgSO₄), and the solvent was distilled off under reduced pressure. Yield 19.5 g. NMR (D₂O): 0.74 ppm (s, —CH₃, orthoester) 1.63 ppm (m, —CH₂—CH₂-orthoester), 2.71 ppm (t, —CH₂-amine), 3.58 ppm (bm, —OCH₂CH₂O—), 3.67 ppm (m, methanesulfonate), 3.89 ppm (s, —CH₂, orthoester). Purity: ˜100%.

Example 8
Preparation of Oxyimine-Linked Dextran(40K)-Butanoic Acid (7)

This reagent was prepared according to the following scheme, described in greater detail below:

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A. Preparation of tetra(ethylene glycol)-α-aminooxyacetamide-ω-butanoic acid (6)

To a solution of (Boc-aminooxy)acetic acid (2.0 g, 0.0105 moles; Sigma-Aldrich), N-hydroxysuccinimide (1.20 g, 0.0105 moles), 1-hydroxybenzotriazole (0.30 g, 0.0022 moles) in anhydrous CH₂Cl₂(100 ml) cooled to ˜5° C., N,N-dicyclohexylcarbodiimide (1.70 g, 0.0115 moles) dissolved in anhydrous CH₂Cl₂(30 ml) was added and the mixture was stirred 1 h at 5-15° C. Tetra(ethylene glycol)-α-amine-ω-butanoic acid orthoester (5), prepared as described in Example 7 (4.0 g, 0.0109 moles), and triethylamine (3.80 ml) were then added, and the mixture was stirred overnight at room temperature under nitrogen atmosphere. The mixture was filtered and the solvent was distilled off. The residue was dissolved in deionized water (80 ml) and the product was extracted with dichloromethane. The extract was dried and the solvent was distilled off under reduced pressure, giving 4.8 of the Boc- and orthoester-protected linker as a liquid product.

The Boc- and orthoester-protected linker, prepared as described above (4.8 g), was dissolved in a mixture of trifluoroacetic acid (30 ml) and anhydrous dichloromethane (30 ml). The resulting solution was stirred 2 h at room temperature, after which time the dichloromethane and trifluoroacetic acid were distilled off under reduced pressure. The residue was dissolved in deionized water (40 ml) and 1.0M sodium hydroxide was added to adjust the pH to 12.2. The mixture was stirred 2 h, keeping the pH 12.1-12.3 by periodical addition of 0.1M sodium hydroxide. The pH was then adjusted to 7.5, and a portion of water was distilled off under reduced pressure, giving 12.2 g of concentrated solution of tetra(ethylene glycol) linker (6) containing terminal oxyamine and butanoic acid groups.

B. Reaction of Heterobifunctional Reagent (6) with Dextran(40K)

To a solution of Dextran 40 (2.5 g; Mw=46,021, Mn=22,617, Mw/Mn=2.03; Sigma-Aldrich) in 0.1M sodium acetate buffer, pH=5.5, a solution of tetra(ethylene glycol)-α-aminooxyacetamide-ω-butanoic acid (6) (from part A above) was added. The pH was readjusted to 5.2 with acetic acid and the mixture was stirred overnight at room temperature. The solution was dialyzed 3 times against DI water using Dialysis Cassette MW CO 3.5K (Pierce). The water was then distilled off under reduced pressure. The wet crude product (7) was dried under vacuum overnight, giving 2.2 g of white solid. NMR analysis performed in D₂O showed that the substitution of end groups of dextran with butanoic acid groups was 38.6%.

Example 9
Purification of Oxyamine-Linked Dextran(40K)-Butanoic Acid (7)

The crude functionalized dextran (7) from step B (1.8 g) was dissolved in deionized water (180 ml) and applied to a DEAE Sepharose FF column (50 ml). The column was then washed with deionized water. The material adsorbed on the column product was eluted with 10% NaCl solution. The eluate (100 ml) was dialyzed 4 times against DI water using Dialysis Cassette MW CO 3.5K (Pierce). The water was distilled off under reduced pressure, and the wet product was dried under vacuum overnight, giving 0.5 g of purified (7) as a white solid. NMR analysis performed in D₂O showed that the substitution of end groups of dextran with butanoic acid groups in the purified product was ˜100%.

Example 10
Preparation of Dextran(6K)-Hexamethylenediamine (8)

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A mixture of hexamethylenediamine (1.8 g), sodium cyanoborohydride (1.2 g), acetic acid (0.44 ml) and DMSO (12 ml) was warmed to 85° C. Dextran 40 (1.5 g; Mw=46,021, Mn=22,617, Mw/Mn=2.03; Sigma-Aldrich) was added slowly during 3 h, and the mixture was stirred 24 h at 85° C. After cooling to room temperature, the reaction mixture was dialyzed 3 times against DI water using Dialysis Cassette MW CO 3.5K (Pierce). The water was distilled off under reduced pressure, and the wet product (8) was dried under vacuum overnight. The product was purified using cation exchange chromatography. NMR analysis performed in D₂O showed that the substitution of end groups of dextran with amine groups was 38.6%.

Example 11
Preparation of Heterobifunctional Reagent Di(Ethylene Glycol)-α-Amino-ω-Oxyamine (11)
A. Preparation of CBZ—NH—CH₂CH₂OCH₂CH₂—OH (9)

To 2-(2-aminoethoxyl)ethanol (20 g) dissolved in dichloromethane (200 ml) was added stepwise triethylamine (26.5 ml) and benzyloxy(carbonyloxy)succinimide (47.47 g). The reaction mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in deionized water (500 ml). The insoluble layer was separated, and the aqueous layer was mixed with 50 g of NaCl and the pH adjusted to 5.0 with 5% H₃PO₄. The product was extracted with dichloromethane (100 ml, 50 ml, and 50 ml) and the extract was dried with MgSO₄, filtered, and evaporated to dryness under reduced pressure. The residue was dried under vacuum overnight, then combined with the previously separated insoluble layer and dissolved in dichloromethane (300 ml). The solution was washed with 5-% aqueous NaCl solution (3×50 ml) and dried with MgSO₄. The solvent was distilled under reduced pressure, and the residue was dried overnight under vacuum, giving 40 g of the desired product.

B. Preparation of CBZ—NH—CH₂CH₂OCH₂CH₂—O(S)₂)CH₃(10)

CBZ-Methanesulfonyl chloride (7.1 ml) dissolved in anhydrous dichloromethane (70 ml) was slowly added to the product (9) of step A, and the mixture was stirred overnight at room temperature under nitrogen atmosphere. The mixture was filtered, stirred 1 h with solid Na₂CO₃(26.6 g), and refiltered. The filtrate was concentrated under reduced pressure, the residue was re-dissolved in toluene (150 ml), and the resulting solution was filtered and concentrated by distillation under reduced pressure. The residue was dried overnight under vacuum, giving 24 g of the desired product (10).

C. Preparation of CBZ—NH—CH₂CH₂OCH₂CH₂—ONH₂(11)

CBZ—NH—CH₂CH₂OCH₂CH₂—O(SO₂)CH₃(10) (24 g), prepared as described in step B, was dissolved in CH₃CN (240 ml), and endo-N-hydroxy-5-norbomene-2,3-dicarboximide (20.5 g) followed by diisopropylethylamine (39.5 ml) was added. The reaction mixture was refluxed at 93° C. overnight under nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and the solvent distilled off under reduced pressure. The residue was dissolved in dichloromethane (200 ml), and the solution was washed with 0.1 M phosphate buffer (pH 5.0, 2×100 ml) and dried with (MgSO₄). The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl alcohol (150 ml), and butylamine (28.0 ml) was added. The mixture was stirred overnight at 90° C. under nitrogen atmosphere. The solution was filtered and the solvent was distilled off under reduced pressure. The crude product was dissolved in 100 mM phosphate buffer, pH=4.5 (120 ml), and the solution was filtered. The impurities were removed by extraction with ethyl ether (3×20 ml). NaCl (15 g) was added, the pH was readjusted to 9 with 1.0 M NaOH, and the product was extracted with dichloromethane (3×50 ml). The extract was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure giving (11) as a clear liquid product.

Example 12
Preparation of Tetra(Ethylene Glycol)-α-Oxyamino-ω-Butyraldehyde, Diethyl Acetal (14)

This reagent can be used to prepare an aldehyde-terminated carbohydrate derivative, as shown in Example 13 below.

A. Tetra(Ethylene Glycol)Mono-Butyraldehyde, Diethyl Acetal (12)

A mixture of tetra(ethylene glycol) (97.1 g, 0.500 moles) and toluene (200 ml) was azeotropically dried by distilling off toluene under reduced pressure. The dried tetra(ethylene glycol) was dissolved in anhydrous toluene (180 ml), and a 1.0 M solution of potassium tert-butoxide in tert-butanol (120.0 ml, 0.120 moles) and 4-chlorobutyraldehyde diethyl acetal (18.1 g, 0.100 moles) were added. The mixture was stirred at 90° C. overnight under argon atmosphere. After cooling to room temperature, the mixture was filtered and the solvents were distilled off under reduced pressure. The crude product was dissolved in 1000 ml deionized water and the resulting solution was filtered through activated carbon. Sodium chloride (10 g) was added and the product was extracted with dichloromethane (250, 200, and 150 ml). The extract was dried (MgSO₄) and the solvent was distilled off under reduced pressure. Yield: 20.3 g. NMR (d₆-DMSO): 1.10 ppm (t, CH₃—C—) 1.51 ppm (m, C—CH₂—CH₂—), 3.49 ppm (bm, —OCH₂CH₂O—), 4.46 ppm (t, —CH, acetal), 4.58 ppm (t, —OH). Purity: ˜100%.

B. Tetra(Ethylene Glycol)-α-Mesylate-ω-Butyraldehyde Diethyl Acetal (13)

A mixture of tetra(ethylene glycol)mono-butyraldehyde diethyl acetal (12) (12.5 g, 0.037 moles), prepared in step A above, and toluene (120 ml) was azeotropically dried by distilling off toluene under reduced pressure. The dried tetra(ethylene glycol)mono-butyraldehyde, diethyl acetal was dissolved in anhydrous toluene (100 ml). To the solution was added 20 ml of anhydrous dichloromethane and 5.7 ml of triethylamine (0.041 moles). Then 4.5 g of methanesulfonyl chloride (0.039 moles) was added dropwise. The solution was stirred at room temperature under nitrogen atmosphere overnight. Sodium carbonate (5 g) was added, and the mixture was stirred 1 h. The solution was filtered and solvents were distilled off under reduced pressure. NMR (d₆-DMSO): 1.10 ppm (t, CH₃—C—) 1.51 ppm (m, C—CH₂—CH₂—), 3.17 ppm (s, CH₃— methanesulfonate), 3.49 ppm (bm, —OCH₂CH₂O—),), 4.30 ppm (m, —CH₂— methanesulfonate), 4.46 ppm (t, —CH, acetal). Purity: ˜100%.

C. Tetra(Ethylene Glycol)-α-Oxyamino-ω-Butyraldehyde Diethyl Acetal (14)

To a solution of tetra(ethylene glycol)-α-mesylate-ω-butyraldehyde diethyl acetal (13) (20.0 g), prepared in step B above, in anhydrous acetonitrile (200 ml), endo-N-hydroxy-5-norbornene-2,3-dicarboximide (13.0 g) and diisopropylethylamine (21.0 ml) was added and the mixture was stirred at 90° C. overnight under nitrogen atmosphere. The solution was filtered and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl alcohol (100 ml) and butylamine (26.0 ml) was added. The mixture was stirred 6 h at 90° C. under nitrogen atmosphere. The solution was filtered and the solvent was distilled off under reduced pressure. The crude product was dissolved in 100 mM phosphate buffer, pH=5.0 (200 ml), and the solution was filtered. The impurities were removed by extraction with ethyl ether (3×25 ml). NaCl (20 g) was then added, the pH was readjusted to 9 with 1.0 M NaOH, and the product was extracted with dichloromethane (3×50 ml). The extract was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure, giving 18 g of clear viscous water white liquid product. NMR (DMSO-d6): 1.11 ppm (t, CH₃—C—) 1.51 ppm (m, C—CH₂—CH₂—), 3.47 ppm (bm, —OCH₂CH₂O—), 4.56 ppm (t, —CH, acetal), 5.97 ppm (s, H₂N—O—). Purity: ˜100%.

Example 13
Preparation of Oxyimine-Linked Dextran(40K)-Butyraldehyde (16)

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a. Oxyimine-Linked Dextran(40K)-Butyraldehyde Diethyl Acetal (15)

To a solution of Dextran 40 (2.5 g; Mw=46,021, Mn=22,617, Mw/Mn=2.03; Sigma-Aldrich) in 0.1 M sodium acetate buffer, pH=5.2 (20 ml), tetra(ethylene glycol)-α-oxyamino-ω-butyraldehyde diethyl acetal (14) (0.30 g), prepared as described in Example 12, was added. The pH was readjusted to 5.2 and the mixture was stirred overnight at room temperature. The solution was dialyzed 3 times against DI water using Dialysis Cassette MW CO 3.5K (Pierce). The water was then distilled off under reduced pressure. The wet product was dried under vacuum overnight, giving 2.3 g of a white solid. NMR analysis performed in D₂O showed that the substitution of end groups of dextran with butyraldehyde diethyl acetal groups was 78.9%.

B. Oxyimine-Linked Dextran(40K)-Butyraldehyde C16)

Dextran(40K)-butyraldehyde diethyl acetal (0.336 g), prepared in step A above, was dissolved in 2 ml of 10 mM phosphate buffer (pH=7.2), and the pH was adjusted to 2.0 with 5% phosphoric acid. The mixture was stirred 1.5 h. The pH was then readjusted to 6.5 with 1.0 N sodium hydroxide. The obtained solution of (16) was used directly for the dextran modification of lysozyme.

Example 14
Reaction of Oxyimine-Linked Dextran(40K)-Butyraldehyde (16) with Lysozyme

To the solution of oxyimine-linked dextran(40K)-butyraldehyde (16) obtained as described in Example 13 above, lysozyme (6 mg; Sigma-Aldrich) was added, and the mixture was stirred for 15 min, followed by addition of 0.21 ml of 0.1 M aqueous solution of sodium cyanoborohydride (Sigma-Aldrich). The mixture was stirred overnight at room temperature. HPLC analysis showed that Dextran-Lysozyme conjugate (17) was formed.

Example 15
Larger Scale Preparation of Oxyimine-Linked Dextran(40K)-Butyraldehyde (16)
A. Oxyimine-Linked Dextran(40K)Butyraldehyde Diethyl Acetal (15)

To a solution of Dextran 40 (130 g; Mw=40,210, Mn=30,931, Mw/Mn=1.3; Pharmacosmos A/S, Denmark) in 0.1M sodium acetate buffer, pH=5.2 (780 ml), tetra(ethylene glycol)-α-oxyamino-ω-butyraldehyde diethyl acetal (14) (20.3 g), prepared as described in Example 12 above, was added. The pH was readjusted to 5.2 with acetic acid and the mixture was stirred overnight at room temperature. The crude product was precipitated with isopropyl alcohol, collected by vacuum filtration and dried. The precipitation process was repeated two more times to remove all unreacted reagent. The yield of the solid dry product (15) was 114 g. NMR analysis performed in D₂O showed that the substitution of end groups of dextran with butyraldehyde diethyl acetal groups was ˜85%.

B. Oxyimine-Linked Dextran(40K)-Butyraldehyde (16)

Dextran(40K)-butyraldehyde diethyl acetal (114 g), prepared in step A above, was dissolved in 1100 ml of deionized water and the pH was adjusted to 3.0 with 10% phosphoric acid, and the mixture was stirred for 1 h. The pH was then readjusted to 6.8 with 1.0 N sodium hydroxide. The solution was concentrated to dryness under reduced pressure, the crude product was redissolved in 600 ml of deionized water, and the solution was lyophilized, giving 108 g of white solid product. NMR analysis performed in D₂O showed that the substitution of end groups of dextran with butyraldehyde groups was ˜80%.

Example 16
Conjugation of Protegrin-1 with Oxyimine-Linked Dextran_40KTetraethylene Glycol Butyraldehyde (16)

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Stock solutions of 0.3 mg/mL protegrin-1 and 55 mg/mL dextran tetraethylene glycol (TEG) butyraldehyde 40K (16), both in 50 mM HEPES, pH 7.0, were prepared. To initiate a reaction, both stock solutions were brought to 25° C. and then mixed in equal volumes. The reaction mixture was stirred at 25° C. After 1 hour reaction, 100 μM sodium cyanoborohydride (final concentration) was added and the reaction was allowed to proceed for an additional 4 hours.

The dextran-protegrin-1 conjugate (18) was purified from the reaction mixture by cation-exchange chromatography using CM Sepharose (GE Healthcare). Thus, upon completion of the conjugation reaction, the reaction mixture was diluted 10-fold with water and loaded onto a column packed with CM Sepharose resin. The resin was washed with buffer B (10 mM HEPES, pH 7, 1M NaCl) and equilibrated with buffer A (10 mM HEPES, pH 7) prior to sample loading. After loading, the column was washed with 2 column volumes buffer A. Conjugated and nonconjugated peptides were eluted in a linear gradient of 0-100% buffer B in 10 column volumes at a flow rate of 7 mL/min.

Fractions containing dextran-butyraldehyde-40K-protegrin-1 were pooled, dialyzed against water, lyophilized and stored at −80° C. SDS-PAGE analysis (4-12% gel) of the purified dextran-butryraldehyde-40K-protegrin-1 conjugate (18) is shown in FIG. 1. Dextran perturbs the gel migration of the dextran-peptide conjugate; the conjugate's band location is not indicative of its size.

Example 17
Conjugation of C-Peptide (S20C) with Oxyimine-Linked Dextran_40KTetraethylene Glycol Butyraldehyde (16)

Stock solutions of 2 mg/mL C-peptide(S20C) and 200 mg/mL oxyimine-linked dextran tetraethylene glycol (TEG)-butyraldehyde 40K (16), both in 500 mM HEPES, pH 7.0, were prepared. To initiate a reaction, both stock solutions were brought to 25° C. and then mixed in equal volumes. The reaction mixture was stirred at 25° C. After 1 hour reaction, 10 mM sodium cyanoborohydride (final concentration) was added, and the reaction was allowed to proceed for an additional 16 hours.

The dextran-C-peptide(S20C) conjugate (19) was purified from the reaction mixture by anion-exchange chromatography using Q HP Sepharose resin (GE Healthcare). Thus, upon completion of the conjugation reaction, the reaction mixture was diluted 2-fold with water and loaded onto a column packed with the Sepharose resin. The resin was washed with buffer B (10 mM HEPES, pH 7, 1M NaCl) and equilibrated with buffer A (10 mM HEPES, pH 7) prior to sample loading. After loading, the column was washed with 2 CV buffer A. Conjugated and nonconjugated peptides were eluted in a linear gradient of 0-100% buffer B in 10 CV at a flow rate of 8 mL/min. A conjugate-containing fraction collected during chromatography with Q HP Sepharose was diluted 10-fold with water and re-loaded onto the Q column in order to concentrate the conjugate. The conjugate (19) was eluted with 100% buffer B.

Fractions collected during both anion exchange chromatography runs were analyzed using reversed-phase HPLC. An Agilent Poroshell 300-SB-C8 column was used with a flow rate of 0.2 ml/min and a column temperature of 50° C. Detection was carried out at 215 nm. The column was equilibrated in 0% Mobile Phase B, and conjugate separation was achieved using the gradient timetable shown below:

Time
% Mobile phase A
% Mobile phase B

(min)
(0.1% TFA in water)
(0.85% TFA in CH₃CN)

0.00
100.0
0.0

5.00
70.0
30.0

15.00
40.0
60.0

20.00
20.0
80.0

The concentrated purified conjugate (19) collected from the second anion exchange chromatography run was dialyzed against water and frozen at −80° C. The purity of the mono-dextran conjugate (19) was >93% by RP-HPLC analysis, and the mass as determined by MALDI-TOF was within the expected range (FIG. 2).

Example 18
Conjugation of Insulin with Oxyimine-Linked Dextran_40K. Tetraethylene Glycol Butyraldehyde (16)

Insulin contains three primary amine groups, all of which can undergo a reductive amination reaction with an aldehyde. Reactions of insulin with oxyimine-linked dextran_40Ktetraethylene glycol butyraldehyde (16) therefore produce a mixture of mono-, di- and tri-conjugated peptides. The relative yields of these products depend primarily on the molar ratios of insulin and the dextran reagent used in the reactions, and the reaction conditions (e.g., reaction time and temperature). The relative yield of the mono-conjugated peptide was determined to be very low unless reaction conditions were selected in which the majority of the insulin remained unreacted. Thus, in order to increase the relative and absolute yields of mono-conjugated insulin, a fraction of the amine groups on the peptide were blocked by acetylation prior to reacting the peptide and the dextran reagent. This example will describe the conjugation of both non-acetylated and partially acetylated insulin.

A. Conjugation of Non-Acetylated Insulin with Oxyimine-Linked Dextran_40KTetraethylene Glycol Butyraldehyde (16)

Stock solutions of 2 mg/ml insulin and 42/mL oxyimine-linked dextran-butyrALD-40K (16) were prepared in DMSO/TEA (95%:5%, v/v). To initiate a reaction, both stock solutions were brought to ambient temperature and then mixed in equal volumes. After 5 min reaction with stirring at ambient temperature, 1 M sodium cyanoborohydride was added, to a final concentration of 20 mM, and the reaction was allowed to proceed with continued stirring for 22 hours at ambient temperature.

The product dextran-butyrALD-40K-insulin (20a) was purified from the reaction mixture by anion-exchange chromatography using Q Sepharose FF (GE Healthcare). Thus, upon completion of the conjugation reaction, the reaction mixture was diluted 15-fold with 20 mM HEPES (pH 7) and the mixture was loaded onto a column packed with Q Sepharose FF resin. The resin was washed with Buffer B (20 mM HEPES, 1.0 M sodium chloride, pH 7) and equilibrated with Buffer A (20 mM HEPES, pH 7) prior to sample loading. After loading, the resin was washed with 5 column volumes Buffer A. Conjugated and nonconjugated peptides were eluted using a linear gradient of 0-100% Buffer B over 10 column volumes at a flow rate of 150 cm/h.

B. Conjugation of Partially Acetylated Insulin with Ox Mine-Linked Dextran_40KTetraethylene Glycol Butyraldehyde (16)

Stock solutions of 2.5 mg/mL (430 μM) insulin, 2.24 mg/mL (8.62 mM) sulfo-N-hydroxysuccinimide (NHS)-acetate, and 138 mg/mL (3.45 mM)oxyimine-linked dextran-butyrALD-40K were prepared in DMSO/TEA (95%:5%, v/v), DMSO, and DMSO/TEA (99.35%:0.65%, v/v), respectively. To initiate an acetylation reaction of insulin, in which a fraction of the amine groups on the peptide are acetylated, the insulin and sulfo-NHS-acetate stock solutions were brought to ambient temperature and mixed at a 4:1 ratio (v/v).

After 30 min acetylation reaction with stirring, conjugation of the peptide with dextran-butyrALD-40K (16) was initiated by the drop-wise addition of an equal volume of stock solution of (16) to the acetylation reaction mixture under vigorous stirring. Tween-20 was then added, to a final concentration of 0.05% (v/v), and the reaction mixture was brought to 37° C. with stirring. After 20 minutes, 1 M sodium cyanoborohydride was added, to a final concentration of 17 mM, and the reaction was allowed to proceed with continued stirring for an additional 20 hours at 37° C.

The product dextran-butyrALD-40K-insulin was purified from the reaction mixture by anion-exchange chromatography using Q Sepharose FF (GE Healthcare). Thus, upon completion of the conjugation reaction, the reaction mixture was diluted 1:3 with 20 mM HEPES (pH 7) and the mixture was loaded onto a column packed with Q Sepharose FF resin. The resin was washed with Buffer B (20 mM HEPES, 1.0 M sodium chloride, pH 7) and equilibrated with Buffer A (20 mM HEPES, pH 7) prior to sample loading. After loading, the resin was washed with 10 column volumes Buffer A. Conjugated and nonconjugated peptides were eluted using a two-step gradient consisting of 0 to 25% Buffer B over 25 column volumes and 25% to 75% Buffer B over 5 column volumes at a flow rate of 90 cm/h.

Fractions containing lower molecular weight, less substituted conjugates were identified by SDS-PAGE. These fractions were pooled, diluted 10-fold with 20 mM HEPES, pH 7 (Buffer A), and applied to a second column packed with Q Sepharose FF resin for sample concentration. The resin was washed with Buffer B and equilibrated with Buffer A prior to sample loading. Dextran-butyrALD-40K-insulin was eluted using a linear gradient of 0-75% Buffer B over 3 column volumes at a flow rate of 90 cm/h.

Fractions containing dextran-butyrALD-40K-insulin were pooled and lyophilized. These fractions were shown SDS-PAGE analysis of the pooled fractions to contain a significant amount of nonconjugated insulin (FIG. 3, Lane 1). The nonconjugated insulin can be removed by selective precipitation of the conjugate from a water/DMSO solution (50/50, v/v) through the addition of an organic solvent (for example, acetonitrile). Dextran-butyrALD-40K-insulin is less soluble than nonconjugated insulin in organic solvents and precipitates upon addition of an organic solvent. Thus, lyophilized dextran-butyrALD-40K-insulin was dissolved in water, to a peptide concentration of 2 mg/mL, and an equal volume of DMSO was added to the solution. After thorough mixing, acetonitrile was added drop-wise until the composition of the mixture was 25% water, 25% DMSO, and 50% acetonitrile (v/v/v). Precipitated conjugated insulin was collected by centrifugation and re-dissolved in water. SDS-PAGE analysis showed that the final concentration of nonconjugated insulin in this product was less than 1% of the total peptide amount (FIG. 3, Lane 2). The redissolved conjugate (20b) was lyophilized and stored at −80° C.

Example 19
Receptor Binding: In Vitro Binding of the Insulin-Dextran Conjugate

The in vitro affinity for the insulin receptor of the insulin-dextran conjugate (20b), prepared as described in Example 18, was evaluated using radioligand binding assays in CHO cells that stably express the recombinant human insulin receptor (CHO-hIR). CHO-hIR cells were plated in 24 well plates and washed with assay buffer containing 120 mM NaCl, 5 mM KCl, 1.2 mM MgSO₄, 9 mM Glucose, 10 mM HEPES, 0.5% BSA, pH 8.0. The insulin-dextran conjugate was 98% pure and contained unto 2% of free and acetylated insulin.

Competition binding assays were conducted by incubating CHO-hIR cells with increasing concentrations of insulin, insulin-dextran conjugate (20b), and glycine dextran and a fixed concentration (100 pM) of ¹²⁵I-labelled recombinant human insulin for 4 hours at 4° C. Cells were washed to remove unbound ligands and solubilized with 0.2 N NaOH, and bound radioactivity was counted using a gamma counter. Non-specific binding was measured in the presence of excess cold insulin, and subtraction of this value from the total binding yielded the specific binding at each test compound concentration. IC₅₀values were obtained from non-linear regression analysis of specific binding versus concentration curves.

The results of the in vitro competition binding assay are shown in FIG. 4. Insulin and the Dextran-TEG-butyrlaldehyde-40K acetyl insulin conjugate (20b) bound to the insulin receptor with IC₅₀values of 4.3 nM and 174.9 nM respectively. Dextran conjugation thus resulted in a 40-fold reduction in the binding affinity of insulin. The dextran itself did not display specific binding to the insulin receptor at concentrations up to 1 μM.

Example 20
In Vivo Effect of Dextran-Conjugated Insulin on Blood Glucose Levels in Db/Db Diabetic Mice

Summary:

Dextran conjugated insulin (20b) (250 μg/mouse) was administered by i.p. injection into diabetic mice having elevated blood glucose levels. Blood glucose levels were measured At different time points after dosing. PBS saline solution and Dextran equivalent doses were administrated as negative controls, and insulin (50 μg/mouse) was injected as positive control. Insulin (5 μg/mouse) was also given to a group of db/db mice to determine whether the presence of ˜2% free insulin in the 250 μg Dextran-insulin prep (i.e. ˜5 μg) would have an effect.

Study Procedure:

Animals were acclimated to researcher's handling procedures. Baseline glucose levels were measured prior to drug administration. Outlier animals with glucose level <300 or >600 mg/dL were excluded from the study. Animals were assigned randomly to different groups, as follows:

Group
Test Article
Route
Dose
Dose Volume
# Animals

1
PBS
ip
—
100 ul
4

2
Dextran-Insulin
ip
250 ug/mouse
100 ul
5

3
Insulin
ip
50 ug/mouse
100 ul
5

4
Insulin
ip
5 ug/mouse
100 ul
5

5
Dextran
ip
1.75 mg/mouse
100 ul
5

At different time points (1, 2, 4, 8, and 24 hrs), blood was collected by tail clipping, and glucose level was measured using a One Touch® Ultra glucometer (Johnson & Johnson; Life Scan Ltd.)

Results:

Glucose levels in db/db mice after drug administration are listed in Table 1 and plotted in FIG. 5. As shown, Dextran-Insulin conjugate (20b) (250 ug/mouse) reduced glucose level from 495+32 mg/dL at time 0 to 263+39 mg/dL at 1 hr (47% reduction) and to 192+36 mg/dL at 2 hrs after administration (61% reduction). Insulin (50 ug/mouse) produced a 53% and 67% reduction at 1 and 2 hrs, respectively, after injection; and insulin (5 ug/mouse) produced a 48% and 31% reduction at 1 and 2 hrs, respectively, after injection.

PBS and Dextran injections were not observed to decrease db/db mice glucose levels throughout the course of the study.

The data shows that the Dextran-Insulin conjugate produced a prolonged effect in comparison with the 5 μg/mouse insulin injections (i.e. 61% vs. 31% reduction at 2 hr).

TABLE 1

Glucose levels in db/db mice after compound administration.

Dex-Ins
Ins 50 ug

Dextran

Time
PBS (N = 4)
250 ug (N = 4)
(N = 5)
Ins 5 ug (N = 5)
1.75 mg (N = 5)

(hr)
Mean
SEM
Mean
SEM
Mean
SEM
Mean
SEM
Mean
SEM

0
486
51
495
32
445
29
510
37
485
31

1
528
54
263
39
210
16
265
51
565
32

2
582
9
192
36
150
15
352
60
565
22

4
597
1
462
30
550
25
587
9
562
27

8
577
14
494
10
558
23
538
30
540
36

24
560
24
517
24
541
19
538
36
531
40

Example 21
Preparation of Oxyimine-Linked Chitosan (3-5K)Tetra(Ethylene Glycol) Maleimidopropionamide (22)
A. Preparation of α-Oxyaminoacetamide-Tetra(Ethylene Glycol)-ω-Maleimidopropionamide (21)

embedded image

To a solution of α,ω-bis-oxyaminotetra(ethylene glycol) (2.0 g) and triethylamine (1.0 ml) in acetonitrile (20 ml) was added dropwise a ten-fold excess of 3-maleimidopropionic acid, N-succinimidyl ester (Pierce) while stirring and maintaining the liquid temperature at 25° C. After stirring for an additional 2 hours, the solids were filtered off and the solvent was removed by vacuum distillation. The residue was dissolved in CH₂Cl₂and extracted with water. The CH₂Cl₂extract was evaporated and distilled water was added to dissolve the residue. This solution, containing a mixture of the desired product and a large amount of bis-TEG-maleimide, was chromatographed on a POROS cation exchange resin to provide 0.26 g of the desired product 21. This product was used directly in the next step.

B. Preparation of Oxyimine-Linked Chitosan (3-5K)Tetra(Ethylene Glycol) Maleimidopropionamide (22)

embedded image

To a solution of chitosan 3-5K (Kitto Life, Kyongki-Do, Korea, 0.1 g; MW=3000-5000 by GPC) in 0.5M sodium phosphate buffer, pH=5 (2 mL), α-oxyaminoacetamide-tetra(ethylene glycol)-ω-maleimidopropionamide (prepared in step A above, 0.060 g) was added. Slowly to the solution, acetonitrile (2 mL) was added. The mixture was stirred overnight at 70° C. The reaction mixture was cooled to room temperature and dialyzed for 3 hours against DI water using Dialysis Cassette MWCO 3500 (Pierce). The water was distilled off under reduced pressure. The wet product was dried under vacuum overnight giving 0.13 g of 22 as a yellowish solid. NMR analysis performed in D2O showed that the substitution of end groups of chitosan with maleimide substitution was >90%.

Example 22
Preparation of Oxyimine-Linked Chitosan (10K)-Butanoic Acid (23)

embedded image

To a solution of chitosan (10K) (0.2 g, Kitto Life, Kyongki-Do, Korea, containing ˜15% acetyl groups, ave. MW=10000 by GPC) in 0.1M sodium acetate buffer, pH=5.5, a solution of tetra(ethylene glycol) linker containing oxyamine group and butanoic acid group (from Example 8 above) was added. The pH was readjusted to 5.2 with acetic acid and the mixture was stirred overnight at room temperature. The solution was dialyzed 3 times against DI water using Dialysis Cassette MW CO 10000K (Pierce). The water was distilled off under reduced pressure. The wet product was dried under vacuum overnight giving 2.2 g of 23 as a white solid. NMR analysis performed in D₂O showed that the substitution of end groups of chitosan with butanoic acid groups was ˜26%.

Example 23
ssRNA-C₆-SS-Mal-TEG-Chitosan Conjugate (24)

The title conjugate was produced by the reduction of 5′capped-RNA (5′-C6-S-SC6-AmCAmACmAGmACmUUmUAmAUmGUmAA-3′, Tri-Link BioTechnologies, San Diego, Calif.) with Tris(2-Carboxyethyl) phosphine Hydrochloride (TCEP.HCl) followed by the coupling with chitosan (3-5K) tetra(ethylene glycol)maleimidopropionamide 22, produced in Example 21. To reduce 5′-capped-RNA, a 0.015 mL solution containing 0.003 mL 5′capped-RNA, 0.003 mL, 1 M, EPPS, pH 8.5 and 0.007 mL 64 mM TCEP HCl was incubated at 25° C. without stirring for 60 minutes. After 60 minutes incubation, 0.015 mL reaction mixture was loaded on a desalting column (pre-equilibrated with 20 mM HEPES, 50 mM NaCl, pH 7.4) and rinsed with 0.045 mL buffer (20 mM HEPES, 50 mM NaCl, pH 7.4). A total of 0.06 mL solution containing RNA with free thiol group (5′-HSC6-AmCAmACmAGmACmUUmUAmAUmGUmAA-3′) was collected.

To couple reduced RNA with the maleimide, 0.005-mL of reduced oligo from the above reaction was mixed with 0.005-ML solution containing the maleimide. The reaction mixture was incubated at 25° C. without stirring for three hours. Analysis of the reaction mixture by ion-exchange HPLC revealed a new peak attributable to the title conjugate.

Number	Date	Country
61153966	Feb 2009	US
61208089	Feb 2009	US
61192672	Sep 2008	US

	Number	Date	Country
Parent	13119276	Mar 2011	US
Child	14167271		US

CARBOHYDRATE-BASED DRUG DELIVERY POLYMERS AND CONJUGATES THEREOF

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