Nucleic acid catalysts with endonuclease activity

Abstract

The present invention relates to nucleic acid molecules with new motifs having catalytic activity, methods of syntheses and uses thereof.

Description

BACKGROUND OF THE INVENTION

This invention relates to nucleic acid molecules with catalytic activity and derivatives thereof.

The following is a brief description of enzymatic nucleic acid molecules. This summary is not meant to be complete but is provided only for understanding of the invention that follows. This summary is not an admission that all of the work described below is prior art to the claimed invention.

Enzymatic nucleic acid molecules (ribozymes) are nucleic acid molecules capable of catalyzing one or more of a variety of reactions, including the ability to repeatedly cleave other separate nucleic acid molecules in a nucleotide base sequence-specific manner. Such enzymatic nucleic acid molecules can be used, for example, to target virtually any RNA transcript (Zaug et al., 324 , Nature 429 1986; Cech, 260 JAMA 3030, 1988; and Jefferies et al., 17 Nucleic Acids Research 1371, 1989).

Because of their sequence-specificity, trans-cleaving enzymatic nucleic acid molecules show promise as therapeutic agents for human disease (Usman & McSwiggen, 1995 Ann. Rep. Med. Chem . 30, 285-294; Christoffersen and Marr, 1995 J. Med. Chem . 38, 2023-2037). Enzymatic nucleic acid molecules can be designed to cleave specific RNA targets within the background of cellular RNA. Such a cleavage event renders the mRNA non-functional and abrogates protein expression from that RNA. In this manner, synthesis of a protein associated with a disease state can be selectively inhibited.

There are seven basic varieties of naturally occurring enzymatic RNAs. Each can catalyze the hydrolysis of RNA phosphodiester bonds in trans (and thus can cleave other RNA molecules) under physiological conditions. In general, enzymatic nucleic acids act by first binding to a target RNA. Such binding occurs through the target binding portion of a enzymatic nucleic acid which is held in close proximity to an enzymatic portion of the molecule that acts to cleave the target RNA. Thus, the enzymatic nucleic acid first recognizes and then binds a target RNA through complementary base pairing, and once bound to the correct site, acts enzymatically to cut the target RNA. Strategic cleavage of such a target RNA will destroy its ability to direct synthesis of an encoded protein. After an enzymatic nucleic acid has bound and cleaved its RNA target, it is released from that RNA to search for another target and can repeatedly bind and cleave new targets.

In addition, several in vitro selection (evolution) strategies (Orgel, 1979 , Proc. R. Soc. London , B 205, 435) have been used to evolve new nucleic acid catalysts capable of catalyzing a variety of reactions, such as cleavage and ligation of phosphodiester linkages and amide linkages, (Joyce, 1989 , Gene , 82, 83-87; Beaudry et al., 1992 , Science 257, 635-641; Joyce, 1992 , Scientific American 267, 90-97; Breaker et al., 1994 , TIBTECH 12, 268; Bartel et al., 1993 , Science 261:1411-1418; Szostak, 1993 , TIBS 17, 89-93; Kumar et al, 1995 , FASEB J ., 9, 1183; Breaker, 1996 , Curr. Op. Biotech ., 7, 442).

The enzymatic nature of a ribozyme is advantageous over other technologies, since the effective concentration of ribozyme necessary to effect a therapeutic treatment is generally lower than that of an antisense oligonucleotide. This advantage reflects the ability of the ribozyme to act enzymatically, Thus, a single ribozyme (enzymatic nucleic acid) molecule is able to cleave many molecules of target RNA. In addition, the ribozyme is a highly specific inhibitor, with the specificity of inhibition depending not only on the base-pairing mechanism of binding, but also on the mechanism by which the molecule inhibits the expression of the RNA to which it binds. That is, the inhibition is caused by cleavage of the RNA target and so specificity is defined as the ratio of the rate of cleavage of the targeted RNA over the rate of cleavage of non-targeted RNA. This cleavage mechanism is dependent upon factors additional to those involved in base pairing. Thus, it is thought that the specificity of action of a ribozyme is greater than that of antisense oligonucleotide binding the same RNA site.

The development of ribozymes that are optimal for catalytic activity would contribute significantly to any strategy that employs RNA-cleaving ribozymes for the purpose of regulating gene expression. The hammerhead ribozyme functions with a catalytic rate (k cat ) of ˜1 min −1 in the presence of saturating (10 mM) concentrations of Mg 2+ cofactor. However, the rate for this ribozyme in Mg 2+ concentrations that are closer to those found inside cells (0.5-2 mM) can be 10- to 100-fold slower. In contrast, the RNase P holoenzyme can catalyze pre-tRNA cleavage with a k cat of ˜30 min −1 under optimal assay conditions. An artificial ‘RNA ligase’ ribozyme has been shown to catalyze the corresponding self-modification reaction with a rate of ˜100 min −1 . In addition, it is known that certain modified hammerhead ribozymes that have substrate binding arms made of DNA catalyze RNA cleavage with multiple turn-over rates that approach 100 min −1 . Finally, replacement of a specific residue within the catalytic core of the hammerhead with certain nucleotide analogues gives modified ribozymes that show as much as a 10-fold improvement in catalytic rate. These findings demonstrate that ribozymes can promote chemical transformations with catalytic rates that are significantly greater than those displayed in vitro by most natural self-cleaving ribozymes. It is then possible that the structures of certain self-cleaving ribozymes may be optimized to give maximal catalytic activity, or that entirely new RNA motifs can be made that display significantly faster rates for RNA phosphodiester cleavage.

An extensive array of site-directed mutagenesis studies have been conducted with the hammerhead ribozyme to probe relationships between nucleotide sequence and catalytic activity. These systematic studies have made clear that most nucleotides in the conserved core of the hammerhead ribozyme cannot be mutated without significant loss of catalytic activity. In contrast, a combinatorial strategy that simultaneously screens a large pool of mutagenized ribozymes for RNAs that retain catalytic activity could be used more efficiently to define immutable sequences and to identify new ribozyme variants. Although similar in vitro selection experiments have been conducted with the hammerhead ribozyme (Nakamaye & Eckstein, 1994 , Biochemistry 33, 1271; Long & Uhlenbeck, 1994 , Proc. Natl. Acad. Sci ., 91, 6977; Ishizaka et al., 1995 , BBRC 214, 403; Vaish et al., 1997 , Biochemistry 36, 6495), none of these efforts have successfully screened full-sized hammerhead ribozymes for all possible combinations of sequence variants that encompass the entire catalytic core.

The hammerhead ribozyme is one of the smallest ribozymes known and has thus attracted much attention for the study of structure-function relationships in catalytic. RNAs as well as for its potential for the sequence-specific inhibition of gene expression (Usman et al., supra). The hammerhead cleaves RNA sequence-specifically adjacent to the general triplet sequence NUX, where N is any nucleotide and X can be A, U or C. Cleavage behind a guanosine such as in GUG is very slow (4.3×10 −5 min −1 ) compared to the triplet substrate GUC (1 min −1 ) (Baidya et al., 1997 , Biochemistry 36, 1108). Although the X-ray structure of this ribozyme has been solved and a mechanism proposed (Pley et al., 1994 Nature , 372, 68; Scott et al., 1996 , Science 274, 2065), the question of what determines its specificity for the NUX sequence is still largely unresolved. One way of obtaining an insight into this problem might be to compare sequences of hammerhead ribozymes with different triplet cleaving specificities. In previous publications, it was demonstrated, using in vitro selection, that the native hammerhead sequence necessary to cleave a typical cleavage triplet, NUX, can not be altered (Nakamaye & Eckstein, 1994 , Biochemistry 33, 1271; Long & Uhlenbeck, 1994 , Proc. Natl. Acad. Sci ., 91, 6977; Ishizaka et al., 1995 , BBRC 214, 403; Vaish et al., 1997 , Biochemistry 36, 6495), indicating that nature has evolved a close to perfect GUC cleaver. It was of interest to see what changes have to be imposed on the native hammerhead sequence for it to cleave after AUG, which usually resists cleavage, and thus arrive at a ribozyme with a new specificity. To achieve this, an in vitro selection was undertaken, where the number of randomized positions in the starting pool corresponded to the number of nucleotides typically found in the core and stem-loop II region of a hammerhead ribozyme. This would allow all possible sequence permutations to be explored in the search for a hammerhead which is able to cleave behind AUG (Robertson & Joyce, 1990 , Nature 344:6265 467-8; Ellington and Szostak, 1990; Tuerk & Gold, 1990; Wright & Joyce, 1997; Carmi et al., 1997; for reviews see Breaker, 1997; Abelson, 1996; Ellington, 1997; Chapman & Szostak, 1994). Tang et al., 1997, RNA 3, 914, reported novel ribozyme sequences with endonuclease activity, where the authors used an in vitro selection approach to isolate these ribozymes.

The platelet derived growth factor (PDGF) system has served as a prototype for the identification of substrates of receptor tyrosine kinases. Certain enzymes become activated by the PDGF receptor kinase, including phospholipase C and phosphatidylinositol 3′ kinase, Ras guanosine triphosphate (GTPase) activating protein (GAP) and src-like tyrosine kinases. GAP regulates the function of the Ras protein. It stimulates the GTPase activity of the 21 kD Ras protein (Barbacid. 56 Ann. Rev. Biochem . 779, 1987). Microinjection of oncogenically activated Ras into NIH 3T3 cells induces DNA synthesis. Mutations that cause oncogenic activation of ras lead to accumulation of Ras bound to GTP, the active form of the molecule. These mutations block the ability of GAP to convert Ras to the inactive form. Mutations that impair the interactions of Ras with GAP also block the biological function of Ras.

While a number of ras alleles exist (N-ras, K-ras, H-ras) which have been implicated in carcinogenesis, the type most often associated with colon and pancreatic carcinomas is the K-ras. Ribozymes which are targeted to certain regions of the K-ras allelic mRNAs may also prove inhibitory to the function of the other allelic mRNAs of the N-ras and H-ras genes.

Transformation is a cumulative process whereby normal control of cell growth and differentiation is interrupted, usually through the accumulation of mutations affecting the expression of genes that regulate cell growth and differentiation.

Scanlon WO91/18625, WO91/18624, and WO91/18913 describe a specific hammerhead ribozyme effective to cleave RNA from the H-ras gene at codon 12 mutation. This ribozyme is said to inhibit H-ras expression in response to exogenous stimuli.

Thompson et al., U.S. Pat. Nos. 5,610,052 and 5,801,158, describes enzymatic RNA molecules against Ras.

Vaish et al., 1998 PNAS 95, 2158-2162, describes the in vitro selection of a hammerhead-like ribozyme with an extended range of cleavable triplets.

The references cited above are distinct from the presently claimed invention since they do not disclose and/or contemplate the catalytic nucleic acid molecules of the instant invention.

SUMMARY OF THE INVENTION

This invention relates to novel nucleic acid molecules with catalytic activity, which are particularly useful for cleavage of RNA or DNA. The nucleic acid catalysts of the instant invention are distinct from other nucleic acid catalysts known in the art. The nucleic acid catalysts of the instant invention do not share sequence homology with other known ribozymes. Specifically, nucleic acid catalysts of the instant invention are capable of catalyzing an intermolecular or intramolecular endonuclease reaction.

In a preferred embodiment, the invention features a nucleic acid molecule with catalytic activity having one of the formulae I-V:

In each of the above formulae, N represents independently a nucleotide or a non-nucleotide linker, which may be the same or different; X and Y are independently oligonucleotides of length sufficient to stably interact (e.g., by forming hydrogen bonds with complementary nucleotides in the target) with a target nucleic acid molecule (the target can be an RNA, DNA or RNA/DNA mixed polymers); m and n are integers independently greater than or equal to 1 and preferably less than about 100, wherein if (N) m and (N) n are nucleotides, (N)m and (N)n are optionally able to interact by hydrogen bond interaction; J is an oligonucleotide of length 6 or 7 nucleotides; K is an oligonucleotide of length 5 nucleotides; L is a linker which may be present or absent (i.e., the molecule is assembled from two separate molecules), but when present, is a nucleotide and/or a non-nucleotide linker, which may be a single-stranded and/or double-stranded region; and ——— represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage or others known in the art). Z is independently a nucleotide numbered as 13.1 ( FIG. 8 ) which can stably interact with a nucleotide at position 14.1 ( FIG. 8 ) in the target nucleic acid molecule, preferably, the N 13.1 -N 14.1 interaction is inosine 13.1 -cytidine 14.1 ; adenosine 13.1 -uridine 14.1 ; guanosine 13.1 -cytidine 14.1 ; uridine 13.1 -adenosine 14.1 ; or cytidine 13.1 -guanosine 14.1 ; and C, G, A, and U represent cytidine, guanosine, adenosine and uridine nucleotides, respectively. The nucleotides in the each of the formulae I-V are unmodified or modified at the sugar, base, and/or phosphate as known in the art.

In a preferred embodiment, the invention features nucleic acid molecules of Formula I, where the sequence of oligonucleotide J is selected from the group comprising 5′-GGCAUCC-3′, 5′-AGCAUU-3′, 5′-GCAUCA-3′, 5′-AGCAUC-3′, and 5′-AGCGUC-3′.

In another preferred embodiment, the invention features nucleic acid molecules of Formula II, where the sequence of oligonucleotide J is 5′-GGAAUC-3′.

In a further preferred embodiment, the invention features nucleic acid molecules of Formula III, where the sequence of oligonucleotide K is selected from the group comprising 5′-UGAUG-3′, 5′-UGAUC-3′, and 5′-UGGGC-3′.

In another embodiment, the nucleotide linker (L) is a nucleic acid sequence selected from the group consisting of 5′-GCACU-3′, 5′-GAACU-3′, 5′-GCACC-3′, 5′-GNACU-3′, 5′-GNGCU-3′, 5′-GNCCU-3′, 5′-GNUCU-3′, 5′-GNGUU-3′, 5′-GNCUU-3′, 5′-GNUUU-3′, 5′-GNAUU-3′, 5′-GNACA-3′, 5′-GNGCA-3′, 5′-GNCCA-3′, and 5′-GNUCA-3′, whereby N can be selected from the group consisting of A, G, C, or U.

In yet another embodiment, the nucleotide linker (L) is a nucleic acid aptamer, such as an ATP aptamer, HIV Rev aptamer (RRE), HIV Tat aptamer (TAR) and others (for a review see Gold et al., 1995 , Annu. Rev. Biochem ., 64, 763; and Szostak & Ellington, 1993, in The RNA World , ed. Gesteland and Atkins, pp. 511, CSH Laboratory Press). A “nucleic acid aptamer” as used herein is meant to indicate a nucleic acid sequence capable of interacting with a ligand. The ligand can be any natural or a synthetic molecule, including but not limited to a resin, metabolites, nucleosides, nucleotides, drugs, toxins, transition state analogs, peptides, lipids, proteins, amino acids, nucleic acid molecules, hormones, carbohydrates, receptors, cells, viruses, bacteria and others.

In yet another embodiment, the non-nucleotide linker (L) is as defined herein. The term “non-nucleotide” as used herein include either abasic nucleotide, polyether, polyamine, polyamide, peptide, carbohydrate, lipid, or polyhydrocarbon compounds. Specific examples include those described by Seela and Kaiser, Nucleic Acids Res . 1990, 18:6353 and Nucleic Acids Res . 1987, 15:3113; Cload and Schepartz, J. Am. Chem. Soc . 1991, 113:6324; Richardson and Schepartz, J. Am. Chem. Soc . 1991, 113:5109; Ma et al., Nucleic Acids Res . 1993, 21:2585 and Biochemistry 1993, 32:1751; Durand et al., Nucleic Acids Res . 1990, 18:6353; McCurdy et al., Nucleosides & Nucleotides 1991, 10:287; Jschke et al., Tetrahedron Lett . 1993, 34:301; Ono et al.; Biochemistry 1991, 30:9914; Arnold et al., International Publication No. WO 89/02439; Usman et al., International Publication No. WO 95/06731; Dudycz et al., International Publication No. WO 95/11910 and Ferentz and Verdine, J. Am. Chem. Soc . 1991, 113:4000, all hereby incorporated by reference herein. Thus, in a preferred embodiment, the invention features an enzymatic nucleic acid molecule having one or more non-nucleotide moieties, and having enzymatic activity to cleave an RNA or DNA molecule. By the term “non-nucleotide” is meant any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound is abasic in that it does not contain a commonly recognized nucleotide base, such as adenine, guanine, cytosine, uracil or thymine. The terms “abasic” or “abasic nucleotide” as used herein encompass sugar moieties lacking a base or having other chemical groups in place of a base at the 1′ position.

In preferred embodiments, the enzymatic nucleic acid includes one or more stretches of RNA, which provide the enzymatic activity of the molecule, linked to the non-nucleotide moiety. The necessary RNA components are known in the art (see for e.g., Usman et al., supra). By RNA is meant a molecule comprising at least one ribonucleotide residue. By “ribonucleotide” is meant a nucleotide with a hydroxyl group at the 2′ position of a β-D-ribo-furanose moiety.

Thus, in one preferred embodiment, the invention features ribozymes that inhibit gene expression and/or cell proliferation. These chemically or enzymatically synthesized nucleic acid molecules contain substrate binding domains that bind to accessible regions of specific target nucleic acid molecules. The nucleic acid molecules also contain domains that catalyze the cleavage of target. Upon binding, the enzymatic nucleic acid molecules cleave the target molecules, preventing, for example, translation and protein accumulation. In the absence of the expression of the target gene, cell proliferation, for example, is inhibited. In another aspect of the invention, enzymatic nucleic acid molecules that cleave target molecules are expressed from transcription units inserted into DNA or RNA vectors. The recombinant vectors are preferably DNA plasmids or viral vectors. Ribozyme expressing viral vectors could be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. Preferably, the recombinant vectors capable of expressing the ribozymes are delivered as described below, and persist in target cells. Alternatively, viral vectors may be used that provide for transient expression of ribozymes. Such vectors can be repeatedly administered as necessary. Once expressed, the ribozymes cleave the target mRNA. Delivery of ribozyme expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that would allow for introduction into the desired target cell (for a review, see, Couture and Stinchcomb, 1996 , TIG ., 12, 510).

As used in herein “cell” is used in its usual biological sense, and does not refer to an entire multicellular organism, e.g., specifically does not refer to a human. The cell may be present in a non-human multicellular organism, e.g., birds, plants and mammals such as cows, sheep, apes, monkeys, swine, dogs, and cats.

In a preferred embodiment, an expression vector comprising a nucleic acid sequence encoding at least one of the nucleic acid catalysts of the instant invention is disclosed. The nucleic acid sequence encoding the nucleic acid catalyst of the instant invention is operable linked in a manner which allows expression of that nucleic acid molecule.

In one embodiment, the expression vector comprises: a transcription initiation region (e.g., eukaryotic pol I, II or III initiation region); b) a transcription termination region (e.g., eukaryotic pol I, II or III termination region); c) a nucleic acid sequence encoding at least one of the nucleic acid catalyst of the instant invention; and wherein said gene is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. The vector may optionally include an open reading frame (ORF) for a protein operably linked on the 5′ side or the 3′-side of the sequence encoding the nucleic acid catalyst of the invention; and/or an intron (intervening sequences).

By “patient” is meant an organism which is a donor or recipient of explanted cells or the cells themselves. “Patient” also refers to an organism to which enzymatic nucleic acid molecules can be administered. Preferably, a patient is a mammal or mammalian cells. More preferably, a patient is a human or human cells.

By “vectors” is meant any nucleic acid- and/or viral-based technique used to deliver a desired nucleic acid.

Another means of accumulating high concentrations of a ribozyme(s) within cells is to incorporate the ribozyme-encoding sequences into a DNA or RNA expression vector. Transcription of the ribozyme sequences are driven from a promoter for eukaryotic RNA polymerase. I (pol I), RNA polymerase II (pol II), or RNA polymerase III (pol III). Transcripts from pol II or pol III promoters will be expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type will depend on the nature of the gene regulatory sequences (enhancers, silencers, etc.) present nearby. Prokaryotic RNA polymerase promoters are also used, providing that the prokaryotic RNA polymerase enzyme is expressed in the appropriate cells (Elroy-Stein and Moss, 1990 Proc. Natl. Acad. Sci. USA , 87, 6743-7; Gao and Huang 1993 Nucleic Acids Res ., 21, 2867-72; Lieber et al., 1993 Methods Enzymol ., 217, 47-66; Zhou et al., 1990 Mol. Cell. Biol ., 10, 4529-37). Several investigators have demonstrated that ribozymes expressed from such promoters can function in mammalian cells (e.g. Kashani-Sabet et al., 1992 Antisense Res. Dev ., 2, 3-15; Ojwang et al., 1992 Proc. Natl. Acad. Sci. USA , 89, 10802-6; Chen et al., 1992 Nucleic Acids Res ., 20, 4581-9; Yu et al., 1993 Proc. Natl. Acad. Sci. USA , 90, 6340-4; L'Huillier et al., 1992 EMBO J . 11, 4411-8; Lisziewicz et al., 1993 Proc. Natl. Acad. Sci. U. S. A ., 90, 8000-4; Thompson et al., 1995 Nucleic Acids Res . 23, 2259; Sullenger & Cech, 1993 , Science 262, 1566). The above ribozyme transcription units can be incorporated into a variety of vectors for introduction into mammalian cells, including but not restricted to, plasmid DNA vectors, viral DNA vectors (such as adenovirus or adeno-associated virus vectors), or viral RNA vectors (such as retroviral or alphavirus vectors) (for a review see Couture and Stinchcomb, 1996, supra).

In another preferred embodiment, catalytic activity of the molecules described in the instant invention can be optimized as described by Draper et al., supra. The details will not be repeated here, but include altering the length of the ribozyme binding arms, or chemically synthesizing ribozymes with modifications (base, sugar and/or phosphate) that prevent their degradation by serum ribonucleases and/or enhance their enzymatic activity (see e.g., Eckstein et al., International Publication No. WO 92/07065; Perrault et al., 1990 Nature 344, 565; Pieken et al., 1991 Science 253, 314; Usman and Cedergren, 1992 Trends in Biochem. Sci . 17, 334; Usman et. al., International Publication No. WO 93/15187; and Rossi et al., International Publication No. WO 91/03162; Sproat, U.S. Pat. No. 5;334,711; and Burgin et al., supra; all of these describe various chemical modifications that can be made to the base, phosphate and/or sugar moieties of enzymatic RNA molecules). Modifications to the molecules, which enhance their efficacy in cells, and removal of bases from stem loop structures to shorten RNA synthesis times and reduce chemical requirements are desired. All these publications are hereby incorporated by reference herein.

By “enhanced enzymatic activity” is meant to include activity measured in cells and/or in vivo where the activity is a reflection of both catalytic activity and ribozyme stability. In this invention, the product of these properties is increased or not significantly (less than 10-fold) decreased in vivo compared to an all RNA ribozyme.

In yet another preferred embodiment, nucleic acid catalysts having chemical modifications, which maintain or enhance enzymatic activity are provided. Such nucleic acid is also generally more resistant to nucleases than unmodified nucleic acid. Thus, in a cell and/or in vivo the activity may not be significantly lowered. As exemplified herein, such ribozymes are useful in a cell and/or in vivo even if activity over all is reduced 10 fold (Burgin et al., 1996 , Biochemistry , 35, 14090). Such ribozymes herein are said to “maintain” the enzymatic activity of an all RNA ribozyme.

In yet another aspect the invention features an enzymatic nucleic acid molecule which cleaves mRNA produced from the human K-ras gene (accession NM — 004985), H-ras gene (accession NM — 005343) or N-ras gene (accession NM — 002524). In one nonlimiting example, the enzymatic nucleic acid molecule of the present invention cleaves mRNA molecules associated with the development or maintenance of colon carcinoma. In preferred embodiments, the enzymatic nucleic acid molecules comprise sequences which are complementary to the substrate sequences in Table II. Examples of such enzymatic nucleic acid molecules also are shown in Table II. Examples of such enzymatic nucleic acid molecules consist essentially of sequences defined in Table II.

Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The drawings will first briefly be described.

DRAWINGS

FIG. 1 A) is a diagrammatic representation of the hammerhead ribozyme domain known in the art. Stem II can be 2 base-pairs long. Each N is independently any base or non-nucleotide as used herein; B) is a diagrammatic representation of a self-cleaving hammerhead ribozyme; C) is a diagrammatic representation of a random pool of self-cleaving RNA. N indicates the region with random nucleotides. (SEQ ID NO: 1171-1174)

FIG. 2 is a schematic representation of a non-limiting in vitro selection strategy used to evolve nucleic acid catalysts. (SEQ ID NO: 1175-1189)

FIG. 3 shows sequences of individual RNAs that represent new classes of self-cleaving ribozymes. Also shown are rates of catalysis (k in-cis (min −1 )) for each of the new self-cleaving RNA sequences. The underlined sequences indicate the regions capable of interacting with each other. (SEQ ID NO: 1175-1189)

FIG. 4 summarizes structure mapping studies on clone 40 RNA. (SEQ ID NO: 1190)

FIG. 5 shows sequence and possible secondary structure of a trans-cleaving ribozyme of the invention. Arrow identifies the site of cleavage. (SEQ ID NO: 1191-1192)

FIG. 6 shows non-limiting examples of trans-cleaving ribozyme-substrate complex of the present invention. (SEQ ID NO: 1193-1198)

FIG. 7 shows non-limiting examples of chemically modified trans-cleaving ribozyme-substrate complex of the present invention. (SEQ ID NO: 1199-1206)

FIG. 8 shows a non-limiting example of a chemically modified trans-cleaving ribozyme-substrate complex of the present invention and the numbering system used for (SEQ ID NO: 1207-1208)

NUCLEIC ACID CATALYSTS

The invention provides nucleic acid catalysts and methods for producing a class of enzymatic nucleic acid cleaving agents which exhibit a high degree of specificity for the nucleic acid sequence of a desired target. The enzymatic nucleic acid molecule is preferably targeted to a highly conserved sequence region of a target such that specific diagnosis and/or treatment of a disease or condition in a variety of biological system can be provided with a single enzymatic nucleic acid. Such enzymatic nucleic acid molecules can be delivered exogenously to specific cells as required. In the preferred hammerhead motif, the small size (less than 60 nucleotides, preferably between 30-40 nucleotides in length) of the molecule allows the cost of treatment to be reduced.

By “nucleic acid catalyst” as used herein is meant a nucleic acid molecule (e.g., the molecule of formulae I-V), capable of catalyzing (altering the velocity and/or rate of) a variety of reactions including the ability to repeatedly cleave other separate nucleic acid molecules (endonuclease activity) in a nucleotide base sequence-specific manner. Such a molecule with endonuclease activity may have complementarity in a substrate binding region (e.g. X and Y in formulae I-V) to a specified-gene target, and also has an enzymatic activity that specifically cleaves RNA or DNA in that target. That is, the nucleic acid molecule with endonuclease activity is able to intramolecularly or intermolecularly cleave RNA or DNA and thereby inactivate a target RNA or DNA molecule. This complementarity functions to allow sufficient hybridization of the enzymatic RNA molecule to the target RNA or DNA to allow the cleavage to occur. 100% complementarity is preferred, but complementarity as low as 50-75% may also be useful in this invention. The nucleic acids may be modified at the base, sugar, and/or phosphate groups. The term enzymatic nucleic acid is used interchangeably with phrases such as ribozymes, catalytic RNA, enzymatic RNA, catalytic DNA, nucleozyme, RNA enzyme, endoribonuclease, endonuclease, minizyme, oligozyme, finderon or nucleic acid catalyst. All of these terminologies describe nucleic acid molecules with enzymatic activity. The specific examples of enzymatic nucleic acid molecules described in the instant application are not limiting in the invention and those skilled in the art will recognize that all that is important in an enzymatic nucleic acid molecule of this invention is that it has a specific substrate binding site which is complementary to one or more of the target nucleic acid regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart a nucleic acid cleaving activity to the molecule.

By “nucleic acid molecule” as used herein is meant a molecule having nucleotides. The nucleic acid can be single, double, or multiple stranded and may comprise modified or unmodified nucleotides or non-nucleotides or various mixtures and combinations thereof.

By “complementarity” is meant that a nucleic acid can form hydrogen bond(s) with another RNA sequence by either traditional Watson-Crick or other non-traditional types. In reference to the nucleic molecules of the present invention, the binding free energy for a nucleic acid molecule with its target or complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., enzymatic nucleic acid cleavage, antisense or triple helix inhibition. Determination of binding free energies for nucleic acid molecules is well-known in the art (see, e.g., Turner et al., 1987 , CSH Symp. Quant. Biol . LII pp.123-133; Frier et al., 1986 , Proc. Nat. Acad. Sci. USA 83:9373-9377; Turner et al., 1987 , J. Am. Chem. Soc . 109:3783-3785. A percent complementarity indicates the percentage of contiguous residues in a nucleic acid molecule which can form hydrogen bonds (e.g., Watson-Crick base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, 10 out of 10 being 50%, 60%, 70%, 80%, 90%, and 100% complementary). “Perfectly complementary” means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence.

The enzymatic nucleic acid molecules of Formulae I-V may independently comprise a cap structure which may independently be present or absent.

By “sufficient length” is meant an oligonucleotide of greater than or equal to 3 nucleotides. For example, for the X and Y portions of the nucleic acid molecules disclosed in formulae I-V “sufficient length” means that the nucleotide length is long enough to provide stable binding to a target site under the expected binding conditions. Preferably, the X and Y portions are not so long as to prevent useful turnover.

By “stably interact” is meant, interaction of the oligonucleotides with target nucleic acid (e.g., by forming hydrogen bonds with complementary nucleotides in the target under physiological conditions).

By “chimeric nucleic acid molecule” or “mixed polymer” is meant that, the molecule may be comprised of both modified or unmodified nucleotides.

By “cap structure” is meant chemical modifications, which have been incorporated at either terminus of the oligonucleotide. These terminal modifications protect the nucleic acid molecule from exonuclease degradation, and may help in delivery and/or localization within a cell. The cap may be present at the 5′-terminus. (5′-cap) or at the 3′-terminus (3′-cap) or may be present on both termini. In non-limiting examples: the 5′-cap is selected from the group comprising inverted abasic residue (moiety); 4′,5′-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide; 4′-thio nucleotide, carbocyclic nucleotide; 1,5-anhydrohexitol nucleotide; L-nucleotides; alpha-nucleotides; modified base nucleotide; phosphorodithioate linkage; threo-pentofuranosyl nucleotide; acyclic 3′,4′-seco nucleotide; acyclic 3,4-dihydroxybutyl nucleotide; acyclic 3,5-dihydroxypentyl nucleotide, 3′-3′-inverted nucleotide moiety; 3′-3′-inverted abasic moiety; 3′-2′-inverted nucleotide moiety; 3′-2′-inverted abasic moiety; 1,4-butanediol phosphate; 3′-phosphoramidate; hexylphosphate; aminohexyl phosphate; 3′-phosphate; 3′-phosphorothioate; phosphorodithioate; or bridging or non-bridging methylphosphonate moiety (for more details see Beigelman et al., International PCT publication No. WO 97/26270, incorporated by reference herein).

In yet another preferred embodiment the 3′-cap is selected from a group comprising, 4′,5′-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide; 4′-thio nucleotide, carbocyclic nucleotide; 5′-amino-alkyl phosphate; 1,3-diamino-2-propyl phosphate, 3-aminopropyl phosphate; 6-aminohexyl phosphate; 1,2-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitol nucleotide; L-nucleotide; alpha-nucleotide; modified base nucleotide; phosphorodithioate; threo-pentofuranosyl nucleotide; acyclic 3′,4′-seco nucleotide; 3,4-dihydroxybutyl nucleotide; 3,5-dihydroxypentyl nucleotide, 5′-5′-inverted nucleotide moiety; 5′-5′-inverted abasic moiety; 5′-phosphoramidate; 5′-phosphorothioate; 1,4-butanediol phosphate; 5′-amino; bridging and/or non-bridging 5′-phosphoramidate, phosphorothioate and/or phosphorodithioate, bridging or non bridging methylphosphonate and 5′-mercapto moieties (for more details, see, Beaucage and Iyer, 1993 , Tetrahedron 49, 1925; incorporated by reference herein).

By the term “non-nucleotide” is meant any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound is abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine. The terms “abasic” or “abasic nucleotide” as used herein encompass sugar moieties lacking a base or having other chemical groups in place of base at the 1′ position.

By “oligonucleotide” as used herein, is meant a molecule comprising two or more nucleotides.

The specific enzymatic nucleic acid molecules described in the instant application are not limiting in the invention and those skilled in the art will recognize that all that is important in an enzymatic nucleic acid molecule of this invention is that it has a specific substrate binding site (e.g., X and Y of Formulae I-V above) which is complementary to one or more of the target nucleic acid regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart a nucleic acid cleaving activity to the molecule.

By “enzymatic portion” is meant that part of the ribozyme essential for cleavage of an RNA substrate.

By “substrate binding arm” or “substrate binding domain” is meant that portion of a ribozyme which is complementary to (i.e., able to base-pair with) a portion of its substrate. Generally, such complementarity is 100%, but can be less if desired. For example, as few as 10 nucleotides out of a total of 14 may be base-paired. Such arms are shown generally in FIG. 1 A and as X and Y in Formulae I-V. That is, these arms contain sequences within a ribozyme which are intended to bring ribozyme and target RNA together through complementary base-pairing interactions. The ribozyme of the invention may have binding arms that are contiguous or non-contiguous and may be of varying lengths. The length of the binding arm(s) are preferably greater than or equal to four nucleotides; specifically 12-100 nucleotides; more specifically 14-24 nucleotides long. The two binding arms are chosen, such that the length of the binding arms are symmetrical (i.e., each of the binding arms is of the same length; e.g., five and five nucleotides, six and six nucleotides or seven and seven nucleotides long) or asymmetrical (i e., the binding arms are of different length; e.g., six and three nucleotides; three and six nucleotides long; four and five nucleotides long; four and six nucleotides long; four and seven nucleotides long; and the like).

Catalytic activity of the ribozymes described in the instant invention can be optimized as described by Draper et al., supra. The details will not be repeated here, but include altering the length of the ribozyme binding arms, or chemically synthesizing ribozymes with modifications (base, sugar and/or phosphate) that prevent their degradation by serum ribonucleases and/or enhance their enzymatic activity (see e.g. Eckstein et al., International Publication No. WO 92/07065; Perrault et al., 1990 Nature 344, 565; Pieken et al., 1991 Science 253, 314, Usman and Cedergren, 1992 Trends in Biochem. Sci . 17, 334; Usman et al., International Publication No. WO 93/15187; and Rossi et al., International Publication No. WO 91/03162; Sproat, U.S. Pat. No. 5,334,711; and Burgin et al., supra; all of these describe various chemical modifications that can be made to the base, phosphate and/or sugar moieties of enzymatic RNA molecules). Modifications which enhance their efficacy in cells, and removal of bases from stem loop structures to shorten RNA synthesis times and reduce chemical requirements are desired. All these publications are hereby incorporated by reference herein.

Therapeutic ribozymes must remain stable within cells until translation of the target RNA has been inhibited long enough to reduce the levels of the undesirable protein. This period of time varies between hours to days depending upon the disease state. Clearly, ribozymes must be resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of RNA (Wincott et al., 1995 Nucleic Acids Res . 23, 2677; incorporated by reference herein) have expanded the ability to modify ribozymes to enhance their nuclease stability. The term “nucleotide” is used as recognized in the art to include natural bases, and modified bases well known in the art. Such bases are generally located at the 1′ position of a sugar moiety. Nucleotides generally comprise a base, sugar and a phosphate group. The nucleotides can be unmodified or modified at the sugar, phosphate and/or base moiety, (see for example, Usman and McSwiggen, supra; Eckstein et al., International PCT Publication No. WO 92/07065; Usman et al., International PCT Publication No. WO 93/15187; all hereby incorporated by reference herein). There are several examples of modified nucleic acid bases known in the art. These recently have been summarized by Limbach et al., 1994 , Nucleic Acids Res . 22, 2183. Some of the non-limiting examples of base modifications that can be introduced into enzymatic nucleic acids without significantly effecting their catalytic activity include, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2, 4, 6-trimethoxy benzene, 3-methyluracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines (e.g. 6-methyluridine) and others (Burgin et al., 1996 , Biochemistry , 35, 14090). By “modified bases” in this aspect is meant nucleotide bases other than adenine, guanine, cytosine and uracil at 1′ position or their equivalents; such bases may be used within the catalytic core of the enzyme and/or in the substrate-binding regions.

In a preferred embodiment, the invention features modified ribozymes with phosphate backbone modifications comprising one or.more phosphorothioate and/or phosphorodithioate substitutions. A non-limiting, preferred example of a ribozyme of the instant invention utilizing phosphorothioate and/or phosphorodithioate modifications in conjunction with 2′-O-methyl ribonucleotides and conserved ribonucleotide residues is shown in FIG. 8 . The incorporation of phosphorothioate and/or phosphorodithioate linkages into the enzymatic nucleic acid of the instant invention results in increased serum stability. Replacement of the 3′-phosphodiester at position 6 with a phosphorothioate or phosphorodithioate linkage ( FIG. 8 ) stabilizes the conserved position 6 ribose moiety, which is prone to nucleolytic cleavage. In a study investigating the serum stability of position 6 modified ribozyme variants which preserve the 2′-hydroxyl function at position 6 (FIG. 8 ), the relative stability of the modifications were ranked as follows:

3′-Phosphorodithioate>>3′-Phosphorothioate>>4′-Thioribofuranose>Phosphodiester

The preferred incorporation of one to four, but preferably two, phosphorothioate linkages at the 5′-end of the position 6 3′-phosphorothioate ribozyme ( FIG. 8 ) does not significantly affect the cleavage rate of the molecule. In a comparison study, the incorporation of up to four phosphorothioate residues at the 5′-end of this molecule is well tolerated. The incorporation of a 3′-phosphorodithioate residue at.position 6 of the ribozyme results in a 50% reduction in catalytic activity over the corresponding position 6 3′-phosphorothioate derivative. The loss of catalytic activity in the case of the position 6 3′-phosphorodithoate substitution may be offset by the increased serum stability that this modification offers and is likely to enhance the effectiveness of the ribozyme in cells.

In a preferred embodiment, the invention features a 3′-phosphorothioate linkage at position 6 of the nucleic acid molecule of the instant invention (FIG. 8 ).

In yet another preferred embodiment, the invention features a 3′-phosphorodithioate linkage at position 6 of the nucleic acid molecule (FIG. 8 ).

In a further preferred embodiment of the instant invention, an inverted deoxy abasic moiety is utilized at the 3′ end of the enzymatic nucleic acid molecule.

In particular, the invention features modified ribozymes having a base substitution selected from pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2, 4, 6-trimethoxy benzene, 3-methyluracil, dihydrouracil, naphthyl, 6-methyl-uracil and aminophenyl.

There are several examples in the art describing sugar and phosphate modifications that can be introduced into enzymatic nucleic acid molecules without significantly effecting catalysis and with significant enhancement in their nuclease stability and efficacy. Ribozymes are modified to enhance stability and/or enhance catalytic activity by modification with nuclease resistant groups, for example, 2′-amino, 2′-C-allyl, 2′-flouro, 2′-O-methyl, 2′-H, nucleotide base modifications (for a review see Usman and Cedergren, 1992 TIBS 17, 34; Usman et al., 1994 Nucleic Acids Symp. Ser . 31, 163; Burgin et al., 1996 Biochemistry 35, 14090). Sugar modifications of enzymatic nucleic acid molecules have been extensively described in the art (see Eckstein et al., International Publication PCT No. WO 92/07065; Perrault et al. Nature 1990, 344, 565-568; Pieken et al. Science 1991, 253, 314-317; Usman and Cedergren, Trends in Biochem. Sci . 1992, 17, 334-339; Usman et al. International Publication PCT No. WO 93/15187; Sproat, U.S. Pat. No. 5,334,711 and Beigelman et al., 1995 J. Biol. Chem . 270, 25702).

Such publications describe general methods and strategies to determine the location of incorporation of sugar, base and/or phosphate modifications and the like into ribozymes without inhibiting catalysis, and are incorporated by reference herein. In view of such teachings, similar modifications can be used as described herein to modify the nucleic acid catalysts of the instant invention.

As the term is used in this application, non-nucleotide-containing enzymatic nucleic acid means a nucleic acid molecule that contains at least one non-nucleotide component which replaces a portion of a ribozyme, e.g., but not limited to, a double-stranded stem, a single-stranded “catalytic core” sequence, a single-stranded loop or a single-stranded recognition sequence. These molecules are able to cleave (preferably, repeatedly cleave) separate RNA or DNA molecules in a nucleotide base sequence specific manner. Such molecules can also act to cleave intramolecularly if that is desired. Such enzymatic molecules can be targeted to virtually any RNA transcript.

The sequences of ribozymes that are chemically synthesized, useful in this invention, are shown in Table II. Those in the art will recognize that these sequences are representative only of many more such sequences where the enzymatic portion of the enzymatic nucleic acid molecule (all but the binding arms) is altered to affect activity. The ribozyme sequences listed in Table II may be formed of ribonucleotides or other nucleotides or non-nucleotides. Such ribozymes with enzymatic activity are equivalent to the ribozymes described specifically in the Table.

Synthesis of Nucleic Acid Molecules

Synthesis of nucleic acids greater than 100 nucleotides in length is difficult using automated methods, and the therapeutic cost of such molecules is prohibitive. In this invention, small nucleic acid motifs (“small refers to nucleic acid motifs no more than 100 nucleotides in length, preferably no more than 80 nucleotides in length, and most preferably no more than 50 nucleotides in length; e.g., antisense oligonucleotides, hammerhead or the hairpin ribozymes) are preferably used for exogenous delivery. The simple structure of these molecules increases the ability of the nucleic acid to invade targeted regions of RNA structure. Exemplary molecules of the instant invention were chemically synthesized, and others can similarly be synthesized. Oligodeoxyribonucleotides were synthesized using standard protocols as described in Caruthers et al., 1992 , Methods in Enzymology 211,3-19, and is incorporated herein by reference.

The method of synthesis used for normal RNA including certain enzymatic nucleic acid molecules follows the procedure as described in Usman et al., 1987 J. Am. Chem. Soc ., 109, 7845; Scaringe et al., 1990 Nucleic Acids Res ., 18, 5433; Wincott et al., 1995 Nucleic Acids Res . 23, 2677-2684; and Wincott et al., 1997 , Methods Mol. Bio ., 74, 59, and makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end. In a non-limiting example, small scale syntheses were conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 μmol scale protocol with a 7.5 min coupling step for alkylsilyl protected nucleotides and a 2.5 min coupling step for 2′-O-methylated nucleotides. Table II outlines the amounts and the contact times of the reagents used in the synthesis cycle. Alternatively, syntheses at the 0.2 μmol scale can be done on a 96-well plate synthesizer, such as the instrument produced by Protogene (Palo Alto, Calif.) with minimal modification to the cycle. A 33-fold excess (60 μL of 0.11 M=6.6 μmol) of 2′-O-methyl phosphoramidite and a 75-fold excess of S-ethyl tetrazole (60 μL of 0.25 M=15 μmol) can be used in each coupling cycle of 2′-O-methyl residues relative to polymer-bound 5′-hydroxyl. A 66-fold excess (120 μL of 0.11 M=13.2 μmol) of alkylsilyl (ribo) protected phosphoramidite and a 150-fold excess of S-ethyl tetrazole (120 μL of 0.25 M=30 μmol) can be used in each coupling cycle of ribo residues relative to polymer-bound 5′-hydroxyl. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by calorimetric quantitation of the trityl fractions, were 97.5-99%. Other oligonucleotide, synthesis reagents for the 394 Applied . Biosystems, Inc. synthesizer; detritylation solution was 3% TCA in methylene chloride (ABI); capping was performed with 16% N-methyl imidazole in THF (ABI) and 10% acetic anhydride/10% 2,6-lutidine in THF (ABI); oxidation solution was 16.9 mM I 2 , 49 mM pyridine, 9% water in THF (PERSEPTIVE™). Burdick & Jackson Synthesis Grade acetonitrile was used directly from the reagent bottle. S-Ethyltetrazole solution (0.25 M in acetonitrile) was made up from the solid obtained from American International Chemical, Inc.

Deprotection of the RNA was performed using either a two-pot or one-pot protocol. For the two-pot protocol, the polymer-bound trityl-on oligoribonucleotide was transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65° C. for 10 min. After cooling to −20° C., the supernatant was removed from the polymer support. The support was washed three times with 1.0 mL of EtOH:MeCN:H2O/3:1:1, vortexed and the supernatant was then added to the first supernatant. The combined supernatants, containing the oligoribonucleotide, were dried to a white powder. The base deprotected oligoribonucleotide was resuspended in anhydrous TEA/HF/NMP solution (300 μL of a solution of 1.5 mL N-methylpyrrolidinone, 750 μL TEA and 1 mL TEA.3HF to provide a 1.4 M HF concentration) and heated to 65° C. After 1.5 h, the oligomer was quenched with 1.5 M NH 4 HCO 3 .

Alternatively, for the one-pot protocol, the polymer-bound trityl-on oligoribonucleotide was transferred to a 4 mL glass screw top vial and suspended in a solution of 33% ethanolic methylamine/DMSO:1/1 (0.8 mL) at 65° C. for 15 min. The vial was brought to r.t. TEA.3HF (0.1 mL) was added and the vial was heated at 65° C. for 15 min. The sample was cooled at −20° C. and then quenched with 1.5 M NH 4 HCO 3 .

For purification of the trityl-on oligomers, the quenched NH 4 HCO 3 solution was loaded onto a C-18 containing cartridge that had been prewashed with acetonitrile followed by 50 mM TEAA. After washing the loaded cartridge with water, the RNA was detritylated with 0.5% TFA for 13 min. The cartridge was then washed again with water, salt exchanged with 1 M NaCl and washed with water again. The oligonucleotide was then eluted with 30% acetonitrile.

Inactive hammerhead ribozymes or binding attenuated control (BAC) oligonucleotides) were synthesized by substituting a U for G 5 and a U for A 14 (numbering from Hertel, K. J., et al., 1992 , Nucleic Acids Res ., 20, 3252). Similarly, one or more nucleotide substitutions can be introduced in other enzymatic nucleic acid molecules to inactivate the molecule and such molecules can serve as a negative control.

The average stepwise coupling yields were >98% (Wincott et al., 1995 Nucleic Acids Res . 23, 2677-2684). Those of ordinary skill in the art will recognize that the scale of synthesis can be adapted to be larger or smaller than the example described above including but not limited to 96-well format, all that is important is the ratio of chemicals used in the reaction.

Alternatively, the nucleic acid molecules of the present invention can be synthesized separately and joined together post-synthetically, for example, by ligation (Moore et al., 1992 , Science 256, 9923; Draper et al., International PCT publication No. WO 93/23569; Shabarova et al., 1991 , Nucleic Acids Research 19, 4247; Bellon et al., 1997 , Nucleosides & Nucleotides , 16, 951; Bellon et al., 1997 Bioconjugate Chem . 8, 204).

Ribozymes of the instant invention are also synthesized from DNA templates using bacteriophage T7 RNA polymerase (Milligan and Uhlenbeck, 1989 , Methods Enzymol . 180, 51).

Ribozymes are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; see, Wincott et al., supra; the totality of which is hereby incorporated herein by reference) and are resuspended in water.

Administration of Ribozymes

Sullivan et al., PCT WO 94/02595, describes the general methods for delivery of enzymatic RNA molecules. Ribozymes may be administered to cells by a variety of methods known to those familiar to the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as hydrogels, cyclodextrins, biodegradable nanocapsules, and bioadhesive microspheres. For some indications, ribozymes may be directly delivered ex vivo to cells or tissues with or without the aforementioned vehicles. Alternatively, the RNA/vehicle combination is locally delivered by direct injection or by use of a catheter, infusion pump or stent. Other routes of delivery include, but are not limited to, intravascular, intramuscular, subcutaneous or joint injection, aerosol inhalation, oral (tablet or pill form), topical, systemic, ocular, intraperitoneal and/or intrathecal delivery. More detailed descriptions of ribozyme delivery and administration are provided in Sullivan et al., supra and Draper et al., PCT WO93/23569 which have been incorporated by reference herein.

The molecules of the instant invention can be used as pharmaceutical agents. Pharmaceutical agents prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state in a patient.

The negatively charged polynucleotides of the invention can be administered (e.g., RNA, DNA or protein) and introduced into a patient by any standard means, with or without stabilizers, buffers, and the like, to form a pharmaceutical composition. When it is desired to use a liposome delivery mechanism, standard protocols for formation of liposomes can be followed. The compositions of the present invention may also be formulated and used as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions, suspensions for injectable administration, and other compositions known in the art.

The present invention also includes pharmaceutically acceptable formulations of the compounds described. These formulations include salts of the above compounds, egg., acid addition salts, for example, salts of hydrochloric, hydrobromic; acetic acid, and benzene sulfonic acid.

A pharmacological composition or formulation refers to a composition or formulation in a form suitable for administration, e.g., systemic administration, into a cell or patient, preferably a human. Suitable forms, in part, depend upon the use or the route of entry, for example, oral, transdermal, or by injection. Such forms should not prevent the composition or formulation from reaching, a target cell (i e., a cell to which the negatively charged polymer is desired to be delivered to). For example, pharmacological compositions injected into the blood stream should be soluble. Other factors are known in the art, and include considerations, such as toxicity and forms which prevent the composition or formulation from exerting its effect.

By “systemic administration” is meant in vivo systemic absorption or accumulation of drugs in the blood stream followed by distribution throughout the entire body. Administration routes which lead to systemic absorption include, without limitations: intravenous, subcutaneous, intraperitoneal, inhalation, oral, intrapulmonary and intramuscular. Each of these administration routes expose the desired negatively charged polymers, e.g., nucleic acids, to an accessible diseased tissue. The rate of entry of a drug into the circulation has been shown to be a function of molecular weight or size. The use of a liposome or other drug carrier comprising the compounds of the instant invention can potentially localize the drug, for example, in certain tissue types, such as the tissues of the reticular endothelial system (RES). A liposome formulation which can facilitate the association of drug with the surface of cells, such as, lymphocytes and macrophages is also useful. This approach may provide enhanced delivery of the drug to target cells by taking advantage of the specificity of macrophage and lymphocyte immune recognition of abnormal cells, such as cancer cells.

The invention also features the use of a composition comprising surface-modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or long-circulating liposomes or stealth liposomes). These formulations offer a method for increasing the accumulation of drugs in target tissues. This class of drug carriers resists opsonization and elimination by the mononuclear phagocytic system (MPS or RES), thereby enabling longer blood circulation times and enhanced tissue exposure for the encapsulated drug (Lasic et al. Chem. Rev . 1995, 95, 2601-2627; Ishiwata et al., Chem. Pharm. Bull . 1995, 43, 1005-1011). Such liposomes have been shown to accumulate selectively in tumors, presumably by extravasation and capture in the neovascularized target tissues (Lasic et al., Science 1995, 267, 1275-1276; Oku et al., 1995 , Biochim. Biophys. Acta , 1238, 86-90). All of these references are incorporated by reference herein. The long-circulating liposomes enhance the pharmacokinetics and pharmacodynamics of DNA and RNA, particularly compared to conventional cationic liposomes which are known to accumulate in tissues of the MPS (Liu et al., J. Biol. Chem . 1995, 42, 24864-24870; Choi et al., International PCT Publication No. WO 96/10391; Ansell et al., International PCT Publication No. WO 96/10390; Holland et al., International PCT Publication No. WO 96/10392; all of which are incorporated by reference herein). Long-circulating liposomes are also likely to protect drugs from nuclease degradation to a greater extent compared to cationic liposomes, based on their ability to avoid accumulation in metabolically aggressive MPS tissues such as the liver and spleen.

The present invention also includes compositions prepared for storage or administration which include a pharmaceutically effective amount of the desired compounds in a pharmaceutically acceptable carrier or diluent. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences , Mack Publishing Co. (A. R. Gennaro edit. 1985) hereby incorporated by reference herein. For example, preservatives, stabilizers, dyes and flavoring agents may be provided. Id. at 1449. These include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. In addition, antioxidants and suspending agents may be used.

A pharmaceutically effective dose is that dose required to prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state. The pharmaceutically effective dose depends on the type of disease, the composition used, the route of administration, the type of mammal being treated, the physical characteristics of the specific mammal under consideration, concurrent medication, and other factors which those skilled in the medical arts will recognize. Generally, an amount between 0.1 mg/kg and 100 mg/kg body weight/day of active ingredients is administered dependent upon potency of the negatively charged polymer. In a one aspect, the invention provides enzymatic nucleic acid molecules that can be delivered exogenously to specific cells as required. The enzymatic nucleic acid molecules are added directly, or can be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to smooth muscle cells. The RNA or RNA complexes can be locally administered to relevant tissues through the use of a catheter, infusion pump or stent, with or without their incorporation in biopolymers. Using the methods described herein, other enzymatic nucleic acid molecules that cleave target nucleic acid may be derived and used as described above. Specific examples of nucleic acid catalysts of the instant invention are provided below in the Tables and figures.

Alternatively, the enzymatic nucleic acid molecules of the instant invention can be expressed within cells from eukaryotic promoters (e.g., Izant and Weintraub, 1985 Science 229, 345; McGarry and Lindquist, 1986 Proc. Natl. Acad. Sci. USA 83, 399; Scanlon et al., 1991 , Proc. Natl. Acad. Sci. USA , 88, 10591-5; Kashani-Sabet et al., 1992 Antisense Res. Dev ., 2, 3-15; Dropulic et al., 1992 J. Virol , 66, 1432-41; Weerasinghe et al., 1991 J. Virol , 65, 5531-4; Ojwang et al., 1992 Proc. Natl. Acad. Sci. USA 89, 10802-6; Chen et al., 1992 Nucleic Acids Res ., 20, 4581-9; Sarver et al., 1990 Science 247, 1222-1225; Thompson et al., 1995 Nucleic Acids Res . 23, 2259; Good et al., 1997 , Gene Therapy, 4, 45; all of the references are hereby incorporated by reference herein in their totalities). Those skilled in the art realize that any nucleic acid can be expressed in eukaryotic cells from the appropriate DNA/RNA vector. The activity of such nucleic acids can be augmented by their release from the primary transcript by a ribozyme (Draper et al., PCT WO 93/23569, and Sullivan et al., PCT WO 94/02595; Ohkawa et al., 1992 Nucleic Acids Symp. Ser ., 27, 15-6; Taira et al., 1991 , Nucleic Acids Res ., 19, 5125-30; Ventura et al., 1993 Nucleic Acids Res ., 21, 3249-55; Chowrira et al., 1994 J. Biol. Chem . 269, 25856; all of the references are hereby incorporated by reference herein in their totalities).

In another aspect of the invention, enzymatic nucleic acid molecules that cleave target molecules are expressed from transcription units (see, for example, Couture et al., 1996 , TIG ., 12, 510) inserted into DNA or RNA vectors. The recombinant vectors are preferably DNA plasmids or viral vectors. Ribozyme expressing viral vectors could be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. Preferably, the recombinant vectors capable of expressing the ribozymes are delivered as described above, and persist in target cells. Alternatively, viral vectors may be used that provide for transient expression of ribozymes. Such vectors might be repeatedly administered as necessary. Once expressed, the ribozymes cleave the target mRNA. The active ribozyme contains an enzymatic center or core equivalent to those in the examples, and binding arms able to bind target nucleic acid molecules such that cleavage at the target site occurs. Other sequences may be present which do not interfere with such cleavage. Delivery of ribozyme expressing vectors could be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that would allow for introduction into the desired target cell (for a review, see Couture et al., 1996 , TIG ., 12, 510).

In one aspect, the invention features, an expression vector comprising a nucleic acid sequence encoding at least one of the nucleic acid catalysts of the instant invention. The nucleic acid sequence encoding the nucleic acid catalyst of the instant invention is operable linked in a manner which allows expression of that nucleic acid molecule.

In another aspect the invention features, an expression vector comprising: a transcription initiation region (e.g., eukaryotic pol I, II or III initiation region); b) a transcription termination region (e.g. eukaryotic pol I, II or III termination region); c) a nucleic acid sequence encoding at least one of the nucleic acid catalyst of the instant invention; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. The vector may optionally include an open reading frame (ORF) for a protein operably linked on the 5′ side or the 3′ side of the sequence encoding the nucleic acid catalyst of the invention; and/or an intron (intervening sequences).

Transcription of the ribozyme sequences are driven from a promoter for eukaryotic RNA polymerase I (pol I), RNA polymerase II (pol II), or RNA polymerase III (pol III). Transcripts from pol II or pol III promoters will be expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type will depend on the, nature of the gene regulatory sequences (enhancers, silencers, etc.) present nearby. Prokaryotic RNA polymerase promoters are also used, providing that the prokaryotic RNA polymerase enzyme is expressed in the appropriate cells (Elroy-Stein and Moss, 1990 Proc. Natl. Acad. Sci. USA , 87, 6743-7; Gao and Huang 1993 Nucleic Acids Res ., 21, 2867-72; Lieber et al., 1993 Methods Enzymol ., 217, 47-66; Zhou et al., 1990 Mol. Cell. Biol ., 10, 4529-37). All of these references are incorporated by reference herein. Several investigators have demonstrated that ribozymes expressed from such promoters can function in mammalian cells (e.g. Kashani-Sabet et al., 1992 Antisense Res. Dev ., 2, 3-15; Ojwang et al., 1992 Proc. Natl. Acad. Sci. USA , 89, 10802-6; Chen et al., 1992 Nucleic Acids Res ., 20, 4581-9; Yu et al., 1993 Proc. Natl. Acad. Sci. USA , 90, 6340-4; L'Huillier et al., 1992 EMBO J . 11, 4411-8; Lisziewicz et al., 1993 Proc. Natl. Acad. Sci. U.S.A ., 90, 8000-4; Thompson et al., 1995 Nucleic Acids Res . 23, 2259; Sullenger & Cech, 1993 , Science , 262, 1566). More specifically, transcription units such as the ones derived from genes encoding U6 small nuclear (snRNA), transfer RNA (tRNA) and adenovirus VA RNA are useful in generating high concentrations of desired RNA molecules such as ribozymes in cells (Thompson et al., supra; Couture and Stinchcomb, 1996, supra; Noonberg et al., 1994 , Nucleic Acid Res ., 22, 2830; Noonberg et al., U.S. Pat. No. 5,624,803; Good et al., 1997 , Gene Ther . 4, 45; Beigelman et al., International PCT Publication No. WO 96/18736; all of these publications are incorporated by reference herein). Examples of transcription units suitable for expression of ribozymes of the instant invention are shown in FIG. 15 . The above ribozyme transcription units can be incorporated into a variety of vectors for introduction into mammalian cells, including but not restricted to, plasmid DNA vectors, viral DNA vectors (such as adenovirus or adeno-associated virus vectors), or viral RNA vectors (such as retroviral or alphavirus vectors) (for a review, see Couture and Stinchcomb, 1996, supra).

In yet another aspect the invention features an expression vector comprising a nucleic acid sequence encoding at least one of the catalytic nucleic acid molecules of the invention, in-a manner which allows expression of that nucleic acid molecule. The expression vector comprises in one embodiment; a) a transcription initiation region; b) a transcription termination region; c) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. In another preferred embodiment the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an open reading frame; d) a sequence encoding at least one said nucleic acid molecule, wherein said gene is operably linked to the 3′-end of said open reading frame; and wherein said gene is operably linked to said initiation region, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. In yet another embodiment the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region, said intron and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. In another embodiment, the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) an open reading frame; e) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said sequence is operably linked to the 3′-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said intron, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

By “consists essentially of” is meant that the active ribozyme contains an enzymatic center or core equivalent to those in the examples, and binding arms able to bind target nucleic acid molecules such that cleavage at the target site occurs. Other sequences may be present which do not interfere with such cleavage.

EXAMPLES

The following are non-limiting examples showing the selection, isolation, synthesis and activity of enzymatic nucleic acids of the instant invention.

An extensive array of site-directed mutagenesis studies have been conducted with the hammerhead to probe relationships between nucleotide sequence and catalytic activity. These systematic studies have made clear that most nucleotides in the conserved core of the hammerhead ribozyme (Forster & Symons, 1987 , Cell , 49, 211) cannot be mutated without significant loss of catalytic activity. In contrast, a combinatorial strategy that simultaneously screens a large pool of mutagenized ribozymes for RNAs that retain catalytic activity could be used more efficiently to define immutable sequences and to identify new ribozyme variants (Breaker, 1997, supra). For example, Joseph and Burke (1993 ; J. Biol. Chem ., 268, 24515) have used an in vitro selection approach to rapidly screen for sequence variants of the ‘hairpin’ self-cleaving RNA that show improved catalytic activity. This approach was successful in identifying two mutations in the hairpin ribozyme that together give a 10-fold improvement in catalytic rate. Although similar in vitro selection experiments have been conducted with the hammerhead ribozyme (Nakamaye & Eckstein, 1994, supra; Long & Uhlenbeck, 1994, supra; Ishizaka et al., 1995, supra), none of these efforts have successfully screened full-sized hammerhead ribozymes for all possible combinations of sequence variants that encompass the entire catalytic core.

Applicant employed in vitro selection strategy to comprehensively test whether the natural consensus sequence for the core of the hammerhead ribozyme produces maximal catalytic rates, or whether sequence variants of this ribozyme could catalyze endonuclease reaction similar to or better than the hammerhead ribozyme.

The procedure reported herein to select for intramolecular AUG cleaving sequences is based on Applicant's previously reported selection of alternative GUC cleaving hammerhead sequences (Vaish et al., 1997 , Biochemistry 36, 6495; incorporated by reference herein).

Example 1

In Vitro Selection of Self-cleaving RNAs From a Random Pool

An initial pool of dsDNAs containing 22 randomized positions flanked by two constant regions was synthesized. These were transcribed, with transcription being initiated with GTPγS, to produce a pool of potential ribozymes. Self-cleavage of active ribozymes occurs during transcription and the cleavage products can then be separated from intact transcripts by means of a mercury gel (Igloi, Biochemistry 27, 3842). The recovered cleavage products were then reverse transcribed and amplified by PCR to give a dsDNA pool of selected ribozymes. This selection procedure was repeated for 13 cycles before the dsDNA pool was cloned and sequenced.

Oligodeoxyribonucleotides and oligoribonucleotides were chemically synthesized and purified as previously described (Vaish et al., 1997 Biochemistry 36, 6495). Primers used in the selection:

Primer 1:

5′-TGGTGCAAGCTT AATACGACTCACTATA GGGAGACTGTCTAGATCATGAGGATGCTA-3′(Seq. ID No. 1167);

Primer 2:

5′-TCTCGGATCCTGCAGATCATNNNNNNNNNNNNNNNNNNNNNNAGGATTAGCATCCTCAT-3′(Seq. ID No. 1168).

These two primers were used for the initial Sequenase® reaction, and Primer 2 also functioned as restoration primer for the reintroduction of the lost sequences during cleavage. Reverse transcription (RT)-Primer, 5′-TCTCGGATCCTGCAGATCAT-3′ (Seq. ID No. 1169); and polymerase chain reaction (PCR)-Primer, 5′-TGGTGCAAGCTT AATACGACTCA -3′ (Seq. ID No. 1170), with HindIII (5′-end) and BamHI and PstI (3′-end) sites in boldface; T7 promoter is underlined; ribozyme cleavage triplet in italics; N, randomized nucleotides. RNA selection was performed as described (Vaish et al., 1997 Biochemistry 36, 6495 incorporated by reference herein) with modifications to the initial two cycles of selection. Transcriptions from Pool 0 and Pool 1 were performed on a larger scale (10×500 μl and 1×250 μl, respectively) for 12 h and PCR amplification (Step 5) was omitted in each case. Successive transcriptions were performed at 100 μl volume. Transcription reactions were for decreasing periods of time from 12 h (1 st cycle) to 1 min (13 th cycle), where reactions for short periods were quenched by addition of EDTA (75 mM final conc.). All transcriptions were performed with 1 μM DNA. DNA template in the PCR mixture was at least 1×10 −15 M. The minimum concentration of RNA template was 1×10 −8 M for reverse transcription. The concentrations were determined assuming a molar extinction coefficient of 6600.

A selection pressure was exerted by progressively reducing the time of transcription from 12 h for the first six cycles, to 6 h for the seventh, 1 h for the eighth, 30 min for the ninth and tenth, 5 min for the eleventh, and 1 min for the twelve and thirteenth cycle. White colonies were randomly selected from pools 7 and 10 and those showing self-cleavage upon transcription were sequenced. There was no homology among the sequences.

Cloning and sequencing was performed as described (Vaish et al., 1997 , Biochemistry 36, 6495) except that the dsDNA was digested with HindIII and BamHI. Clones from pools seven and ten were tested for transcript self-cleavage from linearized plasmids. For clones from Pool 13 plasmid DNA was amplified by PCR, using the RT- and PCR-primers, and then transcribed. Rates of intramolecular cleavage of transcripts were determined as described but with 10 u of enzyme per μl. Active clones were sequenced. A transcript of only 50 nucleotides, without the extra sequences for cloning beyond stem III, showed a k in-cis of 0.32 min −1 .

By “randomized region” is meant a region of completely random sequence and/or partially random sequence. By completely random sequence is meant a sequence wherein theoretically there is equal representation of A, T, G and C nucleotides or modified derivatives thereof, at each position in the sequence. By partially random sequence is meant a sequence wherein there is an unequal representation of A, T, G and C nucleotides or modified derivatives thereof, at each position in the sequence. A partially random sequence can therefore have one or more positions of complete randomness and one or more positions with defined nucleotides.

Characterization of New Self-cleaving Ribozyme Sequences

The intramolecular cleavage rate of the most active sequence of pool 7 was 0.03 min −1 and that of pool 10 was 0.06 min −1 (FIG. 3 ). Seventy clones from pool thirteen were picked and amplified by PCR. Of these, 20 gave full-length DNA and were transcribed; and, of these, 14 showed intramolecular cleavage. These 14 active ribozymes could be divided into two groups: one group contained transcripts with 22 nucleotides in the randomized region and the second group contained a deletion in this region with only 21 nucleotides being present. Several sequences were represented twice such as those of clones 29, 36 and 40. One of the most active sequences, from clone 13/40, with k in-cis of 0.52 min −1 was chosen for further study. In comparison, under these conditions the intramolecular cleavage of the native hammerhead with a GUC triplet was k in-cis of 0.56 min −1 , indicating that the cleavage activity of the selected ribozyme, Rz13/40, with an AUG triplet is comparable. In order to acquire some information on the secondary structure of Rz13/40, a limited nuclease digest of the 3′-end-labeled, full-length ribozyme was performed. Rz13/40 was prepared by transcription in such a way that cleavage was minimized. A full length transcript for the intramolecularly cleaving ribozyme was generated by transcription at 12° C. for 8 h (Frank et al., 1996 , RNA , 2, 1179; incorporated by reference herein) and 3′-end labeled with 32 pCp. Limited nuclease digestions with RNase A, RNase T1 and nuclease S1 were performed as Hodson et al., 1994 , Nucleic Acids Res ., 22, 1620; Loria et al., 1996 , RNA , 2,551; both are incorporated by reference herein). Alkaline hydrolysis of labeled RNA was performed in 50 mM NaHCO 3 at 100° C. for 7.5 minutes.

Limited digestion with RNase A and T1 and nuclease S1, which indicates single-stranded regions, gave a digestion pattern consistent with Rz13/40 adopting a hammerhead-type structure, which comprised three base-paired helices surrounding a single-stranded core (FIG. 4 ). Since the structure of Rz13/40 resembles the hammerhead structure, the same numbering system has been adopted, with positions 3 and 9 in the core being considered vacant.

The data of nuclease digestion corresponded fairly well with the MFOLD structure except for a few discrepancies. MFOLD shows base pairing in the core region between U 7 and G 14 ; G 8 and C 13 ; G L2.1 and U L2.5 ; and U 4 and G 7 although there cleavage at these positions by the nucleases.

Ribozyme Engineering

Sequence, chemical and structural variants of ribozymes of the present invention can be engineered using the techniques shown above and known in the art to cleave a separate target RNA or DNA in trans . For example, the size of ribozymes can, be reduced or increased using the techniques known in the art (Zaug et al., 1986 , Nature , 324, 429; Ruffner et al., 1990 , Biochem ., 29, 10695; Beaudry et al., 1990 , Biochem ., 29, 6534; McCall el al., 1992 , Proc. Natl. Acad. Sci., USA ., 89, 5710; Long et al., 1994, Supra; Hendry et al., 1994 , BBA 1219, 405; Benseler et al., 1993 , JACS , 115, 8483; Thompson et al., 1996 , Nucl. Acids Res ., 24, 4401; Michels et al., 1995 , Biochem ., 34, 2965; Been et al., 1992 , Biochem ., 31, 11843; Guo et al., 1995 , EMBO. J ., 14, 368; Pan et al., 1994 , Biochem ., 33, 9561; Cech, 1992 , Curr. Op. Struc. Bio., 2 , 605 ; Sugiyama et al., 1996 , FEBS Lett ., 392, 215; Beigelman et al., 1994 , Bioorg. Med. Chem ., 4, 1715; all are incorporated in its totality by reference herein). For example, the stem-loop II domain of the ribozymes may not be essential for catalytic activity and hence could be systematically reduced in size using a variety of methods known in the art, to the extent that the overall catalytic activity of the ribozyme is not significantly decreased.

Further rounds of in vitro selection strategies described herein and variations thereof can be readily used by a person skilled in the art to evolve additional nucleic acid catalysts and such new catalysts are within the scope of the instant invention.

Example 2

Trans-cleaving Ribozymes

The self-cleaving ribozymes can be divided into separate ribozyme and substrate domains to create a functional bimolecular complex. This ribozyme presumably interacts with the substrate domain by forming base-paired regions that arc analogous to helices I and II of the hammerhead ribozyme (FIG. 1 ). Likewise, the substrate specificity of ribozymes can presumably be altered by changing the sequences of the substrate-binding arms to complement the sequence of the desired substrate molecule, as was achieved with the ribozyme from clone 40 self-cleaving RNA (FIG. 5 ). The numbering convention used in Example 2 is taken from Vaish et al., 1998 PNAS 95, 2158-2162.

To further characterize the selected ribozyme for intermolecular cleavage, Rz13/40 was divided into a catalytic portion and the corresponding substrate strand (FIG. 5 ). The initial ribozyme construct was designed with 5 bp each in stems I and III for annealing to the substrate. Stems of this length were chosen because they had been reported to give reliable kinetic data with the hammerhead. Cleavage kinetics of intramolecularly cleaving ribozymes was performed with chemically synthesized ribozyme and substrate in 50 mM Tris-HCl (pH 8.0), and 10 mM MgCl 2 with 50 to 500 nM ribozyme and 25 nM substrate for single turnover, and 50 to 500 nM substrate with 5 to 25 nM ribozyme for multiple turnover kinetics as described (Hertel et al., Biochemistry 33, 3374, 1994). The intermolecular version of Rz13/40 of the present invention gave a very high K M (1.1 mM) and low k cat (0.1 min −1 ) under single turnover conditions and was inactive under multiple turnover conditions. As there was no doubt about the intramolecular cleavage of Rz13/40, the lack of catalytic activity under multiple turnover conditions must be associated with the design of the intermolecular version. After analysis of the ribozyme-substrate complex by native gel, it was concluded that formation of the complex was inefficient under the conditions used.

A second ribozyme construct was synthesized, where stem III was extended to 10 base-pairs. Native gel analysis confirmed the formation of the ribozyme-substrate complex and the ribozyme cleaved its corresponding substrate efficiently under both single and multiple turnover conditions (Table III). The discrepancy between kcat and kcat′ (0.06 and 0.91 min −1 respectively) is presumably the result of product inhibition, which is a common effect observed with the native hammerhead. The time course of cleavage was followed for about 12 half-lives under single turnover conditions. Reactions were first order up to 60% cleavage within the first minute and reached a total of 80%. First order end points with the conventional hammerhead are commonly 70 to 75%. Steady state cleavage rates were linear for several turnovers. Although the hammerhead and class I ribozymes cleave at different internucleotide linkages (FIG. 1 ), both ribozymes appear to proceed by a similar chemical mechanism. The hammerhead ribozyme is known to produce a 2′,3′-cyclic phosphate at the terminus of the 5′-cleavage product, thereby leaving a 5′-hydroxyl terminus on the 3′-cleavage fragment.

The site of substrate cleavage was confirmed as being behind G of the AUG cleavage triplet by comparison of the ribozyme cleavage product, obtained under single turnover conditions for 30 min, with the products of a limited alkaline hydrolysis of the 5′-end-labeled substrate and with a partial RNase T1 digest. Reactions were performed in 10 μl containing RNA, 50 mM Tris (pH 8) and CNPase (Sigma Chemicals) (0.62 u to 0.012 u/μl) and incubation at 45° C. for 1.5 h. Product analysis was on a 20% PAGE where the cyclic phosphate-terminated product runs slightly slower than the ring-opened derivative. In addition, the cleavage products were also shown to be the 2′, 3′-cyclic phosphate and a 5′-hydroxyl by hydrolysis with CNPase and labeling with T4 PNK respectively. Thus Rz13/40 cleaves in a similar manner to the hammerhead. In order to investigate the properties and sequence requirements of the selected ribozyme Rz13/40, mutations were made on the substrate and ribozyme strands. In the native hammerhead, stem II has been shortened to as few as two base-pairs without significant loss in activity. However, the removal of a single base-pair (10.3/11.3) in Rz13/40 resulted in a 1000-fold loss in activity for the cleavage behind an AUG triplet indicating the stem-loop structure has a wider role in catalysis.

The effect of mutations around the cleavage site has also been investigated under single and multiple turnover conditions (Table III). Surprisingly, the AUA triplet was also cleaved quite efficiently even though it was not selected for, again yielding a 2′, 3′-cyclic phosphate. Triplets terminating in a uridine or cytidine were either cleaved extremely slowly or not at all. Thus, this ribozyme is purine nucleoside specific. Whether this indicates a necessity for base pairing between U 4 and the nucleotide to be cleaved, as possible with AUG and AUA, is uncertain at present.

As the native hammerhead strictly requires a uridine in the middle of the triplet, it was of interest to test whether this was applicable to Rz13/40. Interestingly the triplet AAG was cleaved with a k cat of 0.57 min −1 under single turnover conditions, multiple turnover conditions showed a k cat of 0.09 min −1 . It was also tested whether the nucleotide next to the cleavage site was of importance. Cleavage of the triplet AUG followed by U or G was found to be only fractionally slower in single turnover than cleavage of AUG-A (Table III).

Inspection of the ribozyme sequences reveals some interesting features. The sequence 5′-GCGCG at positions 11.2 to 14 is present in all ribozymes from pool 10 onwards. This would indicate that this sequence may be an indispensable part for activity just as is the case for the GAA sequence in the conventional hammerhead.

Of the two classes of ribozyme isolated in Pool 13, the ribozymes with a deletion in the randomized region.are the more active intramolecular cleavers. These ribozymes appear to have an overall secondary structure which is similar to that of the native hammerhead, but there are significant differences.

Obvious differences include the ‘vacancies’ at positions 3 and 9 in the core as well as the altered sequence to positions 12 to 14 of the traditional hammerhead ribozyme ( FIG. 1 ) already mentioned. More subtle differences are associated with stem-loop II. In the hammerhead, a variety of structures are tolerated: the stem can be reduced to two base-pairs, and the loop can be of virtually any size and even contain non-nucleotidic linkers. In the selected ribozymes similar to Rz13/40, less variation in the stem-loop structure is observed. In the active ribozymes of this class, the stem-loop II consists of two G:C base-pairs adjacent to the core which are followed by two A:U base-pairs. The stem loop terminates in a five nucleotide loop, where variations at only positions L2.4 and L2.5 of the hammerhead ribozyme have been detected. The length of the stem appears to have a large effect on catalytic efficiency, since the removal of a single base-pair (10.3/11.3) abolishes activity in vitro. The most active sequences in pool 13 have a fully complementary stem II. One mismatch at 10.2/11.2 as in Rz13/1 approximately halves the activity. It is interesting to note that in Pool 13, the more active ribozymes contain a deletion in the randomized region, which is 21 nucleotides instead of 22. Of these only Rz13/31 and 13/29 show reasonable activity. One can draw a secondary structure for these with a stem II with two mismatches and the extra nucleotide in the core region.

Initial experiments to determine cleavage site specificities of ribozymes of the instant invention indicate NR/N as the minimum requirement for ribozyme cleavage, where N represents any nucleotide, R represents any purine nucleotide, and / indicates the site of cleavage. Persons skilled in the art can perform further experiments to determine potential cleavage targets of the ribozymes of the instant invention, such experiments can be performed as described in Ruffner et al., 1990 , Biochem ., 29, 10695, and Joseph et al., 1993 , Genes and Development ., 7, 130-138.

The new triplet specificity should be useful for the application of the ribozyme family of the present invention for the inhibition of gene expression in that it expands the targets on a mRNA for cleavage. Although the conventional NUX triplets might be considered sufficient for a wide application, the accessibility of oligodeoxynucleotides to mRNAs is very restricted. Thus the specificity of the new ribozyme for cleavage at purines, apparently independent of the nature of the neighboring nucleotides, should represent a considerable advantage over the native NUX-cleaving ribozyme for this application.

Example 3

Substrate Specificity Variants

An investigation of base pairs at positions 13.1-14.1 of the ribozyme shown in FIG. 9 was undertaken. Six different ribozyme-substrate combinations were synthesized where N 13.1 -N 14.1 was either adenosine 13.1 -urdine 14.1 (RZ 1), uridine 13.1 -adenosine 14.1 (RZ 2), inosine 13.1 -cytidine 14.1 (RZ 3), guanosine 13.1 -cytidine 14.1 , (Rz 4) cytidine 13.1 -guanosine 14.1 (RZ 5), or guanosine 13.1 -guanosine 14.1 (RZ 6). The time course of the cleavage of ribozymes 3-6 in FIG. 9 with non A-U base pairs was determined (FIG. 10 ). As shown in FIG. 10 , no significant difference was observed between cleavage rates of ribozyme substrate complexes containing the I 13.1 -C 14.1 or G 13.1 -C 14.1 base pair (0.29 vs. 0.21 min −1 , FIG. 10 ). Under comparable conditions the cleavage rate of the AUG substrate was 0.1min −1 with the 6 bp stem III and 5 bp stem I ribozyme (Vaish et al., 1998 PNAS 95, 2158-2162).

Because the A 13.1 -U 14.1 pair can be inverted t U 13.1 -A 14.1 without loss of activity (Example 2 above) it was of interest to study Ribozyme-Substrate complexes containing the C 13.1 -G 14.1 pair (RZ 5). This inverted C 13.1 -G 14.1 arrangement retains significant activity (0.09 min −1 ), and it is only 3-fold less active than the corresponding G-C base pair. The use of a G-G base pair (RZ 6) under the specific conditions used in the example caused a significant reduction in the activity of the ribozyme. The A 13.1 -U 14.1 pair containing ribozyme-substrate complex can cleave a target after an AU 14.1 G triplet; specificity of this ribozyme can be altered to cleave after AG 14.1 G triplets with a G 13.1 to C 13.1 substitution. The AU 14.1 G triplet recognizing ribozyme can therefore be engineered to cleavage after AA 14.1 G (see, Example 2), AC 14.1 G and AG 14.1 G triplets.

Since the original AU 14.1 G cleaving ribozymes have nonspecific requirements for the 1.1 nucleotide (i.e. the nucleotide downstream of G15) and since position 15 may be any purine, the experimental evidence for the acceptance of any nucleoside at the 14.1 position indicates NR 15 /N as the minimum requirement for ribozyme cleavage, where N represents any nucleotide, R represents any purine nucleotide, and / indicates the site of cleavage. The optimization of these variant ribozyme constructs by modification of stem-loop structures as is known in the art can provide for species with improved cleavage activity.

Example 4

Identification of Potential Target Sites in Human K-ras RNA

The sequence of human K-ras was screened for accessible sites using a computer folding algorithm selecting for AUR/, YG/M, and UG/U target sites where R in any purine, Y is any pyrimidine, M is A or C, and A, U, C, G are adenosine, uridine, cytidine, and guanosine, respectively. Regions of the RNA that did not form secondary folding structures and included cleavage sites for the ribozymes of the instant invention were identified. The sequences of these cleavage sites are shown in Table II.

Example 5

Selection of Enzymatic Nucleic Acid Cleavage Sites in Human K-ras RNA

To test whether the sites predicted by the computer-based RNA-folding algorithm corresponded to accessible sites in K-ras RNA ninety-six ribozyme sites from Table II were selected for further analysis. Ribozyme target sites were chosen by analyzing sequences of Human K-ras, (accession number: NM — 004985) and prioritizing the sites on the basis of folding. Ribozymes were designed that could bind each target and were individually analyzed by computer folding (Christoffersen et al., 1994 J. Mol. Struc. Theochem , 311, 273; Jaeger et al., 1989 , Proc. Natl. Acad. Sci. USA , 86, 7706) to assess whether the ribozyme sequences fold into the appropriate secondary structure. Those ribozymes with unfavorable intramolecular interactions between the binding arms and the catalytic core were eliminated from consideration. As noted below, varying binding arm lengths can be chosen to optimize activity. Generally, at least 5 bases on each arm are able to bind to, or otherwise interact with, the target RNA.

Example 6

Chemical Synthesis and Purification of Ribozymes for Efficient Cleavage of K-ras RNA

Ribozymes were designed to anneal to various sites in the RNA message. The binding arms are complementary to the target site sequences described above. The ribozymes were chemically synthesized. The method of synthesis used followed the procedure for normal RNA synthesis as described above and in Usman et al., (1987 J. Am. Chem. Soc ., 109, 7845), Scaringe et al., (1990 Nucleic Acids Res ., 18, 5433) and Wincott et al., supra, and made use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end. The average stepwise coupling yields were >98%.

On instrument dithioate linkage formation via PADS/3-picoline: All processes were performed on an ABI (PE Biosystems) 394 DNA/RNA Synthesizer. Phosphorodithioate containing ribozymes were synthesized using PADS (Phenoxy acetyl disulfide), 3-Picoline, Acetonitrile, 5′-O-DMT-2′-O-TBDMS-Uridine-3′-thiophosphoramidite, and standard synthesis reagents and phosphoramidites. A 0.2 M solution of PADS was prepared in 1:1 acetonitrile:3-picoline. This solution was placed on the instrument and substituted for the normal oxidizing reagent to create the phosphorodithioate triester bond. The thio-amidite (0.1 M in ACN) was coupled for 450 seconds using a standard cycle. At the oxidation step, the PADS solution was delivered for 7.5s at a flow rate of 5 mL/min. and with a 300s wait time after delivery. After completion of the synthesis, the oligo was deprotected and purified in the standard manner (MA/H 2 O, 3HF.TEA, NH 4 HCO 3 quench, T-on solid phase purification).

Example 7

Ribozyme Cleavage of K-ras RNA Target in Vitro

Ribozymes targeted to the human K-ras RNA are designed and synthesized as described above. These ribozymes can be tested for cleavage activity in vitro, for example using the following procedure. The target sequences and the nucleotide location within the K-ras RNA are given in Table II.

Cleavage Reactions: Full-length or partially full-length, intemally-labeled target RNA for ribozyme cleavage assay is prepared by in vitro transcription in the presence of [α- 32 p] CTP, passed over a G 50 Sephadex® column by spin chromatography and used as substrate RNA without further purification. Alternately, substrates are 5′- 32 P-end labeled using T4 polynucleotide kinase enzyme. Assays are performed by pre-warming a 2× concentration of purified ribozyme in ribozyme cleavage buffer (50 mM Tris-HCl, pH 7.5 at 37° C., 10 mM MgCl 2 ) and the cleavage reaction was initiated by adding the 2× ribozyme mix to an equal volume of substrate RNA (maximum of 1-5 nM) that was also pre-warmed in cleavage buffer. As an initial screen, assays are carried out for 1 hour at 37° C. using a final concentration of either 40 nM or 1 mM ribozyme, i.e., ribozyme excess. The reaction is quenched by the addition of an equal volume of 95% formamide, 20 mM EDTA, 0.05% bromophenol blue and 0.05% xylene cyanol after which the sample is heated to 95° C. for 2 minutes, quick chilled and loaded onto a denaturing polyacrylamide gel. Substrate RNA and the specific RNA cleavage products generated by ribozyme cleavage are visualized on an autoradiograph of the gel. The percentage of cleavage is determined by Phosphor Imager® quantitation of bands representing the intact substrate and the cleavage products.

Example 8

Cleavage Reactions for Determining Substrate Specificity of Stabilized Ribozymes (Table IV)

Substrates are 5′- 32 P-end labeled using T4 polynucleotide kinase enzyme. Assays are performed by pre-warming a 2× concentration of purified ribozyme in ribozyme cleavage buffer (50 mM Tris-HCl, pH 8.0 at 37° C., 10 mM MgCl 2 ) and the cleavage reaction is initiated by adding the 2× ribozyme mix to an equal volume of substrate RNA (maximum of 1-5 nM) that was also pre-warmed in cleavage buffer. Assays are carried out for 1 hour at 37° C. using a final concentration of 500 nM ribozyme, i.e., ribozyme excess. The reaction is quenched at specific time points by the addition of an equal volume of 95% formamide, 20 mM EDTA, 0.05% bromophenol blue and 0.05% xylene cyanol after which the time points are heated to 95° C. for 1 minute and loaded onto a denaturing polyacrylamide gel. Substrate RNA and the specific RNA cleavage products generated by ribozyme cleavage are visualized by scanning a Phosphor Imager® screen which has been exposed to the assay gel. The percentage of cleavage is determined by Phosphor Imager® quantitation of bands representing the intact substrate and the cleavage products. Table IV lists the substrate specificity rate constants for stabilized G-cleaver Ribozymes.

Example 9

Ribozyme Stability Assay

A mixture of 1.5 μg 5′- 32 P-end labeled ribozyme and 13 μg unlabeled (cold) ribozyme is dried down and resuspended in 20 μL human serum. The suspension is incubated at 37° C. for 24 hours. Aliquots of the reaction are quenched at specific time points by removal into a 2.5-fold excess of 95% formamide, 20 mM EDTA, 0.05% bromophenol blue and 0.05% xylene cyanol on ice. A portion of each time point is counted on a scintillation counter for normalizing counts per lane. The time points are heated to 95° C. for 1 minute and loaded onto a denaturing polyacrylamide gel at 750 k cpm per lane. Intact ribozyme and the specific RNA degradation products generated by exposure to ribonucleases in the serum are visualized by scanning a Phosphor Imager® screen which has been exposed to the assay gel. The percentage of full-length ribozyme at each time point is determined by Phosphor Imager® quantitation of bands representing the intact ribozyme and the degradation products. A non-limiting example of a ribozyme of the instant invention utilizing phosphorothioate and/or phosphorodithioate modifications in a stabilized 2′-O-methyl ribonucleotide background with essential “core ribonucleotides” is shown in FIG. 8 . The incorporation of phosphorothioate and/or phosphorodithioate linkages into the enzymatic nucleic acid of the instant invention results in increased serum stability. Replacement of the 3′-phosphodiester at position 6 with a phosphorothioate or phosphorodithioate linkage ( FIG. 8 ) stabilizes the conserved position 6 ribose moiety, which is prone to nucleolytic cleavage. In a study investigating the serum stability of position 6 modified ribozyme variants which preserve the 2′-hydroxyl function at position 6 (FIG. 8 ), the relative stability of the modifications were ranked as follows:

 3′-Phosphorodithioate>>3′-Phosphorothioate>>4′-Thioribofuranose>Phosphodiester

Example 10

Cell Culture Models

A selected group of 96 G-cleaver ribozymes targeting K-ras RNA (Table V) were tested in human colorectal cancer cells with a mutated K-ras allele (DLD-1), ovarian cancer cells with a mutated K-ras allele (SKOV3), and human colorectal cancer cells with a mutated K-ras allele (SW680). Cells were plated into four 96 well plates at 15000 cells/well. The 96 ribozymes were split into four groups (on four plates) to be able to include the appropriate controls on each plate. The ribozymes were transfected at 100 nM concentration with 5 μg/ml of GSV and incubated overnight Total RNA was prepared 24 hr after transfection using a Quiagen 96 well Rneasy® kit. An additional DNaseI treatment to remove traces of DNA was introduced. RT reactions were prepared using 4 μl of the RNA eluate with a Clontech RT-kit. Analyses were performed using a Multiplex Taqman® assay(PE ABI Prism® 7700 Sequence Detection System User Bulletin #5, © Copyright 1998, The Perkin-Elmer Corporation) using actin as a control. Results indicate that ribozyme (RPI No. 12819, Table V) reduced K-ras mRNA levels by 50% in DLD-1 cells and SKOV3 cells.

Diagnostic Uses

Enzymatic nucleic acids of this invention may be used as diagnostic tools to examine genetic drift and mutations within diseased cells or to detect the presence of target RNA in a cell. The close relationship between ribozyme activity and the structure of the target RNA allows the detection of mutations in any region of the molecule which alters the base-pairing and three-dimensional structure of the target RNA. By using multiple ribozymes described in this invention, one may map nucleotide changes which are important to RNA structure and function in vitro, as well as in cells and tissues. Cleavage of target RNAs with ribozymes may be used to inhibit gene expression and define the role (essentially) of specified gene products in the progression of disease. In this manner, other genetic targets may be defined as important mediators of the disease. These experiments will lead to better treatment of the disease progression by affording the possibility of combinational therapies (e.g., multiple ribozymes targeted to different genes, ribozymes coupled with known small molecule inhibitors, or intermittent treatment with combinations of ribozymes and/or other chemical or biological molecules). Other in vitro uses of ribozymes of this invention are well known in the art, and include detection of the presence of mRNAs associated with disease condition. Such RNA is detected by determining the presence of.a cleavage product after treatment with a ribozyme using standard methodology.

In a specific example, ribozymes which can cleave only wild-type or mutant forms of the target RNA are used for the assay. The first ribozyme is used to identify wild-type RNA present in the sample and the second ribozyme will be used to identify mutant RNA in the sample. As reaction controls, synthetic substrates of both wild-type and mutant RNA will be cleaved by both ribozymes to demonstrate the relative ribozyme efficiencies in the reactions and the absence of cleavage of the “non-targeted” RNA species. The cleavage products from the synthetic substrates will also serve to generate size markers for the analysis of wild-type and mutant RNAs in the sample population. Thus, each analysis can involve two ribozymes, two substrates and one unknown sample which will be combined into six reactions. The presence of cleavage products will be determined using an RNAse protection assay so that full-length and cleavage fragments of each RNA can be analyzed in one lane of a polyacrylamide gel. It is not absolutely required to quantify the results to gain insight into the expression of mutant RNAs and putative risk of the desired phenotypic changes in target cells. The expression of mRNA whose protein product is implicated in the development of the phenotype is adequate to establish risk. If probes of comparable specific activity are used for both transcripts, then a qualitative comparison of RNA levels will be adequate and will decrease the cost of the initial diagnosis. Higher mutant form to wild-type ratios will be correlated with higher risk whether RNA levels are compared qualitatively or quantitatively.

Additional Uses

Potential usefulness of sequence-specific enzymatic nucleic acid molecules of the instant invention can have many of the same applications for the study of RNA that DNA restriction endonucleases have for the study of DNA (Nathans et al., 1975 Ann. Rev. Biochem . 44:273). For example, the pattern of restriction fragments could be used to establish sequence relationships between two related RNAs, and large RNAs could be specifically cleaved to fragments of a size more useful for study. The ability to engineer sequence specificity of the ribozyme is ideal for cleavage of RNAs of unknown sequence.

All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains. All references cited in this disclosure are incorporated by reference to the same extent as if each reference had been incorporated by reference in its entirety individually.

One skilled in the art would readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The methods and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, such additional embodiments are within the scope of the present invention and the following claims.

The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising”, “consisting essentially of” and “consisting of” may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terns and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments, optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the description and the appended claims.

In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group.

Thus, additional embodiments are within the scope of the invention and within the following claims.

TABLE I
				Wait
Reagent	Equivalents	Amount	Wait Time*	Time*
A. 2.5 μmol Synthesis Cycle ABI 394 Instrument
			2′-O-methyl	RNA
Phosphoramidites	6.5	163 μL	2.5 min	7.5
S-Ethyl Tetrazole	23.8	238 μL	2.5 min	7.5
Acetic Anhydride	100	233 μL	5 sec	5 sec
N-Methyl Imidazole	186	233 μL	5 sec	5 sec
TCA	110.1	2.3 mL	21 sec	21 sec
Iodine	11.2	1.7 mL	45 sec	45 sec
Acetonitrile	NA	6.67 mL	NA	NA
B. 0.2 μmol Synthesis Cycle ABI 394 Instrument
			2′-O-methyl	RNA
Phosphoramidites	15	31 μL	233 sec	465 sec
S-Ethyl Tetrazole	38.7	31 μL	233 min	465 sec
Acetic Anhydride	655	124 μL	5 sec	5 sec
N-Methyl Imidazole	1245	124 μL	5 sec	5 sec
TCA	700	732 μL	10 sec	10 sec
Iodine	20.6	244 μL	15 sec	15 sec
Acetonitrile	NA	2.64 mL	NA	NA
C. 0.2 μmol Synthesis Cycle 96 well Instrument
	2′-O-methyl/	2′-O-methyl/
	Ribo	Ribo	2′-O-methyl	Ribo
Phosphoramidites	33/66	60/120 μL	233 sec	465 sec
S-Ethyl Tetrazole	75/150	60/120 μL	233 min	465 sec
Acetic Anhydride	50/50	50/50 μL	10 sec	10 sec
N-Methyl Imidazole	502/502	50/50 μL	10 sec	10 sec
TCA	16,000/	500/500	15 sec	15 sec
	16,000	μL
Iodine	6.8/6.8	80/80 μL	30 sec	30 sec
Acetonitrile	NA	850/850	NA	NA
		μL
* Wait time does not include contact time during delivery.

TABLE II
Human K-ras Ribozyme and Target Sequence
Nt.		Seq. ID		Seq. ID
Position	Substrate Sequence	Nos.	Ribozyme Sequence	Nos.
16	GGCGGCGGCC G CGGCG	1	CGCCG UGAUGGCAUGCACUAUGCGCG GGCCGCCGCC	528
57	UGGCGGCGGC G AAGGU	2	ACCUU UGAUGGCAUGCACUAUGCGCG GCCGCCGCCA	529
94	CCCGGCCCCC G CCAUU	3	AAUGG UGAUGGCAUGCACUAUGCGCG GGGGGCCGGG	530
113	GACUGGGAGC G AGCGC	4	GCGCU UGAUGGCAUGCACUAUGCGCG GCUCCCAGUC	531
117	GGGAGCGAGC G CGGCG	5	CGCCG UGAUGGCAUGCACUAUGCGCG GCUCGCUCCC	532
122	CGAGCGCGGC G CAGGC	6	GCCUG UGAUGGCAUGCACUAUGCGCG GCCGCGCUCG	533
131	CGCAGGCACU G AAGGC	7	GCCUU UGAUGGCAUGCACUAUGCGCG AGUGCCUGCG	534
171	GCUCCCAGGU G CGGGA	8	UCCCG UGAUGGCAUGCACUAUGCGCG ACCUGGGAGC	535
186	AGAGAGGCCU G CUGAA	9	UUCAG UGAUGGCAUGCACUAUGCGCG AGGCCUCUCU	536
189	GAGGCCUGCU G AAAAU	10	AUUUU UGAUGGCAUGCACUAUGCGCG AGCAGGCCUC	537
195	UGCUGAAAAU G ACUGA	11	UCAGU UGAUGGCAUGCACUAUGCGCG AUUUUCAGCA	538
199	GAAAAUGACU G AAUAU	12	AUAUU UGAUGGCAUGCACUAUGCGCG AGUCAUUUUC	539
203	AUGACUGAAU A UAAAC	13	GUUUA UGAUGGCAUGCACUAUGCGCG AUUCAGUCAU	540
205	GACUGAAUAU A AACUU	14	AAGUU UGAUGGCAUGCACUAUGCGCG AUAUUCAGUC	541
211	AUAUAAACUU G UGGUA	15	UACCA UGAUGGCAUGCACUAUGCGCG AAGUUUAUAU	542
227	GUUGGAGCUU G UGGCG	16	CGCCA UGAUGGCAUGCACUAUGCGCG AAGCUCCAAC	543
244	AGGCAAGAGU G CCUUG	17	CAAGG UGAUGGCAUGCACUAUGCGCG ACUCUUGCCU	544
249	AGAGUGCCUU G ACGAU	18	AUCGU UGAUGGCAUGCACUAUGCGCG AAGGCACUCU	545
252	GUGCCUUGAC G AUACA	19	UGUAU UGAUGGCAUGCACUAUGCGCG GUCAAGGCAC	546
255	CCUUGACGAU A CAGCU	20	AGCUG UGAUGGCAUGCACUAUGCGCG AUCGUCAAGG	547
277	GAAUCAUUUU G UGGAC	21	GUCCA UGAUGGCAUGCACUAUGCGCG AAAAUGAUUC	548
283	UUUUGUGGAC G AAUAU	22	AUAUU UGAUGGCAUGCACUAUGCGCG GUCCACAAAA	549
287	GUGGACGAAU A UGAUC	23	GAUCA UGAUGGCAUGCACUAUGCGCG AUUCGUCCAC	550
289	GGACGAAUAU G AUCCA	24	UGGAU UGAUGGCAUGCACUAUGCGCG AUAUUCGUCC	551
300	AUCCAACAAU A GAGGA	25	UCCUC UGAUGGCAUGCACUAUGCGCG AUUGUUGGAU	552
331	AGUAGUAAUU G AUGGA	26	UCCAU UGAUGGCAUGCACUAUGCGCG AAUUACUACU	553
334	AGUAAUUGAU G GAGAA	27	UUCUC UGAUGGCAUGCACUAUGCGCG AUCAAUUACU	554
344	GGAGAAACCU G UCUCU	28	AGAGA UGAUGGCAUGCACUAUGCGCG AGGUUUCUCC	555
355	UCUCUUGGAU A UUCUC	29	GAGAA UGAUGGCAUGCACUAUGCGCG AUCCAAGAGA	556
361	GGAUAUUCUC G ACACA	30	UGUGU UGAUGGCAUGCACUAUGCGCG GAGAAUAUCC	557
388	GGAGUACAGU G CAAUG	31	CAUUG UGAUGGCAUGCACUAUGCGCG ACUGUACUCC	558
393	ACAGUGCAAU G AGGGA	32	UCCCU UGAUGGCAUGCACUAUGCGCG AUUGCACUGU	559
408	ACCAGUACAU G AGGAC	33	GUCCU UGAUGGCAUGCACUAUGCGCG AUGUACUGGU	560
431	GGCUUUCUUU G UGUAU	34	AUACA UGAUGGCAUGCACUAUGCGCG AAAGAAAGCC	561
433	CUUUCUUUGU G UAUUU	35	AAAUA UGAUGGCAUGCACUAUGCGCG ACAAAGAAAG	562
439	UUGUGUAUUU G CCAUA	36	UAUGG UGAUGGCAUGCACUAUGCGCG AAAUACACAA	563
444	UAUUUGCCAU A AAUAA	37	UUAUU UGAUGGCAUGCACUAUGCGCG AUGGCAAAUA	564
448	UGCCAUAAAU A AUACU	38	AGUAU UGAUGGCAUGCACUAUGCGCG AUUUAUGGCA	565
451	CAUAAAUAAU A CUAAA	39	UUUAG UGAUGGCAUGCACUAUGCGCG AUUAUUUAUG	566
463	UAAAUCAUUU G AAGAU	40	AUCUU UGAUGGCAUGCACUAUGCGCG AAAUGAUUUA	567
469	AUUUGAAGAU A UUCAC	41	GUGAA UGAUGGCAUGCACUAUGCGCG AUCUUCAAAU	568
481	UCACCAUUAU A GAGAA	42	UUCUC UGAUGGCAUGCACUAUGCGCG AUAAUGGUGA	569
511	UAAGGACUCU G AAGAU	43	AUCUU UGAUGGCAUGCACUAUGCGCG AGAGUCCUUA	570
517	CUCUGAAGAU G UACCU	44	AGGUA UGAUGGCAUGCACUAUGCGCG AUCUUCAGAG	571
525	AUGUACCUAU G GUCCU	45	AGGAC UGAUGGCAUGCACUAUGCGCG AUAGGUACAU	572
541	AGUAGGAAAU A AAUGU	46	ACAUU UGAUGGCAUGCACUAUGCGCG AUUUCCUACU	573
545	GGAAAUAAAU G UGAUU	47	AAUCA UGAUGGCAUGCACUAUGCGCG AUUUAUUUCC	574
547	AAAUAAAUGU G AUUUG	48	CAAAU UGAUGGCAUGCACUAUGCGCG ACAUUUAUUU	575
552	AAUGUGAUUU G CCUUC	49	GAAGG UGAUGGCAUGCACUAUGCGCG AAAUCACAUU	576
604	AAGAAGUUAU G GAAUU	50	AAUUC UGAUGGCAUGCACUAUGCGCG AUAACUUCUU	577
619	UCCUUUUAUU G AAACA	51	UGUUU UGAUGGCAUGCACUAUGCGCG AAUAAAAGGA	578
646	AAGACAGGGU G UUGAU	52	AUCAA UGAUGGCAUGCACUAUGCGCG ACCCUGUCUU	579
649	ACAGGGUGUU G AUGAU	53	AUCAU UGAUGGCAUGCACUAUGCGCG AACACCCUGU	580
652	GGGUGUUGAU G AUGCC	54	GGCAU UGAUGGCAUGCACUAUGCGCG AUCAACACCC	581
655	UGUUGAUGAU G CCUUC	55	GAAGG UGAUGGCAUGCACUAUGCGCG AUCAUCAACA	582
664	UGCCUUCUAU A CAUUA	56	UAAUG UGAUGGCAUGCACUAUGCGCG AUAGAAGGCA	583
674	ACAUUAGUUC G AGAAA	57	UUUCU UGAUGGCAUGCACUAUGCGCG GAACUAAUGU	584
683	CGAGAAAUUC G AAAAC	58	GUUUU UGAUGGCAUGCACUAUGCGCG GAAUUUCUCG	585
691	UCGAAAACAU A AAGAA	59	UUCUU UGAUGGCAUGCACUAUGCGCG AUGUUUUCGA	586
702	AAGAAAAGAU G AGCAA	60	UUGCU UGAUGGCAUGCACUAUGCGCG AUCUUUUCUU	587
712	GAGCAAAGAU G GUAAA	61	UUUAC UGAUGGCAUGCACUAUGCGCG AUCUUUGCUC	588
746	AAGACAAAGU G UGUAA	62	UUACA UGAUGGCAUGCACUAUGCGCG ACUUUGUCUU	589
748	GACAAAGUGU G UAAUU	63	AAUUA UGAUGGCAUGCACUAUGCGCG ACACUUUGUC	590
756	GUGUAAUUAU G UAAAU	64	AUUUA UGAUGGCAUGCACUAUGCGCG AUAAUUACAC	591
762	UUAUGUAAAU A CAAUU	65	AAUUG UGAUGGCAUGCACUAUGCGCG AUUUACAUAA	592
769	AAUACAAUUU G UACUU	66	AAGUA UGAUGGCAUGCACUAUGCGCG AAAUUGUAUU	593
789	CUUAAGGCAU A CUAGU	67	ACUAG UGAUGGCAUGCACUAUGCGCG AUGCCUUAAG	594
811	GGUAAUUUUU G UACAU	68	AUGUA UGAUGGCAUGCACUAUGCGCG AAAAAUUACC	595
838	AUUAGCAUUU G UUUUA	69	UAAAA UGAUGGCAUGCACUAUGCGCG AAAUGCUAAU	596
865	UUUUUUUCCU G CUCCA	70	UGGAG UGAUGGCAUGCACUAUGCGCG AGGAAAAAAA	597
872	CCUGCUCCAU G CAGAC	71	GUCUG UGAUGGCAUGCACUAUGCGCG AUGGAGCAGG	598
879	CAUGCAGACU G UUAGC	72	GCUAA UGAUGGCAUGCACUAUGCGCG AGUCUGCAUG	599
898	UACCUUAAAU G CUUAU	73	AUAAG UGAUGGCAUGCACUAUGCGCG AUUUAAGGUA	600
912	AUUUUAAAAU G ACAGU	74	ACUGU UGAUGGCAUGCACUAUGCGCG AUUUUAAAAU	601
936	UUUUUUCCUC G AAGUG	75	CACUU UGAUGGCAUGCACUAUGCGCG GAGGAAAAAA	602
941	UCCUCGAAGU G CCAGU	76	ACUGG UGAUGGCAUGCACUAUGCGCG ACUUCGAGGA	603
968	UUUGGUUUUU G AACUA	77	UAGUU UGAUGGCAUGCACUAUGCGCG AAAAACCAAA	604
979	AACUAGCAAU G CCUGU	78	ACAGG UGAUGGCAUGCACUAUGCGCG AUUGCUAGUU	605
983	AGCAAUGCCU G UGAAA	79	UUUCA UGAUGGCAUGCACUAUGCGCG AGGCAUUGCU	606
985	CAAUGCCUGU G AAAAA	80	UUUUU UGAUGGCAUGCACUAUGCGCG ACAGGCAUUG	607
997	AAAAGAAACU G AAUAC	81	GUAUU UGAUGGCAUGCACUAUGCGCG AGUUUCUUUU	608
1001	GAAACUGAAU A CCUAA	82	UUAGG UGAUGGCAUGCACUAUGCGCG AUUCAGUUUC	609
1014	UAAGAUUUCU G UCUUG	83	CAAGA UGAUGGCAUGCACUAUGCGCG AGAAAUCUUA	610
1031	GGUUUUUGGU G CAUGC	84	GCAUG UGAUGGCAUGCACUAUGCGCG ACCAAAAACC	611
1035	UUUGGUGCAU G CAGUU	85	AACUG UGAUGGCAUGCACUAUGCGCG AUGCACCAAA	612
1041	GCAUGCAGUU G AUUAC	86	GUAAU UGAUGGCAUGCACUAUGCGCG AACUGCAUGC	613
1068	CUUACCAAGU G UGAAU	87	AUUCA UGAUGGCAUGCACUAUGCGCG ACUUGGUAAG	614
1070	UACCAAGUGU G AAUGU	88	ACAUU UGAUGGCAUGCACUAUGCGCG ACACUUGGUA	615
1074	AAGUGUGAAU G UUGGU	89	ACCAA UGAUGGCAUGCACUAUGCGCG AUUCACACUU	616
1080	GAAUGUUGGU G UGAAA	90	UUUCA UGAUGGCAUGCACUAUGCGCG ACCAACAUUC	617
1082	AUGUUGGUGU G AAACA	91	UGUUU UGAUGGCAUGCACUAUGCGCG ACACCAACAU	618
1095	ACAAAUUAAU G AAGCU	92	AGCUU UGAUGGCAUGCACUAUGCGCG AUUAAUUUGU	619
1104	UGAAGCUUUU G AAUCA	93	UGAUU UGAUGGCAUGCACUAUGCGCG AAAAGCUUCA	620
1120	UCCCUAUUCU G UGUUU	94	AAACA UGAUGGCAUGCACUAUGCGCG AGAAUAGGGA	621
1122	CCUAUUCUGU G UUUUA	95	UAAAA UGAUGGCAUGCACUAUGCGCG ACAGAAUAGG	622
1139	CUAGUCACAU A AAUGG	96	CCAUU UGAUGGCAUGCACUAUGCGCG AUGUGACUAG	623
1143	UCACAUAAAU G GAUUA	97	UAAUC UGAUGGCAUGCACUAUGCGCG AUUUAUGUGA	624
1165	AAUUUCAGUU G AGACC	98	GGUCU UGAUGGCAUGCACUAUGCGCG AACUGAAAUU	625
1189	GGUUUUUACU G AAACA	99	UGUUU UGAUGGCAUGCACUAUGCGCG AGUAAAAACC	626
1197	CUGAAACAUU G AGGGA	100	UCCCU UGAUGGCAUGCACUAUGCGCG AAUGUUUCAG	627
1214	ACAAAUUUAU G GGCUU	101	AAGCC UGAUGGCAUGCACUAUGCGCG AUAAAUUUGU	628
1223	UGGGCUUCCU G AUGAU	102	AUCAU UGAUGGCAUGCACUAUGCGCG AGGAAGCCCA	629
1226	GCUUCCUGAU G AUGAU	103	AUCAU UGAUGGCAUGCACUAUGCGCG AUCAGGAAGC	630
1229	UCCUGAUGAU G AUUCU	104	AGAAU UGAUGGCAUGCACUAUGCGCG AUCAUCAGGA	631
1247	UAGGCAUCAU G UCCUA	105	UAGGA UGAUGGCAUGCACUAUGCGCG AUGAUGCCUA	632
1254	CAUGUCCUAU A GUUUG	106	CAAAC UGAUGGCAUGCACUAUGCGCG AUAGGACAUG	633
1259	CCUAUAGUUU G UCAUC	107	GAUGA UGAUGGCAUGCACUAUGCGCG AAACUAUAGG	634
1268	UGUCAUCCCU G AUGAA	108	UUCAU UGAUGGCAUGCACUAUGCGCG AGGGAUGACA	635
1271	CAUCCCUGAU G AAUGU	109	ACAUU UGAUGGCAUGCACUAUGCGCG AUCAGGGAUG	636
1275	CCUGAUGAAU G UAAAG	110	CUUUA UGAUGGCAUGCACUAUGCGCG AUUCAUCAGG	637
1288	AAGUUACACU G UUCAC	111	GUGAA UGAUGGCAUGCACUAUGCGCG AGUGUAACUU	638
1303	CAAAGGUUUU G UCUCC	112	GGAGA UGAUGGCAUGCACUAUGCGCG AAAACCUUUG	639
1317	CCUUUCCACU G CUAUU	113	AAUAG UGAUGGCAUGCACUAUGCGCG AGUGGAAAGG	640
1329	UAUUAGUCAU G GUCAC	114	GUGAC UGAUGGCAUGCACUAUGCGCG AUGACUAAUA	641
1347	UCCCCAAAAU A UUAUA	115	UAUAA UGAUGGCAUGCACUAUGCGCG AUUUUGGGGA	642
1352	AAAAUAUUAU A UUUUU	116	AAAAA UGAUGGCAUGCACUAUGCGCG AUAAUAUUUU	643
1363	UUUUUUCUAU A AAAAG	117	CUUUU UGAUGGCAUGCACUAUGCGCG AUAGAAAAAA	644
1377	AGAAAAAAAU G GAAAA	118	UUUUC UGAUGGCAUGCACUAUGCGCG AUUUUUUUCU	645
1398	ACAAGGCAAU G GAAAC	119	GUUUC UGAUGGCAUGCACUAUGCGCG AUUGCCUUGU	646
1410	AAACUAUUAU A AGGCC	120	GGCCU UGAUGGCAUGCACUAUGCGCG AUAAUAGUUU	647
1436	CACAUUAGAU A AAUUA	121	UAAUU UGAUGGCAUGCACUAUGCGCG AUCUAAUGUG	648
1446	AAAUUACUAU A AAGAC	122	GUCUU UGAUGGCAUGCACUAUGCGCG AUAGUAAUUU	649
1459	GACUCCUAAU A GCUUU	123	AAAGC UGAUGGCAUGCACUAUGCGCG AUUAGGAGUC	650
1470	GCUUUUUCCU G UUAAG	124	CUUAA UGAUGGCAUGCACUAUGCGCG AGGAAAAAGC	651
1489	GACCCAGUAU G AAUGG	125	CCAUU UGAUGGCAUGCACUAUGCGCG AUACUGGGUC	652
1493	CAGUAUGAAU G GGAUU	126	AAUCC UGAUGGCAUGCACUAUGCGCG AUUCAUACUG	653
1504	GGAUUAUUAU A GCAAC	127	GUUGC UGAUGGCAUGCACUAUGCGCG AUAAUAAUCC	654
1524	UUGGGGCUAU A UUUAC	128	GUAAA UGAUGGCAUGCACUAUGCGCG AUAGCCCCAA	655
1532	AUAUUUACAU G CUACU	129	AGUAG UGAUGGCAUGCACUAUGCGCG AUGUAAAUAU	656
1548	AAAUUUUUAU A AUAAU	130	AUUAU UGAUGGCAUGCACUAUGCGCG AUAAAAAUUU	657
1551	UUUUUAUAAU A AUUGA	131	UCAAU UGAUGGCAUGCACUAUGCGCG AUUAUAAAAA	658
1555	UAUAAUAAUU G AAAAG	132	CUUUU UGAUGGCAUGCACUAUGCGCG AAUUAUUAUA	659
1575	UAACAAGUAU A AAAAA	133	UUUUU UGAUGGCAUGCACUAUGCGCG AUACUUGUUA	660
1589	AAAUUCUCAU A GGAAU	134	AUUCC UGAUGGCAUGCACUAUGCGCG AUGAGAAUUU	661
1600	GGAAUUAAAU G UAGUC	135	GACUA UGAUGGCAUGCACUAUGCGCG AUUUAAUUCC	662
1611	UAGUCUCCCU G UGUCA	136	UGACA UGAUGGCAUGCACUAUGCGCG AGGGAGACUA	663
1613	GUCUCCCUGU G UCAGA	137	UCUGA UGAUGGCAUGCACUAUGCGCG ACAGGGAGAC	664
1621	GUGUCAGACU G CUCUU	138	AAGAG UGAUGGCAUGCACUAUGCGCG AGUCUGACAC	665
1631	GCUCUUUCAU A GUAUA	139	UAUAC UGAUGGCAUGCACUAUGCGCG AUGAAAGAGC	666
1636	UUCAUAGUAU A ACUUU	140	AAAGU UGAUGGCAUGCACUAUGCGCG AUACUAUGAA	667
1660	UCUUCAACUU G AGUCU	141	AGACU UGAUGGCAUGCACUAUGCGCG AAGUUGAAGA	668
1668	UUGAGUCUUU G AAGAU	142	AUCUU UGAUGGCAUGCACUAUGCGCG AAAGACUCAA	669
1674	CUUUGAAGAU A GUUUU	143	AAAAC UGAUGGCAUGCACUAUGCGCG AUCUUCAAAG	670
1686	UUUUAAUUCU G CUUGU	144	ACAAG UGAUGGCAUGCACUAUGCGCG AGAAUUAAAA	671
1690	AAUUCUGCUU G UGACA	145	UGUCA UGAUGGCAUGCACUAUGCGCG AAGCAGAAUU	672
1692	UUCUGCUUGU G ACAUU	146	AAUGU UGAUGGCAUGCACUAUGCGCG ACAAGCAGAA	673
1721	GGCCAGUUAU A GCUUA	147	UAAGC UGAUGGCAUGCACUAUGCGCG AUAACUGGCC	674
1733	CUUAUUAGGU G UUGAA	148	UUCAA UGAUGGCAUGCACUAUGCGCG ACCUAAUAAG	675
1736	AUUAGGUGUU G AAGAG	149	CUCUU UGAUGGCAUGCACUAUGCGCG AACACCUAAU	676
1751	GACCAAGGUU G CAAGC	150	GCUUG UGAUGGCAUGCACUAUGCGCG AACCUUGGUC	677
1765	GCCAGGCCCU G UGUGA	151	UCACA UGAUGGCAUGCACUAUGCGCG AGGGCCUGGC	678
1767	CAGGCCCUGU G UGAAC	152	GUUCA UGAUGGCAUGCACUAUGCGCG ACAGGGCCUG	679
1769	GGCCCUGUGU G AACCU	153	AGGUU UGAUGGCAUGCACUAUGCGCG ACACAGGGCC	680
1776	UGUGAACCUU G AGCUU	154	AAGCU UGAUGGCAUGCACUAUGCGCG AAGGUUCACA	681
1786	GAGCUUUCAU A GAGAG	155	CUCUC UGAUGGCAUGCACUAUGCGCG AUGAAAGCUC	682
1803	UUCACAGCAU G GACUG	156	CAGUC UGAUGGCAUGCACUAUGCGCG AUGCUGUGAA	683
1808	AGCAUGGACU G UGUGC	157	GCACA UGAUGGCAUGCACUAUGCGCG AGUCCAUGCU	684
1810	CAUGGACUGU G UGCCC	158	GGGCA UGAUGGCAUGCACUAUGCGCG ACAGUCCAUG	685
1812	UGGACUGUGU G CCCCA	159	UGGGG UGAUGGCAUGCACUAUGCGCG ACACAGUCCA	686
1827	ACGGUCAUCC G AGUGG	160	CCACU UGAUGGCAUGCACUAUGCGCG GGAUGACCGU	687
1835	CCGAGUGGUU G UACGA	161	UCGUA UGAUGGCAUGCACUAUGCGCG AACCACUCGG	688
1839	GUGGUUGUAC G AUGCA	162	UGCAU UGAUGGCAUGCACUAUGCGCG GUACAACCAC	689
1842	GUUGUACGAU G CAUUG	163	CAAUG UGAUGGCAUGCACUAUGCGCG AUCGUACAAC	690
1861	AGUCAAAAAU G GGGAG	164	CUCCC UGAUGGCAUGCACUAUGCGCG AUUUUUGACU	691
1886	CAGUUUGGAU A GCUCA	165	UGAGC UGAUGGCAUGCACUAUGCGCG AUCCAAACUG	692
1899	UCAACAAGAU A CAAUC	166	GAUUG UGAUGGCAUGCACUAUGCGCG AUCUUGUUGA	693
1912	AUCUCACUCU G UGGUG	167	CACCA UGAUGGCAUGCACUAUGCGCG AGAGUGAGAU	694
1923	UGGUGGUCCU G CUGAC	168	GUCAG UGAUGGCAUGCACUAUGCGCG AGGACCACCA	695
1926	UGGUCCUGCU G ACAAA	169	UUUGU UGAUGGCAUGCACUAUGCGCG AGCAGGACCA	696
1943	CAAGAGCAUU G CUUUU	170	AAAAG UGAUGGCAUGCACUAUGCGCG AAUGCUCUUG	697
1949	CAUUGCUUUU G UUUCU	171	AGAAA UGAUGGCAUGCACUAUGCGCG AAAAGCAAUG	698
1993	ACUUUUAAAU A UUAAC	172	GUUAA UGAUGGCAUGCACUAUGCGCG AUUUAAAAGU	699
2008	CUCAAAAGUU G AGAUU	173	AAUCU UGAUGGCAUGCACUAUGCGCG AACUUUUGAG	700
2027	GGGUGGUGGU G UGCCA	174	UGGCA UGAUGGCAUGCACUAUGCGCG ACCACCACCC	701
2029	GUGGUGGUGU G CCAAG	175	CUUGG UGAUGGCAUGCACUAUGCGCG ACACCACCAC	702
2059	UUUAAACAAU G AAGUG	176	CACUU UGAUGGCAUGCACUAUGCGCG AUUGUUUAAA	703
2064	ACAAUGAAGU G AAAAA	177	UUUUU UGAUGGCAUGCACUAUGCGCG ACUUCAUUGU	704
2124	AAUUAACAUU G CAUAA	178	UUAUG UGAUGGCAUGCACUAUGCGCG AAUGUUAAUU	705
2128	AACAUUGCAU A AACAC	179	GUGUU UGAUGGCAUGCACUAUGCGCG AUGCAAUGUU	706
2145	UUUCAAGUCU G AUCCA	180	UGGAU UGAUGGCAUGCACUAUGCGCG AGACUUGAAA	707
2152	UCUGAUCCAU A UUUAA	181	UUAAA UGAUGGCAUGCACUAUGCGCG AUGGAUCAGA	708
2159	CAUAUUUAAU A AUGCU	182	AGCAU UGAUGGCAUGCACUAUGCGCG AUUAAAUAUG	709
2162	AUUUAAUAAU G CUUUA	183	UAAAG UGAUGGCAUGCACUAUGCGCG AUUAUUAAAU	710
2172	GCUUUAAAAU A AAAAU	184	AUUUU UGAUGGCAUGCACUAUGCGCG AUUUUAAAGC	711
2178	AAAUAAAAAU A AAAAC	185	GUUUU UGAUGGCAUGCACUAUGCGCG AUUUUUAUUU	712
2193	CAAUCCUUUU G AUAAA	186	UUUAU UGAUGGCAUGCACUAUGCGCG AAAAGGAUUG	713
2196	UCCUUUUGAU A AAUUU	187	AAAUU UGAUGGCAUGCACUAUGCGCG AUCAAAAGGA	714
2207	AAUUUAAAAU G UUACU	188	AGUAA UGAUGGCAUGCACUAUGCGCG AUUUUAAAUU	715
2224	AUUUUAAAAU A AAUGA	189	UCAUU UGAUGGCAUGCACUAUGCGCG AUUUUAAAAU	716
2228	UAAAAUAAAU G AAGUG	190	CACUU UGAUGGCAUGCACUAUGCGCG AUUUAUUUUA	717
2233	UAAAUGAAGU G AGAUG	191	CAUCU UGAUGGCAUGCACUAUGCGCG ACUUCAUUUA	718
2238	GAAGUGAGAU G GCAUG	192	CAUGC UGAUGGCAUGCACUAUGCGCG AUCUCACUUC	719
2243	GAGAUGGCAU G GUGAG	193	CUCAC UGAUGGCAUGCACUAUGCGCG AUGCCAUCUC	720
2246	AUGGCAUGGU G AGGUG	194	CACCU UGAUGGCAUGCACUAUGCGCG ACCAUGCCAU	721
2251	AUGGUGAGGU G AAAGU	195	ACUUU UGAUGGCAUGCACUAUGCGCG ACCUCACCAU	722
2273	GGACUAGGUU G UUGGU	196	ACCAA UGAUGGCAUGCACUAUGCGCG AACCUAGUCC	723
2279	GGUUGUUGGU G ACUUA	197	UAAGU UGAUGGCAUGCACUAUGCGCG ACCAACAACC	724
2295	GGUUCUAGAU A GGUGU	198	ACACC UGAUGGCAUGCACUAUGCGCG AUCUAGAACC	725
2299	CUAGAUAGGU G UCUUU	199	AAAGA UGAUGGCAUGCACUAUGCGCG ACCUAUCUAG	726
2314	UUAGGACUCU G AUUUU	200	AAAAU UGAUGGCAUGCACUAUGCGCG AGAGUCCUAA	727
2320	CUCUGAUUUU G AGGAC	201	GUCCU UGAUGGCAUGCACUAUGCGCG AAAAUCAGAG	728
2350	AUUUCUUCAU G UUAAA	202	UUUAA UGAUGGCAUGCACUAUGCGCG AUGAAGAAAU	729
2397	UUUACACUAU G UGAUU	203	AAUCA UGAUGGCAUGCACUAUGCGCG AUAGUGUAAA	730
2399	UACACUAUGU G AUUUA	204	UAAAU UGAUGGCAUGCACUAUGCGCG ACAUAGUGUA	731
2406	UGUGAUUUAU A UUCCA	205	UGGAA UGAUGGCAUGCACUAUGCGCG AUAAAUCACA	732
2419	CCAUUUACAU A AGGAU	206	AUCCU UGAUGGCAUGCACUAUGCGCG AUGUAAAUGG	733
2425	ACAUAAGGAU A CACUU	207	AAGUG UGAUGGCAUGCACUAUGCGCG AUCCUUAUGU	734
2435	ACACUUAUUU G UCAAG	208	CUUGA UGAUGGCAUGCACUAUGCGCG AAAUAAGUGU	735
2454	AGCACAAUCU G UAAAU	209	AUUUA UGAUGGCAUGCACUAUGCGCG AGAUUGUGCU	736
2471	UUUAACCUAU G UUACA	210	UGUAA UGAUGGCAUGCACUAUGCGCG AUAGGUUAAA	737
2488	CAUCUUCAGU G CCAGU	211	ACUGG UGAUGGCAUGCACUAUGCGCG ACUGAAGAUG	738
2507	GGGCAAAAUU G UGCAA	212	UUGCA UGAUGGCAUGCACUAUGCGCG AAUUUUGCCC	739
2509	GCAAAAUUGU G CAAGA	213	UCUUG UGAUGGCAUGCACUAUGCGCG ACAAUUUUGC	740
2518	UGCAAGAGGU G AAGUU	214	AACUU UGAUGGCAUGCACUAUGCGCG ACCUCUUGCA	741
2527	UGAAGUUUAU A UUUGA	215	UCAAA UGAUGGCAUGCACUAUGCGCG AUAAACUUCA	742
2531	GUUUAUAUUU G AAUAU	216	AUAUU UGAUGGCAUGCACUAUGCGCG AAAUAUAAAC	743
2535	AUAUUUGAAU A UCCAU	217	AUGGA UGAUGGCAUGCACUAUGCGCG AUUCAAAUAU	744
2566	CUUCUUCCAU A UUAGU	218	ACUAA UGAUGGCAUGCACUAUGCGCG AUGGAAGAAG	745
2572	CCAUAUUAGU G UCAUC	219	GAUGA UGAUGGCAUGCACUAUGCGCG ACUAAUAUGG	746
2580	GUGUCAUCUU G CCUCC	220	GGAGG UGAUGGCAUGCACUAUGCGCG AAGAUGACAC	747
2599	CCUUCCACAU G CCCCA	221	UGGGG UGAUGGCAUGCACUAUGCGCG AUGUGGAAGG	748
2606	CAUGCCCCAU G ACUUG	222	CAAGU UGAUGGCAUGCACUAUGCGCG AUGGGGCAUG	749
2611	CCCAUGACUU G AUGCA	223	UGCAU UGAUGGCAUGCACUAUGCGCG AAGUCAUGGG	750
2614	AUGACUUGAU G CAGUU	224	AACUG UGAUGGCAUGCACUAUGCGCG AUCAAGUCAU	751
2625	CAGUUUUAAU A CUUGU	225	ACAAG UGAUGGCAUGCACUAUGCGCG AUUAAAACUG	752
2629	UUUAAUACUU G UAAUU	226	AAUUA UGAUGGCAUGCACUAUGCGCG AAGUAUUAAA	753
2646	CCCUAACCAU A AGAUU	227	AAUCU UGAUGGCAUGCACUAUGCGCG AUGGUUAGGG	754
2656	AAGAUUUACU G CUGCU	228	AGCAG UGAUGGCAUGCACUAUGCGCG AGUAAAUCUU	755
2659	AUUUACUGCU G CUGUG	229	CACAG UGAUGGCAUGCACUAUGCGCG AGCAGUAAAU	756
2662	UACUGCUGCU G UGGAU	230	AUCCA UGAUGGCAUGCACUAUGCGCG AGCAGCAGUA	757
2668	UGCUGUGGAU A UCUCC	231	GGAGA UGAUGGCAUGCACUAUGCGCG AUCCACAGCA	758
2676	AUAUCUCCAU G AAGUU	232	AACUU UGAUGGCAUGCACUAUGCGCG AUGGAGAUAU	759
2690	UUUUCCCACU G AGUCA	233	UGACU UGAUGGCAUGCACUAUGCGCG AGUGGGAAAA	760
2706	CAUCAGAAAU G CCCUA	234	UAGGG UGAUGGCAUGCACUAUGCGCG AUUUCUGAUG	761
2744	AAGAGAAUCU G ACAGA	235	UCUGU UGAUGGCAUGCACUAUGCGCG AGAUUCUCUU	762
2751	UCUGACAGAU A CCAUA	236	UAUGG UGAUGGCAUGCACUAUGCGCG AUCUGUCAGA	763
2756	CAGAUACCAU A AAGGG	237	CCCUU UGAUGGCAUGCACUAUGCGCG AUGGUAUCUG	764
2766	AAAGGGAUUU G ACCUA	238	UAGGU UGAUGGCAUGCACUAUGCGCG AAAUCCCUUU	765
2796	GGUGGUGGCU G AUGCU	239	AGCAU UGAUGGCAUGCACUAUGCGCG AGCCACCACC	766
2799	GGUGGCUGAU G CUUUG	240	CAAAG UGAUGGCAUGCACUAUGCGCG AUCAGCCACC	767
2804	CUGAUGCUUU G AACAU	241	AUGUU UGAUGGCAUGCACUAUGCGCG AAAGCAUCAG	768
2816	ACAUCUCUUU G CUGCC	242	GGCAG UGAUGGCAUGCACUAUGCGCG AAAGAGAUGU	769
2819	UCUCUUUGCU G CCCAA	243	UUGGG UGAUGGCAUGCACUAUGCGCG AGCAAAGAGA	770
2834	AUCCAUUAGC G ACAGU	244	ACUGU UGAUGGCAUGCACUAUGCGCG GCUAAUGGAU	771
2861	ACCCUGGUAU G AAUAG	245	CUAUU UGAUGGCAUGCACUAUGCGCG AUACCAGGGU	772
2865	UGGUAUGAAU A GACAG	246	CUGUC UGAUGGCAUGCACUAUGCGCG AUUCAUACCA	773
2900	AGAAUUUAAU A AAGAU	247	AUCUU UGAUGGCAUGCACUAUGCGCG AUUAAAUUCU	774
2906	UAAUAAAGAU A GUGCA	248	UGCAC UGAUGGCAUGCACUAUGCGCG AUCUUUAUUA	775
2909	UAAAGAUAGU G CAGAA	249	UUCUG UGAUGGCAUGCACUAUGCGCG ACUAUCUUUA	776
2936	GGUAAUCUAU A ACUAG	250	CUAGU UGAUGGCAUGCACUAUGCGCG AUAGAUUACC	777
2964	UAACAGUAAU A CAUUC	251	GAAUG UGAUGGCAUGCACUAUGCGCG AUUACUGUUA	778
2974	ACAUUCCAUU G UUUUA	252	UAAAA UGAUGGCAUGCACUAUGCGCG AAUGGAAUGU	779
2998	AAAUCUUCAU G CAAUG	253	CAUUG UGAUGGCAUGCACUAUGCGCG AUGAAGAUUU	780
3003	UUCAUGCAAU G AAAAA	254	UUUUU UGAUGGCAUGCACUAUGCGCG AUUGCAUGAA	781
3010	AAUGAAAAAU A CUUUA	255	UAAAG UGAUGGCAUGCACUAUGCGCG AUUUUUCAUU	782
3022	UUUAAUUCAU G AAGCU	256	AGCUU UGAUGGCAUGCACUAUGCGCG AUGAAUUAAA	783
3046	UUUUUUUGGU G UCAGA	257	UCUGA UGAUGGCAUGCACUAUGCGCG ACCAAAAAAA	784
3057	UCAGAGUCUC G CUCUU	258	AAGAG UGAUGGCAUGCACUAUGCGCG GAGACUCUGA	785
3063	UCUCGCUCUU G UCACC	259	GGUGA UGAUGGCAUGCACUAUGCGCG AAGAGCGAGA	786
3080	AGGCUGGAAU G CAGUG	260	CACUG UGAUGGCAUGCACUAUGCGCG AUUCCAGCCU	787
3088	AUGCAGUGGC G CCAUC	261	GAUGG UGAUGGCAUGCACUAUGCGCG GCCACUGCAU	788
3104	UCAGCUCACU G CAACC	262	GGUUG UGAUGGCAUGCACUAUGCGCG AGUGAGCUGA	789
3132	AGGUUCAAGC G AUUCU	263	AGAAU UGAUGGCAUGCACUAUGCGCG GCUUGAACCU	790
3141	CGAUUCUCGU G CCUCG	264	CGAGG UGAUGGCAUGCACUAUGCGCG ACGAGAAUCG	791
3154	UCGGCCUCCU G AGUAG	265	CUACU UGAUGGCAUGCACUAUGCGCG AGGAGGCCGA	792
3176	UUACAGGCGU G UGCAC	266	GUGCA UGAUGGCAUGCACUAUGCGCG ACGCCUGUAA	793
3178	ACAGGCGUGU G CACUA	267	UAGUG UGAUGGCAUGCACUAUGCGCG ACACGCCUGU	794
3200	ACUAAUUUUU G UAUUU	268	AAAUA UGAUGGCAUGCACUAUGCGCG AAAAAUUAGU	795
3229	GGUUUCACCU G UUGGC	269	GCCAA UGAUGGCAUGCACUAUGCGCG AGGUGAAACC	796
3247	GGCUGGUCUC G AACUC	270	GAGUU UGAUGGCAUGCACUAUGCGCG GAGACCAGCC	797
3255	UCGAACUCCU G ACCUC	271	GAGGU UGAUGGCAUGCACUAUGCGCG AGGAGUUCGA	798
3265	GACCUCAAGU G AUUCA	272	UGAAU UGAUGGCAUGCACUAUGCGCG ACUUGAGGUC	799
3287	UUGGCCUCAU A AACCU	273	AGGUU UGAUGGCAUGCACUAUGCGCG AUGAGGCCAA	800
3293	UCAUAAACCU G UUUUG	274	CAAAA UGAUGGCAUGCACUAUGCGCG AGGUUUAUGA	801
3298	AACCUGUUUU G CAGAA	275	UUCUG UGAUGGCAUGCACUAUGCGCG AAAACAGGUU	802
3322	UUCAGCAAAU A UUUAU	276	AUAAA UGAUGGCAUGCACUAUGCGCG AUUUGCUGAA	803
3329	AAUAUUUAUU G AGUGC	277	GCACU UGAUGGCAUGCACUAUGCGCG AAUAAAUAUU	804
3333	UUUAUUGAGU G CCUAC	278	GUAGG UGAUGGCAUGCACUAUGCGCG ACUCAAUAAA	805
3344	CCUACCAGAU G CCAGU	279	ACUGG UGAUGGCAUGCACUAUGCGCG AUCUGGUAGG	806
3354	GCCAGUCACC G CACAA	280	UUGUG UGAUGGCAUGCACUAUGCGCG GGUGACUGGC	807
3372	CACUGGGUAU A UGGUA	281	UACCA UGAUGGCAUGCACUAUGCGCG AUACCCAGUG	808
3374	CUGGGUAUAU G GUAUC	282	GAUAC UGAUGGCAUGCACUAUGCGCG AUAUACCCAG	809
3396	CAAGAGACAU A AUCCC	283	GGGAU UGAUGGCAUGCACUAUGCGCG AUGUCUCUUG	810
3416	CUUAGGUACU G CUAGU	284	ACUAG UGAUGGCAUGCACUAUGCGCG AGUACCUAAG	811
3422	UACUGCUAGU G UGGUC	285	GACCA UGAUGGCAUGCACUAUGCGCG ACUAGCAGUA	812
3429	AGUGUGGUCU G UAAUA	286	UAUUA UGAUGGCAUGCACUAUGCGCG AGACCACACU	813
3434	GGUCUGUAAU A UCUUA	287	UAAGA UGAUGGCAUGCACUAUGCGCG AUUACAGACC	814
3456	CCUUUGGUAU A CGACC	288	GGUCG UGAUGGCAUGCACUAUGCGCG AUACCAAAGG	815
3458	UUUGGUAUAC G ACCCA	289	UGGGU UGAUGGCAUGCACUAUGCGCG GUAUACCAAA	816
3469	ACCCAGAGAU A ACACG	290	CGUGU UGAUGGCAUGCACUAUGCGCG AUCUCUGGGU	817
3474	GAGAUAACAC G AUGCG	291	CGCAU UGAUGGCAUGCACUAUGCGCG GUGUUAUCUC	818
3477	AUAACACGAU G CGUAU	292	AUACG UGAUGGCAUGCACUAUGCGCG AUCGUGUUAU	819
3492	UUUUAGUUUU G CAAAG	293	CUUUG UGAUGGCAUGCACUAUGCGCG AAAACUAAAA	820
3514	UUUGGUCUCU G UGCCA	294	UGGCA UGAUGGCAUGCACUAUGCGCG AGAGACCAAA	821
3516	UGGUCUCUGU G CCAGC	295	GCUGG UGAUGGCAUGCACUAUGCGCG ACAGAGACCA	822
3527	CCAGCUCUAU A AUUGU	296	ACAAU UGAUGGCAUGCACUAUGCGCG AUAGAGCUGG	823
3531	CUCUAUAAUU G UUUUG	297	CAAAA UGAUGGCAUGCACUAUGCGCG AAUUAUAGAG	824
3536	UAAUUGUUUU G CUACG	298	CGUAG UGAUGGCAUGCACUAUGCGCG AAAACAAUUA	825
3541	GUUUUGCUAC G AUUCC	299	GGAAU UGAUGGCAUGCACUAUGCGCG GUAGCAAAAC	826
3550	CGAUUCCACU G AAACU	300	AGUUU UGAUGGCAUGCACUAUGCGCG AGUGGAAUCG	827
3560	GAAACUCUUC G AUCAA	301	UUGAU UGAUGGCAUGCACUAUGCGCG GAAGAGUUUC	828
3576	GCUACUUUAU G UAAAU	302	AUUUA UGAUGGCAUGCACUAUGCGCG AUAAAGUAGC	829
3591	UCACUUCAUU G UUUUA	303	UAAAA UGAUGGCAUGCACUAUGCGCG AAUGAAGUGA	830
3604	UUAAAGGAAU A AACUU	304	AAGUU UGAUGGCAUGCACUAUGCGCG AUUCCUUUAA	831
3610	GAAUAAACUU G AUUAU	305	AUAAU UGAUGGCAUGCACUAUGCGCG AAGUUUAUUC	832
3616	ACUUGAUUAU A UUGUU	306	AACAA UGAUGGCAUGCACUAUGCGCG AUAAUCAAGU	833
3619	UGAUUAUAUU G UUUUU	307	AAAAA UGAUGGCAUGCACUAUGCGCG AAUAUAAUCA	834
3636	UAUUUGGCAU A ACUGU	308	ACAGU UGAUGGCAUGCACUAUGCGCG AUGCCAAAUA	835
3640	UGGCAUAACU G UGAUU	309	AAUCA UGAUGGCAUGCACUAUGCGCG AGUUAUGCCA	836
3642	GCAUAACUGU G AUUCU	310	AGAAU UGAUGGCAUGCACUAUGCGCG ACAGUUAUGC	837
3663	GACAAUUACU G UACAC	311	GUGUA UGAUGGCAUGCACUAUGCGCG AGUAAUUGUC	838
3677	ACAUUAAGGU G UAUGU	312	ACAUA UGAUGGCAUGCACUAUGCGCG ACCUUAAUGU	839
3681	UAAGGUGUAU G UCAGA	313	UCUGA UGAUGGCAUGCACUAUGCGCG AUACACCUUA	840
3688	UAUGUCAGAU A UUCAU	314	AUGAA UGAUGGCAUGCACUAUGCGCG AUCUGACAUA	841
3694	AGAUAUUCAU A UUGAC	315	GUCAA UGAUGGCAUGCACUAUGCGCG AUGAAUAUCU	842
3697	UAUUCAUAUU G ACCCA	316	UGGGU UGAUGGCAUGCACUAUGCGCG AAUAUGAAUA	843
3706	UGACCCAAAU G UGUAA	317	UUACA UGAUGGCAUGCACUAUGCGCG AUUUGGGUCA	844
3708	ACCCAAAUGU G UAAUA	318	UAUUA UGAUGGCAUGCACUAUGCGCG ACAUUUGGGU	845
3713	AAUGUGUAAU A UUCCA	319	UGGAA UGAUGGCAUGCACUAUGCGCG AUUACACAUU	846
3728	AGUUUUCUCU G CAUAA	320	UUAUG UGAUGGCAUGCACUAUGCGCG AGAGAAAACU	847
3732	UUCUCUGCAU A AGUAA	321	UUACU UGAUGGCAUGCACUAUGCGCG AUGCAGAGAA	848
3745	UAAUUAAAAU A UACUU	322	AAGUA UGAUGGCAUGCACUAUGCGCG AUUUUAAUUA	849
3747	AUUAAAAUAU A CUUAA	323	UUAAG UGAUGGCAUGCACUAUGCGCG AUAUUUUAAU	850
3761	AAAAAUUAAU A GUUUU	324	AAAAC UGAUGGCAUGCACUAUGCGCG AUUAAUUUUU	851
3781	GGGUACAAAU A AACAG	325	CUGUU UGAUGGCAUGCACUAUGCGCG AUUUGUACCC	852
3788	AAUAAACAGU G CCUGA	326	UCAGG UGAUGGCAUGCACUAUGCGCG ACUGUUUAUU	853
3792	AACAGUGCCU G AACUA	327	UAGUU UGAUGGCAUGCACUAUGCGCG AGGCACUGUU	854
3823	AAACUUCUAU G UAAAA	328	UUUUA UGAUGGCAUGCACUAUGCGCG AUAGAAGUUU	855
3837	AAAUCACUAU G AUUUC	329	GAAAU UGAUGGCAUGCACUAUGCGCG AUAGUGAUUU	856
3844	UAUGAUUUCU G AAUUG	330	CAAUU UGAUGGCAUGCACUAUGCGCG AGAAAUCAUA	857
3849	UUUCUGAAUU G CUAUG	331	CAUAG UGAUGGCAUGCACUAUGCGCG AAUUCAGAAA	858
3854	GAAUUGCUAU G UGAAA	332	UUUCA UGAUGGCAUGCACUAUGCGCG AUAGCAAUUC	859
3856	AUUGCUAUGU G AAACU	333	AGUUU UGAUGGCAUGCACUAUGCGCG ACAUAGCAAU	860
3880	UUGGAACACU G UUUAG	334	CUAAA UGAUGGCAUGCACUAUGCGCG AGUGUUCCAA	861
3893	UAGGUAGGGU G UUAAG	335	CUUAA UGAUGGCAUGCACUAUGCGCG ACCCUACCUA	862
3903	GUUAAGACUU G ACACA	336	UGUGU UGAUGGCAUGCACUAUGCGCG AAGUCUUAAC	863
3938	AGAAAGAAAU G GCCAU	337	AUGGC UGAUGGCAUGCACUAUGCGCG AUUUCUUUCU	864
3944	AAAUGGCCAU A CUUCA	338	UGAAG UGAUGGCAUGCACUAUGCGCG AUGGCCAUUU	865
3956	UUCAGGAACU G CAGUG	339	CACUG UGAUGGCAUGCACUAUGCGCG AGUUCCUGAA	866
3961	GAACUGCAGU G CUUAU	340	AUAAG UGAUGGCAUGCACUAUGCGCG ACUGCAGUUC	867
3967	CAGUGCUUAU G AGGGG	341	CCCCU UGAUGGCAUGCACUAUGCGCG AUAAGCACUG	868
3975	AUGAGGGGAU A UUUAG	342	CUAAA UGAUGGCAUGCACUAUGCGCG AUCCCCUCAU	869
3988	UAGGCCUCUU G AAUUU	343	AAAUU UGAUGGCAUGCACUAUGCGCG AAGAGGCCUA	870
3996	UUGAAUUUUU G AUGUA	344	UACAU UGAUGGCAUGCACUAUGCGCG AAAAAUUCAA	871
3999	AAUUUUUGAU G UAGAU	345	AUCUA UGAUGGCAUGCACUAUGCGCG AUCAAAAAUU	872
4005	UGAUGUAGAU G GGCAU	346	AUGCC UGAUGGCAUGCACUAUGCGCG AUCUACAUCA	873
4041	UUACCUUUAU G UGAAC	347	GUUCA UGAUGGCAUGCACUAUGCGCG AUAAAGGUAA	874
4043	ACCUUUAUGU G AACUU	348	AAGUU UGAUGGCAUGCACUAUGCGCG ACAUAAAGGU	875
4050	UGUGAACUUU G AAUGG	349	CCAUU UGAUGGCAUGCACUAUGCGCG AAAGUUCACA	876
4054	AACUUUGAAU G GUUUA	350	UAAAC UGAUGGCAUGCACUAUGCGCG AUUCAAAGUU	877
4071	CAAAAGAUUU G UUUUU	351	AAAAA UGAUGGCAUGCACUAUGCGCG AAAUCUUUUG	878
4077	AUUUGUUUUU G UAGAG	352	CUCUA UGAUGGCAUGCACUAUGCGCG AAAAACAAAU	879
4110	UUCUAGAAAU A AAUGU	353	ACAUU UGAUGGCAUGCACUAUGCGCG AUUUCUAGAA	880
4114	AGAAAUAAAU G UUACC	354	GGUAA UGAUGGCAUGCACUAUGCGCG AUUUAUUUCU	881
4152	AAAAAUCCUU G UUGAA	355	UUCAA UGAUGGCAUGCACUAUGCGCG AAGGAUUUUU	882
4155	AAUCCUUGUU G AAGUU	356	AACUU UGAUGGCAUGCACUAUGCGCG AACAAGGAUU	883
4186	UAAAUUACAU A GACUU	357	AAGUC UGAUGGCAUGCACUAUGCGCG AUGUAAUUUA	884
4204	GCAUUAACAU G UUUGU	358	ACAAA UGAUGGCAUGCACUAUGCGCG AUGUUAAUGC	885
4208	UAACAUGUUU G UGGAA	359	UUCCA UGAUGGCAUGCACUAUGCGCG AAACAUGUUA	886
4218	GUGGAAGAAU A UAGCA	360	UGCUA UGAUGGCAUGCACUAUGCGCG AUUCUUCCAC	887
4220	GGAAGAAUAU A GCAGA	361	UCUGC UGAUGGCAUGCACUAUGCGCG AUAUUCUUCC	888
4231	GCAGACGUAU A UUGUA	362	UACAA UGAUGGCAUGCACUAUGCGCG AUACGUCUGC	889
4234	GACGUAUAUU G UAUCA	363	UGAUA UGAUGGCAUGCACUAUGCGCG AAUAUACGUC	890
4243	UGUAUCAUUU G AGUGA	364	UCACU UGAUGGCAUGCACUAUGCGCG AAAUGAUACA	891
4247	UCAUUUGAGU G AAUGU	365	ACAUU UGAUGGCAUGCACUAUGCGCG ACUCAAAUGA	892
4251	UUGAGUGAAU G UUCCC	366	GGGAA UGAUGGCAUGCACUAUGCGCG AUUCACUCAA	893
4285	CUAUUUAACU G AGUCA	367	UGACU UGAUGGCAUGCACUAUGCGCG AGUUAAAUAG	894
4295	GAGUCACACU G CAUAG	368	CUAUG UGAUGGCAUGCACUAUGCGCG AGUGUGACUC	895
4299	CACACUGCAU A GGAAU	369	AUUCC UGAUGGCAUGCACUAUGCGCG AUGCAGUGUG	896
4323	UAACUUUUAU A GGUUA	370	UAACC UGAUGGCAUGCACUAUGCGCG AUAAAAGUUA	897
4337	UAUCAAAACU G UUGUC	371	GACAA UGAUGGCAUGCACUAUGCGCG AGUUUUGAUA	898
4340	CAAAACUGUU G UCACC	372	GGUGA UGAUGGCAUGCACUAUGCGCG AACAGUUUUG	899
4349	UGUCACCAUU G CACAA	373	UUGUG UGAUGGCAUGCACUAUGCGCG AAUGGUGACA	900
4359	GCACAAUUUU G UCCUA	374	UAGGA UGAUGGCAUGCACUAUGCGCG AAAAUUGUGC	901
4367	UUGUCCUAAU A UAUAC	375	GUAUA UGAUGGCAUGCACUAUGCGCG AUUAGGACAA	902
4369	GUCCUAAUAU A UACAU	376	AUGUA UGAUGGCAUGCACUAUGCGCG AUAUUAGGAC	903
4371	CCUAAUAUAU A CAUAG	377	CUAUG UGAUGGCAUGCACUAUGCGCG AUAUAUUAGG	904
4375	AUAUAUACAU A GAAAC	378	GUUUC UGAUGGCAUGCACUAUGCGCG AUGUAUAUAU	905
4384	UAGAAACUUU G UGGGG	379	CCCCA UGAUGGCAUGCACUAUGCGCG AAAGUUUCUA	906
4393	UGUGGGGCAU G UUAAG	380	CUUAA UGAUGGCAUGCACUAUGCGCG AUGCCCCACA	907
4408	GUUACAGUUU G CACAA	381	UUGUG UGAUGGCAUGCACUAUGCGCG AAACUGUAAC	908
4427	CAUCUCAUUU G UAUUC	382	GAAUA UGAUGGCAUGCACUAUGCGCG AAAUGAGAUG	909
4437	GUAUUCCAUU G AUUUU	383	AAAAU UGAUGGCAUGCACUAUGCGCG AAUGGAAUAC	910
4480	AAAACAGUAU A UAUAA	384	UUAUA UGAUGGCAUGCACUAUGCGCG AUACUGUUUU	911
4482	AACAGUAUAU A UAACU	385	AGUUA UGAUGGCAUGCACUAUGCGCG AUAUACUGUU	912
4484	CAGUAUAUAU A ACUUU	386	AAAGU UGAUGGCAUGCACUAUGCGCG AUAUAUACUG	913
4527	AAAACUAUCU G AAGAU	387	AUCUU UGAUGGCAUGCACUAUGCGCG AGAUAGUUUU	914
4541	AUUUCCAUUU G UCAAA	388	UUUGA UGAUGGCAUGCACUAUGCGCG AAAUGGAAAU	915
4554	AAAAAGUAAU G AUUUC	389	GAAAU UGAUGGCAUGCACUAUGCGCG AUUACUUUUU	916
4562	AUGAUUUCUU G AUAAU	390	AUUAU UGAUGGCAUGCACUAUGCGCG AAGAAAUCAU	917
4565	AUUUCUUGAU A AUUGU	391	ACAAU UGAUGGCAUGCACUAUGCGCG AUCAAGAAAU	918
4569	CUUGAUAAUU G UGUAG	392	CUACA UGAUGGCAUGCACUAUGCGCG AAUUAUCAAG	919
4571	UGAUAAUUGU G UAGUG	393	CACUA UGAUGGCAUGCACUAUGCGCG ACAAUUAUCA	920
4576	AUUGUGUAGU G AAUGU	394	ACAUU UGAUGGCAUGCACUAUGCGCG ACUACACAAU	921
4580	UGUAGUGAAU G UUUUU	395	AAAAA UGAUGGCAUGCACUAUGCGCG AUUCACUACA	922
4606	CAGUUACCUU G AAAGC	396	GCUUU UGAUGGCAUGCACUAUGCGCG AAGGUAACUG	923
4613	CUUGAAAGCU G AAUUU	397	AAAUU UGAUGGCAUGCACUAUGCGCG AGCUUUCAAG	924
4621	CUGAAUUUAU A UUUAG	398	CUAAA UGAUGGCAUGCACUAUGCGCG AUAAAUUCAG	925
4635	AGUAACUUCU G UGUUA	399	UAACA UGAUGGCAUGCACUAUGCGCG AGAAGUUACU	926
4637	UAACUUCUGU G UUAAU	400	AUUAA UGAUGGCAUGCACUAUGCGCG ACAGAAGUUA	927
4643	CUGUGUUAAU A CUGGA	401	UCCAG UGAUGGCAUGCACUAUGCGCG AUUAACACAG	928
4650	AAUACUGGAU A GCAUG	402	CAUGC UGAUGGCAUGCACUAUGCGCG AUCCAGUAUU	929
4655	UGGAUAGCAU G AAUUC	403	GAAUU UGAUGGCAUGCACUAUGCGCG AUGCUAUCCA	930
4662	CAUGAAUUCU G CAUUG	404	CAAUG UGAUGGCAUGCACUAUGCGCG AGAAUUCAUG	931
4667	AUUCUGCAUU G AGAAA	405	UUUCU UGAUGGCAUGCACUAUGCGCG AAUGCAGAAU	932
4675	UUGAGAAACU G AAUAG	406	CUAUU UGAUGGCAUGCACUAUGCGCG AGUUUCUCAA	933
4679	GAAACUGAAU A GCUGU	407	ACAGC UGAUGGCAUGCACUAUGCGCG AUUCAGUUUC	934
4683	CUGAAUAGCU G UCAUA	408	UAUGA UGAUGGCAUGCACUAUGCGCG AGCUAUUCAG	935
4688	UAGCUGUCAU A AAAUG	409	CAUUU UGAUGGCAUGCACUAUGCGCG AUGACAGCUA	936
4693	GUCAUAAAAU G CUUUC	410	GAAAG UGAUGGCAUGCACUAUGCGCG AUUUUAUGAC	937
4715	AAAGAAAGAU A CUCAC	411	GUGAG UGAUGGCAUGCACUAUGCGCG AUCUUUCUUU	938
4723	AUACUCACAU G AGUUC	412	GAACU UGAUGGCAUGCACUAUGCGCG AUGUGAGUAU	939
4731	AUGAGUUCUU G AAGAA	413	UUCUU UGAUGGCAUGCACUAUGCGCG AAGAACUCAU	940
4738	CUUGAAGAAU A GUCAU	414	AUGAC UGAUGGCAUGCACUAUGCGCG AUUCUUCAAG	941
4744	GAAUAGUCAU A ACUAG	415	CUAGU UGAUGGCAUGCACUAUGCGCG AUGACUAUUC	942
4760	AUUAAGAUCU G UGUUU	416	AAACA UGAUGGCAUGCACUAUGCGCG AGAUCUUAAU	943
4762	UAAGAUCUGU G UUUUA	417	UAAAA UGAUGGCAUGCACUAUGCGCG ACAGAUCUUA	944
4775	UUAGUUUAAU A GUUUG	418	CAAAC UGAUGGCAUGCACUAUGCGCG AUUAAACUAA	945
4780	UUAAUAGUUU G AAGUG	419	CACUU UGAUGGCAUGCACUAUGCGCG AAACUAUUAA	946
4785	AGUUUGAAGU G CCUGU	420	ACAGG UGAUGGCAUGCACUAUGCGCG ACUUCAAACU	947
4789	UGAAGUGCCU G UUUGG	421	CCAAA UGAUGGCAUGCACUAUGCGCG AGGCACUUCA	948
4798	UGUUUGGGAU A AUGAU	422	AUCAU UGAUGGCAUGCACUAUGCGCG AUCCCAAACA	949
4801	UUGGGAUAAU G AUAGG	423	CCUAU UGAUGGCAUGCACUAUGCGCG AUUAUCCCAA	950
4804	GGAUAAUGAU A GGUAA	424	UUACC UGAUGGCAUGCACUAUGCGCG AUCAUUAUCC	951
4817	UAAUUUAGAU G AAUUU	425	AAAUU UGAUGGCAUGCACUAUGCGCG AUCUAAAUUA	952
4843	AAAGUUAUCU G CAGUU	426	AACUG UGAUGGCAUGCACUAUGCGCG AGAUAACUUU	953
4851	CUGCAGUUAU G UUGAG	427	CUCAA UGAUGGCAUGCACUAUGCGCG AUAACUGCAG	954
4854	CAGUUAUGUU G AGGGC	428	GCCCU UGAUGGCAUGCACUAUGCGCG AACAUAACUG	955
4904	GGGUUACAGU G UUUUA	429	UAAAA UGAUGGCAUGCACUAUGCGCG ACUGUAACCC	956
4913	UGUUUUAUCC G AAAGU	430	ACUUU UGAUGGCAUGCACUAUGCGCG GGAUAAAACA	957
4932	CAAUUCCACU G UCUUG	431	CAAGA UGAUGGCAUGCACUAUGCGCG AGUGGAAUUG	958
4937	CCACUGUCUU G UGUUU	432	AAACA UGAUGGCAUGCACUAUGCGCG AAGACAGUGG	959
4939	ACUGUCUUGU G UUUUC	433	GAAAA UGAUGGCAUGCACUAUGCGCG ACAAGACAGU	960
4947	GUGUUUUCAU G UUGAA	434	UUCAA UGAUGGCAUGCACUAUGCGCG AUGAAAACAC	961
4950	UUUUCAUGUU G AAAAU	435	AUUUU UGAUGGCAUGCACUAUGCGCG AACAUGAAAA	962
4956	UGUUGAAAAU A CUUUU	436	AAAAG UGAUGGCAUGCACUAUGCGCG AUUUUCAACA	963
4962	AAAUACUUUU G CAUUU	437	AAAUG UGAUGGCAUGCACUAUGCGCG AAAAGUAUUU	964
4975	UUUUUCCUUU G AGUGC	438	GCACU UGAUGGCAUGCACUAUGCGCG AAAGGAAAAA	965
4979	UCCUUUGAGU G CCAAU	439	AUUGG UGAUGGCAUGCACUAUGCGCG ACUCAAAGGA	966
5009	AUUUCUUAAU G UAACA	440	UGUUA UGAUGGCAUGCACUAUGCGCG AUUAAGAAAU	967
5016	AAUGUAACAU G UUUAC	441	GUAAA UGAUGGCAUGCACUAUGCGCG AUGUUACAUU	968
5029	UACCUGGCCU G UCUUU	442	AAAGA UGAUGGCAUGCACUAUGCGCG AGGCCAGGUA	969
5046	AACUAUUUUU G UAUAG	443	CUAUA UGAUGGCAUGCACUAUGCGCG AAAAAUAGUU	970
5050	AUUUUUGUAU A GUGUA	444	UACAC UGAUGGCAUGCACUAUGCGCG AUACAAAAAU	971
5053	UUUGUAUAGU G UAAAC	445	GUUUA UGAUGGCAUGCACUAUGCGCG ACUAUACAAA	972
5060	AGUGUAAACU G AAACA	446	UGUUU UGAUGGCAUGCACUAUGCGCG AGUUUACACU	973
5067	ACUGAAACAU G CACAU	447	AUGUG UGAUGGCAUGCACUAUGCGCG AUGUUUCAGU	974
5076	UGCACAUUUU G UACAU	448	AUGUA UGAUGGCAUGCACUAUGCGCG AAAAUGUGCA	975
5083	UUUGUACAUU G UGCUU	449	AAGCA UGAUGGCAUGCACUAUGCGCG AAUGUACAAA	976
5085	UGUACAUUGU G CUUUC	450	GAAAG UGAUGGCAUGCACUAUGCGCG ACAAUGUACA	977
5095	GCUUUCUUUU G UGGGU	451	ACCCA UGAUGGCAUGCACUAUGCGCG AAAAGAAAGC	978
5104	UGUGGGUCAU A UGCAG	452	CUGCA UGAUGGCAUGCACUAUGCGCG AUGACCCACA	979
5106	UGGGUCAUAU G CAGUG	453	CACUG UGAUGGCAUGCACUAUGCGCG AUAUGACCCA	980
5111	CAUAUGCAGU G UGAUC	454	GAUCA UGAUGGCAUGCACUAUGCGCG ACUGCAUAUG	981
5113	UAUGCAGUGU G AUCCA	455	UGGAU UGAUGGCAUGCACUAUGCGCG ACACUGCAUA	982
5122	UGAUCCAGUU G UUUUC	456	GAAAA UGAUGGCAUGCACUAUGCGCG AACUGGAUCA	983
5140	UCAUUUGGUU G CGCUG	457	CAGCG UGAUGGCAUGCACUAUGCGCG AACCAAAUGA	984
5142	AUUUGGUUGC G CUGAC	458	GUCAG UGAUGGCAUGCACUAUGCGCG GCAACCAAAU	985
5145	UGGUUGCGCU G ACCUA	459	UAGGU UGAUGGCAUGCACUAUGCGCG AGCGCAACCA	986
5156	ACCUAGGAAU G UUGGU	460	ACCAA UGAUGGCAUGCACUAUGCGCG AUUCCUAGGU	987
5165	UGUUGGUCAU A UCAAA	461	UUUGA UGAUGGCAUGCACUAUGCGCG AUGACCAACA	988
5181	CAUUAAAAAU G ACCAC	462	GUGGU UGAUGGCAUGCACUAUGCGCG AUUUUUAAUG	989
5196	CUCUUUUAAU G AAAUU	463	AAUUU UGAUGGCAUGCACUAUGCGCG AUUAAAAGAG	990
5213	ACUUUUAAAU G UUUAU	464	AUAAA UGAUGGCAUGCACUAUGCGCG AUUUAAAAGU	991
5219	AAAUGUUUAU A GGAGU	465	ACUCC UGAUGGCAUGCACUAUGCGCG AUAAACAUUU	992
5227	AUAGGAGUAU G UGCUG	466	CAGCA UGAUGGCAUGCACUAUGCGCG AUACUCCUAU	993
5229	AGGAGUAUGU G CUGUG	467	CACAG UGAUGGCAUGCACUAUGCGCG ACAUACUCCU	994
5232	AGUAUGUGCU G UGAAG	468	CUUCA UGAUGGCAUGCACUAUGCGCG AGCACAUACU	995
5234	UAUGUGCUGU G AAGUG	469	CACUU UGAUGGCAUGCACUAUGCGCG ACAGCACAUA	996
5239	GCUGUGAAGU G AUCUA	470	UAGAU UGAUGGCAUGCACUAUGCGCG ACUUCACAGC	997
5251	UCUAAAAUUU G UAAUA	471	UAUUA UGAUGGCAUGCACUAUGCGCG AAAUUUUAGA	998
5256	AAUUUGUAAU A UUUUU	472	AAAAA UGAUGGCAUGCACUAUGCGCG AUUACAAAUU	999
5262	UAAUAUUUUU G UCAUG	473	CAUGA UGAUGGCAUGCACUAUGCGCG AAAAAUAUUA	1000
5267	UUUUUGUCAU G AACUG	474	CAGUU UGAUGGCAUGCACUAUGCGCG AUGACAAAAA	1001
5272	GUCAUGAACU G UACUA	475	UAGUA UGAUGGCAUGCACUAUGCGCG AGUUCAUGAC	1002
5290	CCUAAUUAUU G UAAUG	476	CAUUA UGAUGGCAUGCACUAUGCGCG AAUAAUUAGG	1003
5295	UUAUUGUAAU G UAAUA	477	UAUUA UGAUGGCAUGCACUAUGCGCG AUUACAAUAA	1004
5300	GUAAUGUAAU A AAAAU	478	AUUUU UGAUGGCAUGCACUAUGCGCG AUUACAUUAC	1005
5306	UAAUAAAAAU A GUUAC	479	GUAAC UGAUGGCAUGCACUAUGCGCG AUUUUUAUUA	1006
5315	UAGUUACAGU G ACUAU	480	AUAGU UGAUGGCAUGCACUAUGCGCG ACUGUAACUA	1007
5321	CAGUGACUAU G AGUGU	481	ACACU UGAUGGCAUGCACUAUGCGCG AUAGUCACUG	1008
5325	GACUAUGAGU G UGUAU	482	AUACA UGAUGGCAUGCACUAUGCGCG ACUCAUAGUC	1009
5327	CUAUGAGUGU G UAUUU	483	AAAUA UGAUGGCAUGCACUAUGCGCG ACACUCAUAG	1010
5339	AUUUAUUCAU G CAAAU	484	AUUUG UGAUGGCAUGCACUAUGCGCG AUGAAUAAAU	1011
5347	AUGCAAAUUU G AACUG	485	CAGUU UGAUGGCAUGCACUAUGCGCG AAAUUUGCAU	1012
5352	AAUUUGAACU G UUUGC	486	GCAAA UGAUGGCAUGCACUAUGCGCG AGUUCAAAUU	1013
5356	UGAACUGUUU G CCCCG	487	CGGGG UGAUGGCAUGCACUAUGCGCG AAACAGUUCA	1014
5361	UGUUUGCCCC G AAAUG	488	CAUUU UGAUGGCAUGCACUAUGCQCG GGGGCAAACA	1015
5366	GCCCCGAAAU G GAUAU	489	AUAUC UGAUGGCAUGCACUAUGCGCG AUUUCGGGGC	1016
5370	CGAAAUGGAU A UGGAU	490	AUCCA UGAUGGCAUGCACUAUGCGCG AUCCAUUUCG	1017
5372	AAAUGGAUAU G GAUAC	491	GUAUC UGAUGGCAUGCACUAUGCGCG AUAUCCAUUU	1018
5376	GGAUAUGGAU A CUUUA	492	UAAAG UGAUGGCAUGCACUAUGCGCG AUCCAUAUCC	1019
5383	GAUACUUUAU A AGCCA	493	UGGCU UGAUGGCAUGCACUAUGCGCG AUAAAGUAUC	1020
5390	UAUAAGCCAU A GACAC	494	GUGUC UGAUGGCAUGCACUAUGCGCG AUGGCUUAUA	1021
5399	UAGACACUAU A GUAUA	495	UAUAC UGAUGGCAUGCACUAUGCGCG AUAGUGUCUA	1022
5404	ACUAUAGUAU A CCAGU	496	ACUGG UGAUGGCAUGCACUAUGCGCG AUACUAUAGU	1023
5410	GUAUACCAGU G AAUCU	497	AGAUU UGAUGGCAUGCACUAUGCGCG ACUGGUAUAC	1024
5421	AAUCUUUUAU G CAGCU	498	AGCUG UGAUGGCAUGCACUAUGCGCG AUAAAAGAUU	1025
5428	UAUGCAGCUU G UUAGA	499	UCUAA UGAUGGCAUGCACUAUGCGCG AAGCUGCAUA	1026
5459	UCUAAAAGGU G CUGUG	500	CACAG UGAUGGCAUGCACUAUGCGCG ACCUUUUAGA	1027
5462	AAAAGGUGCU G UGGAU	501	AUCCA UGAUGGCAUGCACUAUGCGCG AGCACCUUUU	1028
5468	UGCUGUGGAU A UUAUG	502	CAUAA UGAUGGCAUGCACUAUGCGCG AUCCACAGCA	1029
5473	UGGAUAUUAU G UAAAG	503	CUUUA UGAUGGCAUGCACUAUGCGCG AUAAUAUCCA	1030
5483	GUAAAGGCGU G UUUGC	504	GCAAA UGAUGGCAUGCACUAUGCGCG ACGCCUUUAC	1031
5487	AGGCGUGUUU G CUUAA	505	UUAAG UGAUGGCAUGCACUAUGCGCG AAACACGCCU	1032
5505	AAUUUUCCAU A UUUAG	506	CUAAA UGAUGGCAUGCACUAUGCGCG AUGGAAAAUU	1033
5519	AGAAGUAGAU G CAAAA	507	UUUUG UGAUGGCAUGCACUAUGCGCG AUCUACUUCU	1034
5532	AAACAAAUCU G CCUUU	508	AAAGG UGAUGGCAUGCACUAUGCGCG AGAUUUGUUU	1035
5540	CUGCCUUUAU G ACAAA	509	UUUGU UGAUGGCAUGCACUAUGCGCG AUAAAGGCAG	1036
5551	ACAAAAAAAU A GGAUA	510	UAUCC UGAUGGCAUGCACUAUGCGCG AUUUUUUUGU	1037
5556	AAAAUAGGAU A ACAUU	511	AAUGU UGAUGGCAUGCACUAUGCGCG AUCCUAUUUU	1038
5586	UUUUAUCAAU A AGGUA	512	UACCU UGAUGGCAUGCACUAUGCGCG AUUGAUAAAA	1039
5595	UAAGGUAAUU G AUACA	513	UGUAU UGAUGGCAUGCACUAUGCGCG AAUUACCUUA	1040
5598	GGUAAUUGAU A CACAA	514	UUGUG UGAUGGCAUGCACUAUGCGCG AUCAAUUACC	1041
5609	CACAACAGGU G ACUUG	515	CAAGU UGAUGGCAUGCACUAUGCGCG ACCUGUUGUG	1042
5650	CAACAUUAAU A AUGGA	516	UCCAU UGAUGGCAUGCACUAUGCGCG AUUAAUGUUG	1043
5653	CAUUAAUAAU G GAAAU	517	AUUUC UGAUGGCAUGCACUAUGCGCG AUUAUUAAUG	1044
5659	UAAUGGAAAU A AUUGA	518	UCAAU UGAUGGCAUGCACUAUGCGCG AUUUCCAUUA	1045
5663	GGAAAUAAUU G AAUAG	519	CUAUU UGAUGGCAUGCACUAUGCGCG AAUUAUUUCC	1046
5667	AUAAUUGAAU A GUUAG	520	CUAAC UGAUGGCAUGCACUAUGCGCG AUUCAAUUAU	1047
5677	AGUUAGUUAU G UAUGU	521	ACAUA UGAUGGCAUGCACUAUGCGCG AUAACUAACU	1048
5681	AGUUAUGUAU G UUAAU	522	AUUAA UGAUGGCAUGCACUAUGCGCG AUACAUAACU	1049
5687	GUAUGUUAAU G CCAGU	523	ACUGG UGAUGGCAUGCACUAUGCGCG AUUAACAUAC	1050
5725	CAGAAGUAAU G ACUCC	524	GGAGU UGAUGGCAUGCACUAUGCGCG AUUACUUCUG	1051
5733	AUGACUCCAU A CAUAU	525	AUAUG UGAUGGCAUGCACUAUGCGCG AUGGAGUCAU	1052
5737	CUCCAUACAU A UUAUU	526	AAUAA UGAUGGCAUGCACUAUGCGCG AUGUAUGGAG	1053
5752	UUAUUUCUAU A ACUAC	527	GUAGU UGAUGGCAUGCACUAUGCGCG AUAGAAAUAA	1054
Input Sequence = KRAS2 Cut Site = AUR/, YG/M or UG/U.
Stem Length = 5/10. Core Sequence = UGAUGGCAUGCACUAUGCGCG
Seq1 = KRAS2 ( Homo sapiens v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homolog (KRAS2) mRNA.; 5775 bp)

TABLE III
Table III. Rate constants for ribozyme 40 cleavage at various triplets
with next nucleotide specified. Reaction conditions as in text, na = no
activity detectable, single turnover kinetics.
Cleavable Triplet                k                                                                        cat                                                                     (min                                                                        −1                                                                    )
A                                                                        14.2                                                                    U                                                                        14.1                                                                    G                                                                        15                                                                    /A                                                                        1.1 0.91
A                                                                        14.2                                                                    U                                                                        14.1                                                                    A                                                                        15                                                                    /A                                                                        1.1 0.34
A                                                                        14.2                                                                    U                                                                        14.1                                                                    U                                                                        15                                                                    /A                                                                        1.1 0.007
A                                                                        14.2                                                                    A                                                                        14.1                                                                    G                                                                        15                                                                    /A                                                                        1.1 0.57
A                                                                        14.2                                                                    U                                                                        14.1                                                                    G                                                                        15                                                                    /U                                                                        1.1 0.35
A                                                                        14.2                                                                    U                                                                        14.1                                                                    G                                                                        15                                                                    /G                                                                        1.1 0.66
/ = site of cleavage
Numbering convention as shown in                                                       FIG. 8

TABLE IV
Sequence Specificity and Rate Constants for Stabilized Ribozymes
Cleavage
Site				k rel to
Sequence	RPI #	Corresponding Ribozyme	Seq. ID Nos	WT
WT =	13159	5′-aac guu GAU s ggc auG cac uau gcg cga ugg cua ggc-3′	1055	1
UG/A
UG/C	12768	5′-aac ggu GAU s ggc auG cac uau gcg cga ugg cua ggc-3′	1056	0.97
CG/A	13161	5′-aac guu GAU s ggc auG cac uau gcg cgg ugg cua ggc-3′	1057	0.76
AG/A	12763	5′-aac guu GAU s ggc auG cac uau gcg cgu ugg cua ggc-3′	1058	0.70
UG/U	12764	5′-aac gau GAU s ggc auG cac uau gcg cga ugg cua ggc-3′	1059	0.35
CG/U	12766	5′-aac gau GAU s ggc auG cac uau gcg cgg ugg cua ggc-3′	1060	0.12
CG/C	12770	5′-aac ggu GAU s ggc auG cac uau gcg cgg ugg cua ggc-3′	1061	0.1
AG/C	12771	5′-aac ggu GAU s ggc auG cac uau gcg cgu ugg cua ggc-3′	1062	0.07
AG/U	12767	5′-aac gau GAU s ggc auG cac uau gcg cgu ugg cua ggc-3′	1063	0.06
CG/G	12774	5′-aac gcu GAU s ggc auG cac uau gcg cgg ugg cua ggc-3′	1064	0.06
UG/G	12772	5′-aac gcu GAU s ggc auG cac uau gcg cga ugg cua ggc-3′	1065	0.04
GG/A	13160	5′-aac guu GAU s ggc auG cac uau gcg cgc ugg cua ggc-3′	1066	0.02
GG/C	12769	5′-aac ggu GAU s ggc auG cac uau gcg cgc ugg cua ggc-3′	1067	0.01
AG/G	12775	5′-aac gcu GAU s ggc auG cac uau gcg cgu ugg cua ggc-3′	1068	0.008
GG/U	12765	5′-aac gau GAU s ggc auG cac uau gcg cgc ugg cua ggc-3′	1069	0.007
GG/G	12773	5′-aac gcu GAU s ggc auG cac uau gcg cgc ugg cua ggc-3′	1070	0.002
Lower case = 2′-O-Methyl
Upper case = Ribo
s = phosphorothioate
/= site of cleavage
WT U 14.1 G 15 /A 1.1 ( FIG. 8 ) K obs = 0.266 min −1

TABLE V
Human K-ras Ribozyme Sequences
	Nt.			Seq. ID
RPI #	Position	Alias	Ribozyme Sequence	No.
12779	63	krasM-63 GCl.Rz-5/10 stab1	a s g s cug uGAU s g gcauGcacuaugc gcg aucgucaagg B	1071
12780	95	krasM-95 GCl.Rz-5/10 stab1	g s a s uca uGAU s g gcauGcacuaugc gcg auucguccac B	1072
12781	142	krasM-142 GCl.Rz-5/10 stab1	u s u s cuc uGAU s g gcauGcacuaugc gcg aucaauuacu B	1073
12782	163	krasM-163 GCl.Rz-5/10 stab1	g s a s gaa uGAU s g gcauGcacuaugc gcg auccaagaga B	1074
12783	201	krasM-201 GCl.Rz-5/10 stab1	u s c s ccu uGAU s g gcauGcacuaugc gcg auugcacugu B	1075
12784	216	krasM-216 GCl.Rz-5/10 stab1	g s u s ccu uGAU s g gcauGcacuaugc gcg auguacuggu B	1076
12785	256	krasM-256 GCl.Rz-5/10 stab1	a s g s uau uGAU s g gcauGcacuaugc gcg auuuauggca B	1077
12786	325	krasM-325 GCl.Rz-5/10 stab1	a s g s gua uGAU s g gcauGcacuaugc gcg aucuucagag B	1078
12787	333	krasM-333 GCl.Rz-5/10 stab1	a s g s gac uGAU s g gcauGcacuaugc gcg auagguacau B	1079
12788	353	krasM-353 GCl.Rz-5/10 stab1	a s a s uca uGAU s g gcauGcacuaugc gcg auuuauuucc B	1080
12789	412	krasM-412 GCl.Rz-5/10 stab1	a s a s uuc uGAU s g gcauGcacuaugc gcg auaacuucuu B	1081
12790	460	krasM-460 GCl.Rz-5/10 stab1	g s g s cau uGAU s g gcauGcacuaugc gcg aucaacaccc B	1082
12791	463	krasM-463 GCl.Rz-5/10 stab1	g s a s agg uGAU s g gcauGcacuaugc gcg aucaucaaca B	1083
12792	472	krasM-472 GCl.Rz-5/10 stab1	u s a s aug uGAU s g gcauGcacuaugc gcg auagaaggca B	1084
12793	520	krasM-520 GCl.Rz-5/10 stab1	u s u s uac uGAU s g gcauGcacuaugc gcg aucuuugcuc B	1085
12794	706	krasM-706 GCl.Rz-5/10 stab1	a s u s aag uGAU s g gcauGcacuaugc gcg auuuaaggua B	1086
12795	787	krasM-787 GCl.Rz-5/10 stab1	a s c s agg uGAU s g gcauGcacuaugc gcg auugcuaguu B	1087
12796	843	krasM-843 GCl.Rz-5/10 stab1	a s a s cug uGAU s g gcauGcacuaugc gcg augcaccaaa B	1088
12797	882	krasM-882 GCl.Rz-5/10 stab1	a s c s caa uGAU s g gcauGcacuaugc gcg auucacacuu B	1089
12798	903	krasM-903 GCl.Rz-5/10 stab1	a s g s cuu uGAU s g gcauGcacuaugc gcg auuaauuugu B	1090
12799	951	krasM-951 GCl.Rz-5/10 stab1	u s a s auc uGAU s g gcauGcacuaugc gcg auuuauguga B	1091
12800	1022	krasM-1022 GCl.Rz-5/10 stab1	a s a s gcc uGAU s g gcauGcacuaugc gcg auaaauuugu B	1092
12801	1034	krasM-1034 GCl.Rz-5/10 stab1	a s u s cau uGAU s g gcauGcacuaugc gcg aucaggaagc B	1093
12802	1037	krasM-1037 GCl.Rz-5/10 stab1	a s g s aau uGAU s g gcauGcacuaugc gcg aucaucagga B	1094
12803	1079	krasM-1079 GCl.Rz-5/10 stab1	a s c s auu uGAU s g gcauGcacuaugc gcg aucagggaug B	1095
12804	1083	krasM-1083 GCl.Rz-5/10 stab1	c s u s uua uGAU s g gcauGcacuaugc gcg auucaucagg B	1096
12805	1206	krasM-1206 GCl.Rz-5/10 stab1	g s u s uuc uGAU s g gcauGcacuaugc gcg auugccuugu B	1097
12806	1218	krasM-1218 GCl.Rz-5/10 stab1	g s g s ccu uGAU s g gcauGcacuaugc gcg auaauaguuu B	1098
12807	1267	krasM-1267 GCl.Rz-5/10 stab1	a s a s agc uGAU s g gcauGcacuaugc gcg auuaggaguc B	1099
12808	1301	krasM-1301 GCl.Rz-5/10 stab1	a s a s ucc uGAU s g gcauGcacuaugc gcg auucauacug B	1100
12809	1312	krasM-1312 GCl.Rz-5/10 stab1	g s u s ugc uGAU s g gcauGcacuaugc gcg auaauaaucc B	1101
12810	1529	krasM-1529 GCl.Rz-5/10 stab1	u s a s agc uGAU s g gcauGcacuaugc gcg auaacuggcc B	1102
12811	1594	krasM-1594 GCl.Rz-5/10 stab1	c s u s cuc uGAU s g gcauGcacuaugc gcg augaaagcuc B	1103
12812	1611	krasM-1611 GCl.Rz-5/10 stab1	c s a s guc uGAU s g gcauGcacuaugc gcg augcugugaa B	1104
12813	1650	krasM-1650 GCl.Rz-5/10 stab1	c s a s aug uGAU s g gcauGcacuaugc gcg aucguacaac B	1105
12814	1694	krasM-1694 GCl.Rz-5/10 stab1	u s g s agc uGAU s g gcauGcacuaugc gcg auccaaacug B	1106
12815	1867	krasM-1867 GCl.Rz-5/10 stab1	c s a s cuu uGAU s g gcauGcacuaugc gcg auuguuuaaa B	1107
12816	1936	krasM-1936 GCl.Rz-5/10 stab1	g s u s guu uGAU s g gcauGcacuaugc gcg augcaauguu B	1108
12817	1960	krasM-1960 GCl.Rz-5/10 stab1	u s u s aaa uGAU s g gcauGcacuaugc gcq auggaucaga B	1109
12818	2046	krasM-2046 GCl.Rz-5/10 stab1	c s a s ugc uGAU s g gcauGcacuaugc gcg aucucacuuc B	1110
12819	2051	krasM-2051 GCl.Rz-5/10 stab1	c s u s cac uGAU s g gcauGcacuaugc gcg augccaucuc B	1111
12820	2103	krasM-2103 GCl.Rz-5/10 stab1	a s c s acc uGAU s g gcauGcacuaugc gcg aucuagaacc B	1112
12821	2158	krasM-2158 GCl.Rz-5/10 stab1	u s u s uaa uGAU s g gcauGcacuaugc gcg augaagaaau B	1113
12822	2214	krasM-2214 GCl.Rz-5/10 stab1	u s g s gaa uGAU s g gcauGcacuaugc gcg auaaaucaca B	1114
12823	2227	krasM-2227 GCl.Rz-5/10 stab1	a s u s ccu uGAU s g gcauGcacuaugc gcg auguaaaugg B	1115
12824	2422	krasM-2422 GCl.Rz-5/10 stab1	a s a s cug uGAU s g gcauGcacuaugc gcg aucaagucau B	1116
12825	2454	krasM-2454 GCl.Rz-5/10 stab1	a s a s ucu uGAU s g gcauGcacuaugc gcg augguuaggg B	1117
12826	2476	krasM-2476 GCl.Rz-5/10 stab1	g s g s aga uGAU s g gcauGcacuaugc gcg auccacagca B	1118
12827	2484	krasM-2484 GCl.Rz-5/10 stab1	a s a s cuu uGAU s g gcauGcacuaugc gcg auggagauau B	1119
12828	2514	krasM-2514 GCl.Rz-5/10 stab1	u s a s ggg uGAU s g gcauGcacuaugc gcg auuucugaug B	1120
12829	2564	krasM-2564 GCl Rz-5/10 stab1	c s c s cuu uGAU s g gcauGcacuaugc gcg augguaucug B	1121
12830	2607	krasM-2607 GCl.Rz-5/10 stab1	c s a s aag uGAU s g gcauGcacuaugc gcg aucagccacc B	1122
12831	2669	krasM-2669 GCl.Rz-5/10 stab1	c s u s auu uGAU s g gcauGcacuaugc gcg auaccagggu B	1123
12832	2806	krasM-2806 GCl.Rz-5/10 stab1	c s a s uug uGAU s g gcauGcacuaugc gcg augaagauuu B	1124
12833	2830	krasM-2830 GCl.Rz-5/10 stab1	a s g s cuu uGAU s g gcauGcacuaugc gcg augaauuaaa B	1125
12834	2888	krasM-2888 GCl.Rz-5/10 stab1	c s a s cug uGAU s g gcauGcacuaugc gcg auuccagccu B	1126
12835	3095	krasM-3095 GCl.Rz-5/10 stab1	a s g s guu uGAU s g gcauGcacuaugc gcg augaggccaa B	1127
12836	3130	krasM-3130 GCl.Rz-5/10 stab1	a s u s aaa uGAU s g gcauGcacuaugc gcg auuugcugaa B	1128
12837	3152	krasM-3152 GCl.Rz-5/10 stab1	a s c s ugg uGAU s g gcauGcacuaugc gcg aucugguagg B	1129
12838	3180	krasM-3180 GCl.Rz-5/10 stab1	u s a s cca uGAU s g gcauGcacuaugc gcg auacccagug B	1130
12839	3182	krasM-3182 GCl.Rz-5/10 stab1	g s a s uac uGAU s g gcauGcacuaugc gcg auauacccag B	1131
12840	3204	krasM-3204 GCl.Rz-5/10 stab1	g s g s gau uGAU s g gcauGcacuaugc gcg augucucuug B	1132
12841	3264	krasM-3264 GCl.Rz-5/10 stab1	g s g s ucg uGAU s g gcauGcacuaugc gcg auaccaaagg B	1133
12842	3277	krasM-3277 GCl.Rz-5/10 stab1	c s g s ugu uGAU s g gcauGcacuaugc gcg aucucugggu B	1134
12843	3285	krasM-3285 GCl.Rz-5/10 stab1	a s u s acg uGAU s g gcauGcacuaugc gcg aucguguuau B	1135
12844	3335	krasM-3335 GCl.Rz-5/10 stab1	a s c s aau uGAU s g gcauGcacuaugc gcg auagagcugg B	1136
12845	3412	krasM-3412 GCl.Rz-5/10 stab1	a s a s guu uGAU s g gcauGcacuaugc gcg auuccuuuaa B	1137
12846	3444	krasM-3444 GCl.Rz-5/10 stab1	a s c s agu uGAU s g gcauGcacuaugc gcg augccaaaua B	1138
12847	3514	krasM-3514 GCl.Rz-5/10 stab1	u s u s aca uGAU s g gcauGcacuaugc gcg auuuggguca B	1139
12848	3521	krasM-3521 GCl.Rz-5/10 stab1	u s g s gaa uGAU s g gcauGcacuaugc gcg auuacacauu B	1140
12849	3540	krasM-3540 GCl.Rz-5/10 stab1	u s u s acu uGAU s g gcauGcacuaugc gcg augcagagaa B	1141
12850	3589	krasM-3589 GCl.Rz-5/10 stab1	c s u s guu uGAU s g gcauGcacuaugc gcg auuuguaccc B	1142
12851	3662	krasM-3662 GCl.Rz-5/10 stab1	u s u s uca uGAU s g gcauGcacuaugc gcg auagcaauuc B	1143
12852	3746	krasM-3746 GCl.Rz-5/10 stab1	a s u s ggc uGAU s g gcauGcacuaugc gcg auuucuuucu B	1144
12853	3752	krasM-3752 GCl.Rz-5/10 stab1	u s g s aag uGAU s g gcauGcacuaugc gcg auggccauuu B	1145
12854	3813	krasM-3813 GCl.Rz-5/10 stab1	a s u s gcc uGAU s g gcauGcacuaugc gcg aucuacauca B	1146
12855	3849	krasM-3849 GCl.Rz-5/10 stab1	g s u s uca uGAU s g gcauGcacuaugc gcg auaaagguaa B	1147
12856	3862	krasM-3862 GCl.Rz-5/10 stab1	u s a s aac uGAU s g gcauGcacuaugc gcg auucaaaguu B	1148
12857	4012	krasM-4012 GCl.Rz-5/10 stab1	a s c s aaa uGAU s g gcauGcacuaugc gcg auguuaaugc B	1149
12858	4026	krasM-4026 GCl.Rz-5/10 stab1	u s g s cua uGAU s g gcauGcacuaugc gcg auucuuccac B	1150
12859	4028	krasM-4028 GCl.Rz-5/10 stab1	u s c s ugc uGAU s g gcauGcacuaugc gcg auauucuucc B	1151
12860	4039	krasM-4039 GCl.Rz-5/10 stab1	u s a s caa uGAU s g gcauGcacuaugc gcg auacgucugc B	1152
12861	4059	krasM-4059 GCl.Rz-5/10 stab1	g s g s gaa uGAU s g gcauGcacuaugc gcg auucacucaa B	1153
12862	4107	krasM-4107 GCl.Rz-5/10 stab1	a s u s ucc uGAU s g gcauGcacuaugc gcg augcagugug B	1154
12863	4458	krasM-4458 GCl.Rz-5/10 stab1	c s a s ugc uGAU s g gcauGcacuaugc gcg auccaguauu B	1155
12864	4463	krasM-4463 GCl.Rz-5/10 stab1	g s a s auu uGAU s g gcauGcacuaugc gcg augcuaucca B	1156
12865	4487	krasM-4487 GCl.Rz-5/10 stab1	a s c s agc uGAU s g gcauGcacuaugc gcg auucaguuuc B	1157
12866	4606	krasM-4606 GCl.Rz-5/10 stab1	a s u s cau uGAU s g gcauGcacuaugc gcg aucccaaaca B	1158
12867	4609	krasM-4609 GCl.Rz-5/10 stab1	c s c s uau uGAU s g gcauGcacuaugc gcg auuaucccaa B	1159
12868	4659	krasM-4659 GCl.Rz-5/10 stab1	c s u s caa uGAU s g gcauGcacuaugc gcg auaacugcag B	1160
12869	4875	krasM-4875 GCl.Rz-5/10 stab1	a s u s gug uGAU s g gcauGcacuaugc gcg auguuucagu B	1161
12870	4912	krasM-4912 GCl.Rz-5/10 stab1	c s u s gca uGAU s g gcauGcacuaugc gcg augacccaca B	1162
12871	4914	krasM-4914 GCl.Rz-5/10 stab1	c s a s cug uGAU s g gcauGcacuaugc gcg auaugaccca B	1163
12872	4964	krasM-4964 GCl.Rz-5/10 stab1	a s c s caa uGAU s g gcauGcacuaugc gcg auuccuaggu B	1164
12873	4973	krasM-4973 GCl.Rz-5/10 stab1	u s u s uga uGAU s g gcauGcacuaugc gcg augaccaaca B	1165
12874	5035	krasM-5035 GCl.Rz-5/10 stab1	c s a s gca uGAU s g gcauGcacuaugc gcg auacuccuau B	1166
Lower Case = 2′-O-methyl
Upper Case = Ribo
s = phosphorothioate linkage
B = inverted deoxyabasic

1208 1 16 RNA Homo sapiens 1ggcggcggcc gcggcg 16 2 16 RNA Homo sapiens 2uggcggcggc gaaggu 16 3 16 RNA Homo sapiens 3cccggccccc gccauu 16 4 16 RNA Homo sapiens 4gacugggagc gagcgc 16 5 16 RNA Homo sapiens 5gggagcgagc gcggcg 16 6 16 RNA Homo sapiens 6cgagcgcggc gcaggc 16 7 16 RNA Homo sapiens 7cgcaggcacu gaaggc 16 8 16 RNA Homo sapiens 8gcucccaggu gcggga 16 9 16 RNA Homo sapiens 9agagaggccu gcugaa 16 10 16 RNA Homo sapiens 10gaggccugcu gaaaau 16 11 16 RNA Homo sapiens 11ugcugaaaau gacuga 16 12 16 RNA Homo sapiens 12gaaaaugacu gaauau 16 13 16 RNA Homo sapiens 13augacugaau auaaac 16 14 16 RNA Homo sapiens 14gacugaauau aaacuu 16 15 16 RNA Homo sapiens 15auauaaacuu guggua 16 16 16 RNA Homo sapiens 16guuggagcuu guggcg 16 17 16 RNA Homo sapiens 17aggcaagagu gccuug 16 18 16 RNA Homo sapiens 18agagugccuu gacgau 16 19 16 RNA Homo sapiens 19gugccuugac gauaca 16 20 16 RNA Homo sapiens 20ccuugacgau acagcu 16 21 16 RNA Homo sapiens 21gaaucauuuu guggac 16 22 16 RNA Homo sapiens 22uuuuguggac gaauau 16 23 16 RNA Homo sapiens 23guggacgaau augauc 16 24 16 RNA Homo sapiens 24ggacgaauau gaucca 16 25 16 RNA Homo sapiens 25auccaacaau agagga 16 26 16 RNA Homo sapiens 26aguaguaauu gaugga 16 27 16 RNA Homo sapiens 27aguaauugau ggagaa 16 28 16 RNA Homo sapiens 28ggagaaaccu gucucu 16 29 16 RNA Homo sapiens 29ucucuuggau auucuc 16 30 16 RNA Homo sapiens 30ggauauucuc gacaca 16 31 16 RNA Homo sapiens 31ggaguacagu gcaaug 16 32 16 RNA Homo sapiens 32acagugcaau gaggga 16 33 16 RNA Homo sapiens 33accaguacau gaggac 16 34 16 RNA Homo sapiens 34ggcuuucuuu guguau 16 35 16 RNA Homo sapiens 35cuuucuuugu guauuu 16 36 16 RNA Homo sapiens 36uuguguauuu gccaua 16 37 16 RNA Homo sapiens 37uauuugccau aaauaa 16 38 16 RNA Homo sapiens 38ugccauaaau aauacu 16 39 16 RNA Homo sapiens 39cauaaauaau acuaaa 16 40 16 RNA Homo sapiens 40uaaaucauuu gaagau 16 41 16 RNA Homo sapiens 41auuugaagau auucac 16 42 16 RNA Homo sapiens 42ucaccauuau agagaa 16 43 16 RNA Homo sapiens 43uaaggacucu gaagau 16 44 16 RNA Homo sapiens 44cucugaagau guaccu 16 45 16 RNA Homo sapiens 45auguaccuau gguccu 16 46 16 RNA Homo sapiens 46aguaggaaau aaaugu 16 47 16 RNA Homo sapiens 47ggaaauaaau gugauu 16 48 16 RNA Homo sapiens 48aaauaaaugu gauuug 16 49 16 RNA Homo sapiens 49aaugugauuu gccuuc 16 50 16 RNA Homo sapiens 50aagaaguuau ggaauu 16 51 16 RNA Homo sapiens 51uccuuuuauu gaaaca 16 52 16 RNA Homo sapiens 52aagacagggu guugau 16 53 16 RNA Homo sapiens 53acaggguguu gaugau 16 54 16 RNA Homo sapiens 54ggguguugau gaugcc 16 55 16 RNA Homo sapiens 55uguugaugau gccuuc 16 56 16 RNA Homo sapiens 56ugccuucuau acauua 16 57 16 RNA Homo sapiens 57acauuaguuc gagaaa 16 58 16 RNA Homo sapiens 58cgagaaauuc gaaaac 16 59 16 RNA Homo sapiens 59ucgaaaacau aaagaa 16 60 16 RNA Homo sapiens 60aagaaaagau gagcaa 16 61 16 RNA Homo sapiens 61gagcaaagau gguaaa 16 62 16 RNA Homo sapiens 62aagacaaagu guguaa 16 63 16 RNA Homo sapiens 63gacaaagugu guaauu 16 64 16 RNA Homo sapiens 64guguaauuau guaaau 16 65 16 RNA Homo sapiens 65uuauguaaau acaauu 16 66 16 RNA Homo sapiens 66aauacaauuu guacuu 16 67 16 RNA Homo sapiens 67cuuaaggcau acuagu 16 68 16 RNA Homo sapiens 68gguaauuuuu guacau 16 69 16 RNA Homo sapiens 69auuagcauuu guuuua 16 70 16 RNA Homo sapiens 70uuuuuuuccu gcucca 16 71 16 RNA Homo sapiens 71ccugcuccau gcagac 16 72 16 RNA Homo sapiens 72caugcagacu guuagc 16 73 16 RNA Homo sapiens 73uaccuuaaau gcuuau 16 74 16 RNA Homo sapiens 74auuuuaaaau gacagu 16 75 16 RNA Homo sapiens 75uuuuuuccuc gaagug 16 76 16 RNA Homo sapiens 76uccucgaagu gccagu 16 77 16 RNA Homo sapiens 77uuugguuuuu gaacua 16 78 16 RNA Homo sapiens 78aacuagcaau gccugu 16 79 16 RNA Homo sapiens 79agcaaugccu gugaaa 16 80 16 RNA Homo sapiens 80caaugccugu gaaaaa 16 81 16 RNA Homo sapiens 81aaaagaaacu gaauac 16 82 16 RNA Homo sapiens 82gaaacugaau accuaa 16 83 16 RNA Homo sapiens 83uaagauuucu gucuug 16 84 16 RNA Homo sapiens 84gguuuuuggu gcaugc 16 85 16 RNA Homo sapiens 85uuuggugcau gcaguu 16 86 16 RNA Homo sapiens 86gcaugcaguu gauuac 16 87 16 RNA Homo sapiens 87cuuaccaagu gugaau 16 88 16 RNA Homo sapiens 88uaccaagugu gaaugu 16 89 16 RNA Homo sapiens 89aagugugaau guuggu 16 90 16 RNA Homo sapiens 90gaauguuggu gugaaa 16 91 16 RNA Homo sapiens 91auguuggugu gaaaca 16 92 16 RNA Homo sapiens 92acaaauuaau gaagcu 16 93 16 RNA Homo sapiens 93ugaagcuuuu gaauca 16 94 16 RNA Homo sapiens 94ucccuauucu guguuu 16 95 16 RNA Homo sapiens 95ccuauucugu guuuua 16 96 16 RNA Homo sapiens 96cuagucacau aaaugg 16 97 16 RNA Homo sapiens 97ucacauaaau ggauua 16 98 16 RNA Homo sapiens 98aauuucaguu gagacc 16 99 16 RNA Homo sapiens 99gguuuuuacu gaaaca 16 100 16 RNA Homo sapiens 100cugaaacauu gaggga 16 101 16 RNA Homo sapiens 101acaaauuuau gggcuu 16 102 16 RNA Homo sapiens 102ugggcuuccu gaugau 16 103 16 RNA Homo sapiens 103gcuuccugau gaugau 16 104 16 RNA Homo sapiens 104uccugaugau gauucu 16 105 16 RNA Homo sapiens 105uaggcaucau guccua 16 106 16 RNA Homo sapiens 106cauguccuau aguuug 16 107 16 RNA Homo sapiens 107ccuauaguuu gucauc 16 108 16 RNA Homo sapiens 108ugucaucccu gaugaa 16 109 16 RNA Homo sapiens 109caucccugau gaaugu 16 110 16 RNA Homo sapiens 110ccugaugaau guaaag 16 111 16 RNA Homo sapiens 111aaguuacacu guucac 16 112 16 RNA Homo sapiens 112caaagguuuu gucucc 16 113 16 RNA Homo sapiens 113ccuuuccacu gcuauu 16 114 16 RNA Homo sapiens 114uauuagucau ggucac 16 115 16 RNA Homo sapiens 115uccccaaaau auuaua 16 116 16 RNA Homo sapiens 116aaaauauuau auuuuu 16 117 16 RNA Homo sapiens 117uuuuuucuau aaaaag 16 118 16 RNA Homo sapiens 118agaaaaaaau ggaaaa 16 119 16 RNA Homo sapiens 119acaaggcaau ggaaac 16 120 16 RNA Homo sapiens 120aaacuauuau aaggcc 16 121 16 RNA Homo sapiens 121cacauuagau aaauua 16 122 16 RNA Homo sapiens 122aaauuacuau aaagac 16 123 16 RNA Homo sapiens 123gacuccuaau agcuuu 16 124 16 RNA Homo sapiens 124gcuuuuuccu guuaag 16 125 16 RNA Homo sapiens 125gacccaguau gaaugg 16 126 16 RNA Homo sapiens 126caguaugaau gggauu 16 127 16 RNA Homo sapiens 127ggauuauuau agcaac 16 128 16 RNA Homo sapiens 128uuggggcuau auuuac 16 129 16 RNA Homo sapiens 129auauuuacau gcuacu 16 130 16 RNA Homo sapiens 130aaauuuuuau aauaau 16 131 16 RNA Homo sapiens 131uuuuuauaau aauuga 16 132 16 RNA Homo sapiens 132uauaauaauu gaaaag 16 133 16 RNA Homo sapiens 133uaacaaguau aaaaaa 16 134 16 RNA Homo sapiens 134aaauucucau aggaau 16 135 16 RNA Homo sapiens 135ggaauuaaau guaguc 16 136 16 RNA Homo sapiens 136uagucucccu guguca 16 137 16 RNA Homo sapiens 137gucucccugu gucaga 16 138 16 RNA Homo sapiens 138gugucagacu gcucuu 16 139 16 RNA Homo sapiens 139gcucuuucau aguaua 16 140 16 RNA Homo sapiens 140uucauaguau aacuuu 16 141 16 RNA Homo sapiens 141ucuucaacuu gagucu 16 142 16 RNA Homo sapiens 142uugagucuuu gaagau 16 143 16 RNA Homo sapiens 143cuuugaagau aguuuu 16 144 16 RNA Homo sapiens 144uuuuaauucu gcuugu 16 145 16 RNA Homo sapiens 145aauucugcuu gugaca 16 146 16 RNA Homo sapiens 146uucugcuugu gacauu 16 147 16 RNA Homo sapiens 147ggccaguuau agcuua 16 148 16 RNA Homo sapiens 148cuuauuaggu guugaa 16 149 16 RNA Homo sapiens 149auuagguguu gaagag 16 150 16 RNA Homo sapiens 150gaccaagguu gcaagc 16 151 16 RNA Homo sapiens 151gccaggcccu guguga 16 152 16 RNA Homo sapiens 152caggcccugu gugaac 16 153 16 RNA Homo sapiens 153ggcccugugu gaaccu 16 154 16 RNA Homo sapiens 154ugugaaccuu gagcuu 16 155 16 RNA Homo sapiens 155gagcuuucau agagag 16 156 16 RNA Homo sapiens 156uucacagcau ggacug 16 157 16 RNA Homo sapiens 157agcauggacu gugugc 16 158 16 RNA Homo sapiens 158cauggacugu gugccc 16 159 16 RNA Homo sapiens 159uggacugugu gcccca 16 160 16 RNA Homo sapiens 160acggucaucc gagugg 16 161 16 RNA Homo sapiens 161ccgagugguu guacga 16 162 16 RNA Homo sapiens 162gugguuguac gaugca 16 163 16 RNA Homo sapiens 163guuguacgau gcauug 16 164 16 RNA Homo sapiens 164agucaaaaau ggggag 16 165 16 RNA Homo sapiens 165caguuuggau agcuca 16 166 16 RNA Homo sapiens 166ucaacaagau acaauc 16 167 16 RNA Homo sapiens 167aucucacucu guggug 16 168 16 RNA Homo sapiens 168uggugguccu gcugac 16 169 16 RNA Homo sapiens 169ugguccugcu gacaaa 16 170 16 RNA Homo sapiens 170caagagcauu gcuuuu 16 171 16 RNA Homo sapiens 171cauugcuuuu guuucu 16 172 16 RNA Homo sapiens 172acuuuuaaau auuaac 16 173 16 RNA Homo sapiens 173cucaaaaguu gagauu 16 174 16 RNA Homo sapiens 174gggugguggu gugcca 16 175 16 RNA Homo sapiens 175gugguggugu gccaag 16 176 16 RNA Homo sapiens 176uuuaaacaau gaagug 16 177 16 RNA Homo sapiens 177acaaugaagu gaaaaa 16 178 16 RNA Homo sapiens 178aauuaacauu gcauaa 16 179 16 RNA Homo sapiens 179aacauugcau aaacac 16 180 16 RNA Homo sapiens 180uuucaagucu gaucca 16 181 16 RNA Homo sapiens 181ucugauccau auuuaa 16 182 16 RNA Homo sapiens 182cauauuuaau aaugcu 16 183 16 RNA Homo sapiens 183auuuaauaau gcuuua 16 184 16 RNA Homo sapiens 184gcuuuaaaau aaaaau 16 185 16 RNA Homo sapiens 185aaauaaaaau aaaaac 16 186 16 RNA Homo sapiens 186caauccuuuu gauaaa 16 187 16 RNA Homo sapiens 187uccuuuugau aaauuu 16 188 16 RNA Homo sapiens 188aauuuaaaau guuacu 16 189 16 RNA Homo sapiens 189auuuuaaaau aaauga 16 190 16 RNA Homo sapiens 190uaaaauaaau gaagug 16 191 16 RNA Homo sapiens 191uaaaugaagu gagaug 16 192 16 RNA Homo sapiens 192gaagugagau ggcaug 16 193 16 RNA Homo sapiens 193gagauggcau ggugag 16 194 16 RNA Homo sapiens 194auggcauggu gaggug 16 195 16 RNA Homo sapiens 195auggugaggu gaaagu 16 196 16 RNA Homo sapiens 196ggacuagguu guuggu 16 197 16 RNA Homo sapiens 197gguuguuggu gacuua 16 198 16 RNA Homo sapiens 198gguucuagau aggugu 16 199 16 RNA Homo sapiens 199cuagauaggu gucuuu 16 200 16 RNA Homo sapiens 200uuaggacucu gauuuu 16 201 16 RNA Homo sapiens 201cucugauuuu gaggac 16 202 16 RNA Homo sapiens 202auuucuucau guuaaa 16 203 16 RNA Homo sapiens 203uuuacacuau gugauu 16 204 16 RNA Homo sapiens 204uacacuaugu gauuua 16 205 16 RNA Homo sapiens 205ugugauuuau auucca 16 206 16 RNA Homo sapiens 206ccauuuacau aaggau 16 207 16 RNA Homo sapiens 207acauaaggau acacuu 16 208 16 RNA Homo sapiens 208acacuuauuu gucaag 16 209 16 RNA Homo sapiens 209agcacaaucu guaaau 16 210 16 RNA Homo sapiens 210uuuaaccuau guuaca 16 211 16 RNA Homo sapiens 211caucuucagu gccagu 16 212 16 RNA Homo sapiens 212gggcaaaauu gugcaa 16 213 16 RNA Homo sapiens 213gcaaaauugu gcaaga 16 214 16 RNA Homo sapiens 214ugcaagaggu gaaguu 16 215 16 RNA Homo sapiens 215ugaaguuuau auuuga 16 216 16 RNA Homo sapiens 216guuuauauuu gaauau 16 217 16 RNA Homo sapiens 217auauuugaau auccau 16 218 16 RNA Homo sapiens 218cuucuuccau auuagu 16 219 16 RNA Homo sapiens 219ccauauuagu gucauc 16 220 16 RNA Homo sapiens 220gugucaucuu gccucc 16 221 16 RNA Homo sapiens 221ccuuccacau gcccca 16 222 16 RNA Homo sapiens 222caugccccau gacuug 16 223 16 RNA Homo sapiens 223cccaugacuu gaugca 16 224 16 RNA Homo sapiens 224augacuugau gcaguu 16 225 16 RNA Homo sapiens 225caguuuuaau acuugu 16 226 16 RNA Homo sapiens 226uuuaauacuu guaauu 16 227 16 RNA Homo sapiens 227cccuaaccau aagauu 16 228 16 RNA Homo sapiens 228aagauuuacu gcugcu 16 229 16 RNA Homo sapiens 229auuuacugcu gcugug 16 230 16 RNA Homo sapiens 230uacugcugcu guggau 16 231 16 RNA Homo sapiens 231ugcuguggau aucucc 16 232 16 RNA Homo sapiens 232auaucuccau gaaguu 16 233 16 RNA Homo sapiens 233uuuucccacu gaguca 16 234 16 RNA Homo sapiens 234caucagaaau gcccua 16 235 16 RNA Homo sapiens 235aagagaaucu gacaga 16 236 16 RNA Homo sapiens 236ucugacagau accaua 16 237 16 RNA Homo sapiens 237cagauaccau aaaggg 16 238 16 RNA Homo sapiens 238aaagggauuu gaccua 16 239 16 RNA Homo sapiens 239ggugguggcu gaugcu 16 240 16 RNA Homo sapiens 240gguggcugau gcuuug 16 241 16 RNA Homo sapiens 241cugaugcuuu gaacau 16 242 16 RNA Homo sapiens 242acaucucuuu gcugcc 16 243 16 RNA Homo sapiens 243ucucuuugcu gcccaa 16 244 16 RNA Homo sapiens 244auccauuagc gacagu 16 245 16 RNA Homo sapiens 245acccugguau gaauag 16 246 16 RNA Homo sapiens 246ugguaugaau agacag 16 247 16 RNA Homo sapiens 247agaauuuaau aaagau 16 248 16 RNA Homo sapiens 248uaauaaagau agugca 16 249 16 RNA Homo sapiens 249uaaagauagu gcagaa 16 250 16 RNA Homo sapiens 250gguaaucuau aacuag 16 251 16 RNA Homo sapiens 251uaacaguaau acauuc 16 252 16 RNA Homo sapiens 252acauuccauu guuuua 16 253 16 RNA Homo sapiens 253aaaucuucau gcaaug 16 254 16 RNA Homo sapiens 254uucaugcaau gaaaaa 16 255 16 RNA Homo sapiens 255aaugaaaaau acuuua 16 256 16 RNA Homo sapiens 256uuuaauucau gaagcu 16 257 16 RNA Homo sapiens 257uuuuuuuggu gucaga 16 258 16 RNA Homo sapiens 258ucagagucuc gcucuu 16 259 16 RNA Homo sapiens 259ucucgcucuu gucacc 16 260 16 RNA Homo sapiens 260aggcuggaau gcagug 16 261 16 RNA Homo sapiens 261augcaguggc gccauc 16 262 16 RNA Homo sapiens 262ucagcucacu gcaacc 16 263 16 RNA Homo sapiens 263agguucaagc gauucu 16 264 16 RNA Homo sapiens 264cgauucucgu gccucg 16 265 16 RNA Homo sapiens 265ucggccuccu gaguag 16 266 16 RNA Homo sapiens 266uuacaggcgu gugcac 16 267 16 RNA Homo sapiens 267acaggcgugu gcacua 16 268 16 RNA Homo sapiens 268acuaauuuuu guauuu 16 269 16 RNA Homo sapiens 269gguuucaccu guuggc 16 270 16 RNA Homo sapiens 270ggcuggucuc gaacuc 16 271 16 RNA Homo sapiens 271ucgaacuccu gaccuc 16 272 16 RNA Homo sapiens 272gaccucaagu gauuca 16 273 16 RNA Homo sapiens 273uuggccucau aaaccu 16 274 16 RNA Homo sapiens 274ucauaaaccu guuuug 16 275 16 RNA Homo sapiens 275aaccuguuuu gcagaa 16 276 16 RNA Homo sapiens 276uucagcaaau auuuau 16 277 16 RNA Homo sapiens 277aauauuuauu gagugc 16 278 16 RNA Homo sapiens 278uuuauugagu gccuac 16 279 16 RNA Homo sapiens 279ccuaccagau gccagu 16 280 16 RNA Homo sapiens 280gccagucacc gcacaa 16 281 16 RNA Homo sapiens 281cacuggguau auggua 16 282 16 RNA Homo sapiens 282cuggguauau gguauc 16 283 16 RNA Homo sapiens 283caagagacau aauccc 16 284 16 RNA Homo sapiens 284cuuagguacu gcuagu 16 285 16 RNA Homo sapiens 285uacugcuagu gugguc 16 286 16 RNA Homo sapiens 286aguguggucu guaaua 16 287 16 RNA Homo sapiens 287ggucuguaau aucuua 16 288 16 RNA Homo sapiens 288ccuuugguau acgacc 16 289 16 RNA Homo sapiens 289uuugguauac gaccca 16 290 16 RNA Homo sapiens 290acccagagau aacacg 16 291 16 RNA Homo sapiens 291gagauaacac gaugcg 16 292 16 RNA Homo sapiens 292auaacacgau gcguau 16 293 16 RNA Homo sapiens 293uuuuaguuuu gcaaag 16 294 16 RNA Homo sapiens 294uuuggucucu gugcca 16 295 16 RNA Homo sapiens 295uggucucugu gccagc 16 296 16 RNA Homo sapiens 296ccagcucuau aauugu 16 297 16 RNA Homo sapiens 297cucuauaauu guuuug 16 298 16 RNA Homo sapiens 298uaauuguuuu gcuacg 16 299 16 RNA Homo sapiens 299guuuugcuac gauucc 16 300 16 RNA Homo sapiens 300cgauuccacu gaaacu 16 301 16 RNA Homo sapiens 301gaaacucuuc gaucaa 16 302 16 RNA Homo sapiens 302gcuacuuuau guaaau 16 303 16 RNA Homo sapiens 303ucacuucauu guuuua 16 304 16 RNA Homo sapiens 304uuaaaggaau aaacuu 16 305 16 RNA Homo sapiens 305gaauaaacuu gauuau 16 306 16 RNA Homo sapiens 306acuugauuau auuguu 16 307 16 RNA Homo sapiens 307ugauuauauu guuuuu 16 308 16 RNA Homo sapiens 308uauuuggcau aacugu 16 309 16 RNA Homo sapiens 309uggcauaacu gugauu 16 310 16 RNA Homo sapiens 310gcauaacugu gauucu 16 311 16 RNA Homo sapiens 311gacaauuacu guacac 16 312 16 RNA Homo sapiens 312acauuaaggu guaugu 16 313 16 RNA Homo sapiens 313uaagguguau gucaga 16 314 16 RNA Homo sapiens 314uaugucagau auucau 16 315 16 RNA Homo sapiens 315agauauucau auugac 16 316 16 RNA Homo sapiens 316uauucauauu gaccca 16 317 16 RNA Homo sapiens 317ugacccaaau guguaa 16 318 16 RNA Homo sapiens 318acccaaaugu guaaua 16 319 16 RNA Homo sapiens 319aauguguaau auucca 16 320 16 RNA Homo sapiens 320aguuuucucu gcauaa 16 321 16 RNA Homo sapiens 321uucucugcau aaguaa 16 322 16 RNA Homo sapiens 322uaauuaaaau auacuu 16 323 16 RNA Homo sapiens 323auuaaaauau acuuaa 16 324 16 RNA Homo sapiens 324aaaaauuaau aguuuu 16 325 16 RNA Homo sapiens 325ggguacaaau aaacag 16 326 16 RNA Homo sapiens 326aauaaacagu gccuga 16 327 16 RNA Homo sapiens 327aacagugccu gaacua 16 328 16 RNA Homo sapiens 328aaacuucuau guaaaa 16 329 16 RNA Homo sapiens 329aaaucacuau gauuuc 16 330 16 RNA Homo sapiens 330uaugauuucu gaauug 16 331 16 RNA Homo sapiens 331uuucugaauu gcuaug 16 332 16 RNA Homo sapiens 332gaauugcuau gugaaa 16 333 16 RNA Homo sapiens 333auugcuaugu gaaacu 16 334 16 RNA Homo sapiens 334uuggaacacu guuuag 16 335 16 RNA Homo sapiens 335uagguagggu guuaag 16 336 16 RNA Homo sapiens 336guuaagacuu gacaca 16 337 16 RNA Homo sapiens 337agaaagaaau ggccau 16 338 16 RNA Homo sapiens 338aaauggccau acuuca 16 339 16 RNA Homo sapiens 339uucaggaacu gcagug 16 340 16 RNA Homo sapiens 340gaacugcagu gcuuau 16 341 16 RNA Homo sapiens 341cagugcuuau gagggg 16 342 16 RNA Homo sapiens 342augaggggau auuuag 16 343 16 RNA Homo sapiens 343uaggccucuu gaauuu 16 344 16 RNA Homo sapiens 344uugaauuuuu gaugua 16 345 16 RNA Homo sapiens 345aauuuuugau guagau 16 346 16 RNA Homo sapiens 346ugauguagau gggcau 16 347 16 RNA Homo sapiens 347uuaccuuuau gugaac 16 348 16 RNA Homo sapiens 348accuuuaugu gaacuu 16 349 16 RNA Homo sapiens 349ugugaacuuu gaaugg 16 350 16 RNA Homo sapiens 350aacuuugaau gguuua 16 351 16 RNA Homo sapiens 351caaaagauuu guuuuu 16 352 16 RNA Homo sapiens 352auuuguuuuu guagag 16 353 16 RNA Homo sapiens 353uucuagaaau aaaugu 16 354 16 RNA Homo sapiens 354agaaauaaau guuacc 16 355 16 RNA Homo sapiens 355aaaaauccuu guugaa 16 356 16 RNA Homo sapiens 356aauccuuguu gaaguu 16 357 16 RNA Homo sapiens 357uaaauuacau agacuu 16 358 16 RNA Homo sapiens 358gcauuaacau guuugu 16 359 16 RNA Homo sapiens 359uaacauguuu guggaa 16 360 16 RNA Homo sapiens 360guggaagaau auagca 16 361 16 RNA Homo sapiens 361ggaagaauau agcaga 16 362 16 RNA Homo sapiens 362gcagacguau auugua 16 363 16 RNA Homo sapiens 363gacguauauu guauca 16 364 16 RNA Homo sapiens 364uguaucauuu gaguga 16 365 16 RNA Homo sapiens 365ucauuugagu gaaugu 16 366 16 RNA Homo sapiens 366uugagugaau guuccc 16 367 16 RNA Homo sapiens 367cuauuuaacu gaguca 16 368 16 RNA Homo sapiens 368gagucacacu gcauag 16 369 16 RNA Homo sapiens 369cacacugcau aggaau 16 370 16 RNA Homo sapiens 370uaacuuuuau agguua 16 371 16 RNA Homo sapiens 371uaucaaaacu guuguc 16 372 16 RNA Homo sapiens 372caaaacuguu gucacc 16 373 16 RNA Homo sapiens 373ugucaccauu gcacaa 16 374 16 RNA Homo sapiens 374gcacaauuuu guccua 16 375 16 RNA Homo sapiens 375uuguccuaau auauac 16 376 16 RNA Homo sapiens 376guccuaauau auacau 16 377 16 RNA Homo sapiens 377ccuaauauau acauag 16 378 16 RNA Homo sapiens 378auauauacau agaaac 16 379 16 RNA Homo sapiens 379uagaaacuuu gugggg 16 380 16 RNA Homo sapiens 380uguggggcau guuaag 16 381 16 RNA Homo sapiens 381guuacaguuu gcacaa 16 382 16 RNA Homo sapiens 382caucucauuu guauuc 16 383 16 RNA Homo sapiens 383guauuccauu gauuuu 16 384 16 RNA Homo sapiens 384aaaacaguau auauaa 16 385 16 RNA Homo sapiens 385aacaguauau auaacu 16 386 16 RNA Homo sapiens 386caguauauau aacuuu 16 387 16 RNA Homo sapiens 387aaaacuaucu gaagau 16 388 16 RNA Homo sapiens 388auuuccauuu gucaaa 16 389 16 RNA Homo sapiens 389aaaaaguaau gauuuc 16 390 16 RNA Homo sapiens 390augauuucuu gauaau 16 391 16 RNA Homo sapiens 391auuucuugau aauugu 16 392 16 RNA Homo sapiens 392cuugauaauu guguag 16 393 16 RNA Homo sapiens 393ugauaauugu guagug 16 394 16 RNA Homo sapiens 394auuguguagu gaaugu 16 395 16 RNA Homo sapiens 395uguagugaau guuuuu 16 396 16 RNA Homo sapiens 396caguuaccuu gaaagc 16 397 16 RNA Homo sapiens 397cuugaaagcu gaauuu 16 398 16 RNA Homo sapiens 398cugaauuuau auuuag 16 399 16 RNA Homo sapiens 399aguaacuucu guguua 16 400 16 RNA Homo sapiens 400uaacuucugu guuaau 16 401 16 RNA Homo sapiens 401cuguguuaau acugga 16 402 16 RNA Homo sapiens 402aauacuggau agcaug 16 403 16 RNA Homo sapiens 403uggauagcau gaauuc 16 404 16 RNA Homo sapiens 404caugaauucu gcauug 16 405 16 RNA Homo sapiens 405auucugcauu gagaaa 16 406 16 RNA Homo sapiens 406uugagaaacu gaauag 16 407 16 RNA Homo sapiens 407gaaacugaau agcugu 16 408 16 RNA Homo sapiens 408cugaauagcu gucaua 16 409 16 RNA Homo sapiens 409uagcugucau aaaaug 16 410 16 RNA Homo sapiens 410gucauaaaau gcuuuc 16 411 16 RNA Homo sapiens 411aaagaaagau acucac 16 412 16 RNA Homo sapiens 412auacucacau gaguuc 16 413 16 RNA Homo sapiens 413augaguucuu gaagaa 16 414 16 RNA Homo sapiens 414cuugaagaau agucau 16 415 16 RNA Homo sapiens 415gaauagucau aacuag 16 416 16 RNA Homo sapiens 416auuaagaucu guguuu 16 417 16 RNA Homo sapiens 417uaagaucugu guuuua 16 418 16 RNA Homo sapiens 418uuaguuuaau aguuug 16 419 16 RNA Homo sapiens 419uuaauaguuu gaagug 16 420 16 RNA Homo sapiens 420aguuugaagu gccugu 16 421 16 RNA Homo sapiens 421ugaagugccu guuugg 16 422 16 RNA Homo sapiens 422uguuugggau aaugau 16 423 16 RNA Homo sapiens 423uugggauaau gauagg 16 424 16 RNA Homo sapiens 424ggauaaugau agguaa 16 425 16 RNA Homo sapiens 425uaauuuagau gaauuu 16 426 16 RNA Homo sapiens 426aaaguuaucu gcaguu 16 427 16 RNA Homo sapiens 427cugcaguuau guugag 16 428 16 RNA Homo sapiens 428caguuauguu gagggc 16 429 16 RNA Homo sapiens 429ggguuacagu guuuua 16 430 16 RNA Homo sapiens 430uguuuuaucc gaaagu 16 431 16 RNA Homo sapiens 431caauuccacu gucuug 16 432 16 RNA Homo sapiens 432ccacugucuu guguuu 16 433 16 RNA Homo sapiens 433acugucuugu guuuuc 16 434 16 RNA Homo sapiens 434guguuuucau guugaa 16 435 16 RNA Homo sapiens 435uuuucauguu gaaaau 16 436 16 RNA Homo sapiens 436uguugaaaau acuuuu 16 437 16 RNA Homo sapiens 437aaauacuuuu gcauuu 16 438 16 RNA Homo sapiens 438uuuuuccuuu gagugc 16 439 16 RNA Homo sapiens 439uccuuugagu gccaau 16 440 16 RNA Homo sapiens 440auuucuuaau guaaca 16 441 16 RNA Homo sapiens 441aauguaacau guuuac 16 442 16 RNA Homo sapiens 442uaccuggccu gucuuu 16 443 16 RNA Homo sapiens 443aacuauuuuu guauag 16 444 16 RNA Homo sapiens 444auuuuuguau agugua 16 445 16 RNA Homo sapiens 445uuuguauagu guaaac 16 446 16 RNA Homo sapiens 446aguguaaacu gaaaca 16 447 16 RNA Homo sapiens 447acugaaacau gcacau 16 448 16 RNA Homo sapiens 448ugcacauuuu guacau 16 449 16 RNA Homo sapiens 449uuuguacauu gugcuu 16 450 16 RNA Homo sapiens 450uguacauugu gcuuuc 16 451 16 RNA Homo sapiens 451gcuuucuuuu gugggu 16 452 16 RNA Homo sapiens 452ugugggucau augcag 16 453 16 RNA Homo sapiens 453ugggucauau gcagug 16 454 16 RNA Homo sapiens 454cauaugcagu gugauc 16 455 16 RNA Homo sapiens 455uaugcagugu gaucca 16 456 16 RNA Homo sapiens 456ugauccaguu guuuuc 16 457 16 RNA Homo sapiens 457ucauuugguu gcgcug 16 458 16 RNA Homo sapiens 458auuugguugc gcugac 16 459 16 RNA Homo sapiens 459ugguugcgcu gaccua 16 460 16 RNA Homo sapiens 460accuaggaau guuggu 16 461 16 RNA Homo sapiens 461uguuggucau aucaaa 16 462 16 RNA Homo sapiens 462cauuaaaaau gaccac 16 463 16 RNA Homo sapiens 463cucuuuuaau gaaauu 16 464 16 RNA Homo sapiens 464acuuuuaaau guuuau 16 465 16 RNA Homo sapiens 465aaauguuuau aggagu 16 466 16 RNA Homo sapiens 466auaggaguau gugcug 16 467 16 RNA Homo sapiens 467aggaguaugu gcugug 16 468 16 RNA Homo sapiens 468aguaugugcu gugaag 16 469 16 RNA Homo sapiens 469uaugugcugu gaagug 16 470 16 RNA Homo sapiens 470gcugugaagu gaucua 16 471 16 RNA Homo sapiens 471ucuaaaauuu guaaua 16 472 16 RNA Homo sapiens 472aauuuguaau auuuuu 16 473 16 RNA Homo sapiens 473uaauauuuuu gucaug 16 474 16 RNA Homo sapiens 474uuuuugucau gaacug 16 475 16 RNA Homo sapiens 475gucaugaacu guacua 16 476 16 RNA Homo sapiens 476ccuaauuauu guaaug 16 477 16 RNA Homo sapiens 477uuauuguaau guaaua 16 478 16 RNA Homo sapiens 478guaauguaau aaaaau 16 479 16 RNA Homo sapiens 479uaauaaaaau aguuac 16 480 16 RNA Homo sapiens 480uaguuacagu gacuau 16 481 16 RNA Homo sapiens 481cagugacuau gagugu 16 482 16 RNA Homo sapiens 482gacuaugagu guguau 16 483 16 RNA Homo sapiens 483cuaugagugu guauuu 16 484 16 RNA Homo sapiens 484auuuauucau gcaaau 16 485 16 RNA Homo sapiens 485augcaaauuu gaacug 16 486 16 RNA Homo sapiens 486aauuugaacu guuugc 16 487 16 RNA Homo sapiens 487ugaacuguuu gccccg 16 488 16 RNA Homo sapiens 488uguuugcccc gaaaug 16 489 16 RNA Homo sapiens 489gccccgaaau ggauau 16 490 16 RNA Homo sapiens 490cgaaauggau auggau 16 491 16 RNA Homo sapiens 491aaauggauau ggauac 16 492 16 RNA Homo sapiens 492ggauauggau acuuua 16 493 16 RNA Homo sapiens 493gauacuuuau aagcca 16 494 16 RNA Homo sapiens 494uauaagccau agacac 16 495 16 RNA Homo sapiens 495uagacacuau aguaua 16 496 16 RNA Homo sapiens 496acuauaguau accagu 16 497 16 RNA Homo sapiens 497guauaccagu gaaucu 16 498 16 RNA Homo sapiens 498aaucuuuuau gcagcu 16 499 16 RNA Homo sapiens 499uaugcagcuu guuaga 16 500 16 RNA Homo sapiens 500ucuaaaaggu gcugug 16 501 16 RNA Homo sapiens 501aaaaggugcu guggau 16 502 16 RNA Homo sapiens 502ugcuguggau auuaug 16 503 16 RNA Homo sapiens 503uggauauuau guaaag 16 504 16 RNA Homo sapiens 504guaaaggcgu guuugc 16 505 16 RNA Homo sapiens 505aggcguguuu gcuuaa 16 506 16 RNA Homo sapiens 506aauuuuccau auuuag 16 507 16 RNA Homo sapiens 507agaaguagau gcaaaa 16 508 16 RNA Homo sapiens 508aaacaaaucu gccuuu 16 509 16 RNA Homo sapiens 509cugccuuuau gacaaa 16 510 16 RNA Homo sapiens 510acaaaaaaau aggaua 16 511 16 RNA Homo sapiens 511aaaauaggau aacauu 16 512 16 RNA Homo sapiens 512uuuuaucaau aaggua 16 513 16 RNA Homo sapiens 513uaagguaauu gauaca 16 514 16 RNA Homo sapiens 514gguaauugau acacaa 16 515 16 RNA Homo sapiens 515cacaacaggu gacuug 16 516 16 RNA Homo sapiens 516caacauuaau aaugga 16 517 16 RNA Homo sapiens 517cauuaauaau ggaaau 16 518 16 RNA Homo sapiens 518uaauggaaau aauuga 16 519 16 RNA Homo sapiens 519ggaaauaauu gaauag 16 520 16 RNA Homo sapiens 520auaauugaau aguuag 16 521 16 RNA Homo sapiens 521aguuaguuau guaugu 16 522 16 RNA Homo sapiens 522aguuauguau guuaau 16 523 16 RNA Homo sapiens 523guauguuaau gccagu 16 524 16 RNA Homo sapiens 524cagaaguaau gacucc 16 525 16 RNA Homo sapiens 525augacuccau acauau 16 526 16 RNA Homo sapiens 526cuccauacau auuauu 16 527 16 RNA Homo sapiens 527uuauuucuau aacuac 16 528 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 528cgccgugaug gcaugcacua ugcgcgggcc gccgcc 36 529 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 529accuuugaug gcaugcacua ugcgcggccg ccgcca 36 530 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 530aauggugaug gcaugcacua ugcgcggggg gccggg 36 531 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 531gcgcuugaug gcaugcacua ugcgcggcuc ccaguc 36 532 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 532cgccgugaug gcaugcacua ugcgcggcuc gcuccc 36 533 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 533gccugugaug gcaugcacua ugcgcggccg cgcucg 36 534 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 534gccuuugaug gcaugcacua ugcgcgagug ccugcg 36 535 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 535ucccgugaug gcaugcacua ugcgcgaccu gggagc 36 536 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 536uucagugaug gcaugcacua ugcgcgaggc cucucu 36 537 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 537auuuuugaug gcaugcacua ugcgcgagca ggccuc 36 538 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 538ucaguugaug gcaugcacua ugcgcgauuu ucagca 36 539 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 539auauuugaug gcaugcacua ugcgcgaguc auuuuc 36 540 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 540guuuaugaug gcaugcacua ugcgcgauuc agucau 36 541 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 541aaguuugaug gcaugcacua ugcgcgauau ucaguc 36 542 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 542uaccaugaug gcaugcacua ugcgcgaagu uuauau 36 543 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 543cgccaugaug gcaugcacua ugcgcgaagc uccaac 36 544 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 544caaggugaug gcaugcacua ugcgcgacuc uugccu 36 545 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 545aucguugaug gcaugcacua ugcgcgaagg cacucu 36 546 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 546uguauugaug gcaugcacua ugcgcgguca aggcac 36 547 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 547agcugugaug gcaugcacua ugcgcgaucg ucaagg 36 548 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 548guccaugaug gcaugcacua ugcgcgaaaa ugauuc 36 549 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 549auauuugaug gcaugcacua ugcgcggucc acaaaa 36 550 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 550gaucaugaug gcaugcacua ugcgcgauuc guccac 36 551 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 551uggauugaug gcaugcacua ugcgcgauau ucgucc 36 552 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 552uccucugaug gcaugcacua ugcgcgauug uuggau 36 553 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 553uccauugaug gcaugcacua ugcgcgaauu acuacu 36 554 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 554uucucugaug gcaugcacua ugcgcgauca auuacu 36 555 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 555agagaugaug gcaugcacua ugcgcgaggu uucucc 36 556 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 556gagaaugaug gcaugcacua ugcgcgaucc aagaga 36 557 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 557uguguugaug gcaugcacua ugcgcggaga auaucc 36 558 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 558cauugugaug gcaugcacua ugcgcgacug uacucc 36 559 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 559ucccuugaug gcaugcacua ugcgcgauug cacugu 36 560 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 560guccuugaug gcaugcacua ugcgcgaugu acuggu 36 561 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 561auacaugaug gcaugcacua ugcgcgaaag aaagcc 36 562 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 562aaauaugaug gcaugcacua ugcgcgacaa agaaag 36 563 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 563uauggugaug gcaugcacua ugcgcgaaau acacaa 36 564 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 564uuauuugaug gcaugcacua ugcgcgaugg caaaua 36 565 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 565aguauugaug gcaugcacua ugcgcgauuu auggca 36 566 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 566uuuagugaug gcaugcacua ugcgcgauua uuuaug 36 567 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 567aucuuugaug gcaugcacua ugcgcgaaau gauuua 36 568 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 568gugaaugaug gcaugcacua ugcgcgaucu ucaaau 36 569 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 569uucucugaug gcaugcacua ugcgcgauaa ugguga 36 570 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 570aucuuugaug gcaugcacua ugcgcgagag uccuua 36 571 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 571agguaugaug gcaugcacua ugcgcgaucu ucagag 36 572 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 572aggacugaug gcaugcacua ugcgcgauag guacau 36 573 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 573acauuugaug gcaugcacua ugcgcgauuu ccuacu 36 574 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 574aaucaugaug gcaugcacua ugcgcgauuu auuucc 36 575 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 575caaauugaug gcaugcacua ugcgcgacau uuauuu 36 576 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 576gaaggugaug gcaugcacua ugcgcgaaau cacauu 36 577 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 577aauucugaug gcaugcacua ugcgcgauaa cuucuu 36 578 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 578uguuuugaug gcaugcacua ugcgcgaaua aaagga 36 579 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 579aucaaugaug gcaugcacua ugcgcgaccc ugucuu 36 580 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 580aucauugaug gcaugcacua ugcgcgaaca cccugu 36 581 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 581ggcauugaug gcaugcacua ugcgcgauca acaccc 36 582 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 582gaaggugaug gcaugcacua ugcgcgauca ucaaca 36 583 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 583uaaugugaug gcaugcacua ugcgcgauag aaggca 36 584 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 584uuucuugaug gcaugcacua ugcgcggaac uaaugu 36 585 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 585guuuuugaug gcaugcacua ugcgcggaau uucucg 36 586 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 586uucuuugaug gcaugcacua ugcgcgaugu uuucga 36 587 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 587uugcuugaug gcaugcacua ugcgcgaucu uuucuu 36 588 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 588uuuacugaug gcaugcacua ugcgcgaucu uugcuc 36 589 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 589uuacaugaug gcaugcacua ugcgcgacuu ugucuu 36 590 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 590aauuaugaug gcaugcacua ugcgcgacac uuuguc 36 591 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 591auuuaugaug gcaugcacua ugcgcgauaa uuacac 36 592 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 592aauugugaug gcaugcacua ugcgcgauuu acauaa 36 593 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 593aaguaugaug gcaugcacua ugcgcgaaau uguauu 36 594 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 594acuagugaug gcaugcacua ugcgcgaugc cuuaag 36 595 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 595auguaugaug gcaugcacua ugcgcgaaaa auuacc 36 596 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 596uaaaaugaug gcaugcacua ugcgcgaaau gcuaau 36 597 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 597uggagugaug gcaugcacua ugcgcgagga aaaaaa 36 598 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 598gucugugaug gcaugcacua ugcgcgaugg agcagg 36 599 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 599gcuaaugaug gcaugcacua ugcgcgaguc ugcaug 36 600 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 600auaagugaug gcaugcacua ugcgcgauuu aaggua 36 601 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 601acuguugaug gcaugcacua ugcgcgauuu uaaaau 36 602 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 602cacuuugaug gcaugcacua ugcgcggagg aaaaaa 36 603 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 603acuggugaug gcaugcacua ugcgcgacuu cgagga 36 604 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 604uaguuugaug gcaugcacua ugcgcgaaaa accaaa 36 605 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 605acaggugaug gcaugcacua ugcgcgauug cuaguu 36 606 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 606uuucaugaug gcaugcacua ugcgcgaggc auugcu 36 607 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 607uuuuuugaug gcaugcacua ugcgcgacag gcauug 36 608 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 608guauuugaug gcaugcacua ugcgcgaguu ucuuuu 36 609 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 609uuaggugaug gcaugcacua ugcgcgauuc aguuuc 36 610 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 610caagaugaug gcaugcacua ugcgcgagaa aucuua 36 611 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 611gcaugugaug gcaugcacua ugcgcgacca aaaacc 36 612 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 612aacugugaug gcaugcacua ugcgcgaugc accaaa 36 613 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 613guaauugaug gcaugcacua ugcgcgaacu gcaugc 36 614 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 614auucaugaug gcaugcacua ugcgcgacuu gguaag 36 615 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 615acauuugaug gcaugcacua ugcgcgacac uuggua 36 616 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 616accaaugaug gcaugcacua ugcgcgauuc acacuu 36 617 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 617uuucaugaug gcaugcacua ugcgcgacca acauuc 36 618 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 618uguuuugaug gcaugcacua ugcgcgacac caacau 36 619 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 619agcuuugaug gcaugcacua ugcgcgauua auuugu 36 620 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 620ugauuugaug gcaugcacua ugcgcgaaaa gcuuca 36 621 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 621aaacaugaug gcaugcacua ugcgcgagaa uaggga 36 622 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 622uaaaaugaug gcaugcacua ugcgcgacag aauagg 36 623 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 623ccauuugaug gcaugcacua ugcgcgaugu gacuag 36 624 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 624uaaucugaug gcaugcacua ugcgcgauuu auguga 36 625 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 625ggucuugaug gcaugcacua ugcgcgaacu gaaauu 36 626 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 626uguuuugaug gcaugcacua ugcgcgagua aaaacc 36 627 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 627ucccuugaug gcaugcacua ugcgcgaaug uuucag 36 628 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 628aagccugaug gcaugcacua ugcgcgauaa auuugu 36 629 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 629aucauugaug gcaugcacua ugcgcgagga agccca 36 630 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 630aucauugaug gcaugcacua ugcgcgauca ggaagc 36 631 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 631agaauugaug gcaugcacua ugcgcgauca ucagga 36 632 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 632uaggaugaug gcaugcacua ugcgcgauga ugccua 36 633 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 633caaacugaug gcaugcacua ugcgcgauag gacaug 36 634 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 634gaugaugaug gcaugcacua ugcgcgaaac uauagg 36 635 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 635uucauugaug gcaugcacua ugcgcgaggg augaca 36 636 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 636acauuugaug gcaugcacua ugcgcgauca gggaug 36 637 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 637cuuuaugaug gcaugcacua ugcgcgauuc aucagg 36 638 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 638gugaaugaug gcaugcacua ugcgcgagug uaacuu 36 639 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 639ggagaugaug gcaugcacua ugcgcgaaaa ccuuug 36 640 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 640aauagugaug gcaugcacua ugcgcgagug gaaagg 36 641 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 641gugacugaug gcaugcacua ugcgcgauga cuaaua 36 642 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 642uauaaugaug gcaugcacua ugcgcgauuu ugggga 36 643 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 643aaaaaugaug gcaugcacua ugcgcgauaa uauuuu 36 644 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 644cuuuuugaug gcaugcacua ugcgcgauag aaaaaa 36 645 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 645uuuucugaug gcaugcacua ugcgcgauuu uuuucu 36 646 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 646guuucugaug gcaugcacua ugcgcgauug ccuugu 36 647 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 647ggccuugaug gcaugcacua ugcgcgauaa uaguuu 36 648 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 648uaauuugaug gcaugcacua ugcgcgaucu aaugug 36 649 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 649gucuuugaug gcaugcacua ugcgcgauag uaauuu 36 650 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 650aaagcugaug gcaugcacua ugcgcgauua ggaguc 36 651 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 651cuuaaugaug gcaugcacua ugcgcgagga aaaagc 36 652 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 652ccauuugaug gcaugcacua ugcgcgauac uggguc 36 653 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 653aauccugaug gcaugcacua ugcgcgauuc auacug 36 654 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 654guugcugaug gcaugcacua ugcgcgauaa uaaucc 36 655 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 655guaaaugaug gcaugcacua ugcgcgauag ccccaa 36 656 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 656aguagugaug gcaugcacua ugcgcgaugu aaauau 36 657 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 657auuauugaug gcaugcacua ugcgcgauaa aaauuu 36 658 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 658ucaauugaug gcaugcacua ugcgcgauua uaaaaa 36 659 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 659cuuuuugaug gcaugcacua ugcgcgaauu auuaua 36 660 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 660uuuuuugaug gcaugcacua ugcgcgauac uuguua 36 661 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 661auuccugaug gcaugcacua ugcgcgauga gaauuu 36 662 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 662gacuaugaug gcaugcacua ugcgcgauuu aauucc 36 663 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 663ugacaugaug gcaugcacua ugcgcgaggg agacua 36 664 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 664ucugaugaug gcaugcacua ugcgcgacag ggagac 36 665 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 665aagagugaug gcaugcacua ugcgcgaguc ugacac 36 666 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 666uauacugaug gcaugcacua ugcgcgauga aagagc 36 667 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 667aaaguugaug gcaugcacua ugcgcgauac uaugaa 36 668 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 668agacuugaug gcaugcacua ugcgcgaagu ugaaga 36 669 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 669aucuuugaug gcaugcacua ugcgcgaaag acucaa 36 670 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 670aaaacugaug gcaugcacua ugcgcgaucu ucaaag 36 671 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 671acaagugaug gcaugcacua ugcgcgagaa uuaaaa 36 672 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 672ugucaugaug gcaugcacua ugcgcgaagc agaauu 36 673 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 673aauguugaug gcaugcacua ugcgcgacaa gcagaa 36 674 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 674uaagcugaug gcaugcacua ugcgcgauaa cuggcc 36 675 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 675uucaaugaug gcaugcacua ugcgcgaccu aauaag 36 676 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 676cucuuugaug gcaugcacua ugcgcgaaca ccuaau 36 677 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 677gcuugugaug gcaugcacua ugcgcgaacc uugguc 36 678 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 678ucacaugaug gcaugcacua ugcgcgaggg ccuggc 36 679 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 679guucaugaug gcaugcacua ugcgcgacag ggccug 36 680 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 680agguuugaug gcaugcacua ugcgcgacac agggcc 36 681 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 681aagcuugaug gcaugcacua ugcgcgaagg uucaca 36 682 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 682cucucugaug gcaugcacua ugcgcgauga aagcuc 36 683 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 683cagucugaug gcaugcacua ugcgcgaugc ugugaa 36 684 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 684gcacaugaug gcaugcacua ugcgcgaguc caugcu 36 685 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 685gggcaugaug gcaugcacua ugcgcgacag uccaug 36 686 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 686uggggugaug gcaugcacua ugcgcgacac agucca 36 687 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 687ccacuugaug gcaugcacua ugcgcgggau gaccgu 36 688 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 688ucguaugaug gcaugcacua ugcgcgaacc acucgg 36 689 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 689ugcauugaug gcaugcacua ugcgcgguac aaccac 36 690 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 690caaugugaug gcaugcacua ugcgcgaucg uacaac 36 691 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 691cucccugaug gcaugcacua ugcgcgauuu uugacu 36 692 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 692ugagcugaug gcaugcacua ugcgcgaucc aaacug 36 693 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 693gauugugaug gcaugcacua ugcgcgaucu uguuga 36 694 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 694caccaugaug gcaugcacua ugcgcgagag ugagau 36 695 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 695gucagugaug gcaugcacua ugcgcgagga ccacca 36 696 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 696uuuguugaug gcaugcacua ugcgcgagca ggacca 36 697 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 697aaaagugaug gcaugcacua ugcgcgaaug cucuug 36 698 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 698agaaaugaug gcaugcacua ugcgcgaaaa gcaaug 36 699 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 699guuaaugaug gcaugcacua ugcgcgauuu aaaagu 36 700 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 700aaucuugaug gcaugcacua ugcgcgaacu uuugag 36 701 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 701uggcaugaug gcaugcacua ugcgcgacca ccaccc 36 702 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 702cuuggugaug gcaugcacua ugcgcgacac caccac 36 703 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 703cacuuugaug gcaugcacua ugcgcgauug uuuaaa 36 704 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 704uuuuuugaug gcaugcacua ugcgcgacuu cauugu 36 705 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 705uuaugugaug gcaugcacua ugcgcgaaug uuaauu 36 706 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 706guguuugaug gcaugcacua ugcgcgaugc aauguu 36 707 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 707uggauugaug gcaugcacua ugcgcgagac uugaaa 36 708 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 708uuaaaugaug gcaugcacua ugcgcgaugg aucaga 36 709 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 709agcauugaug gcaugcacua ugcgcgauua aauaug 36 710 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 710uaaagugaug gcaugcacua ugcgcgauua uuaaau 36 711 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 711auuuuugaug gcaugcacua ugcgcgauuu uaaagc 36 712 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 712guuuuugaug gcaugcacua ugcgcgauuu uuauuu 36 713 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 713uuuauugaug gcaugcacua ugcgcgaaaa ggauug 36 714 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 714aaauuugaug gcaugcacua ugcgcgauca aaagga 36 715 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 715aguaaugaug gcaugcacua ugcgcgauuu uaaauu 36 716 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 716ucauuugaug gcaugcacua ugcgcgauuu uaaaau 36 717 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 717cacuuugaug gcaugcacua ugcgcgauuu auuuua 36 718 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 718caucuugaug gcaugcacua ugcgcgacuu cauuua 36 719 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 719caugcugaug gcaugcacua ugcgcgaucu cacuuc 36 720 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 720cucacugaug gcaugcacua ugcgcgaugc caucuc 36 721 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 721caccuugaug gcaugcacua ugcgcgacca ugccau 36 722 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 722acuuuugaug gcaugcacua ugcgcgaccu caccau 36 723 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 723accaaugaug gcaugcacua ugcgcgaacc uagucc 36 724 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 724uaaguugaug gcaugcacua ugcgcgacca acaacc 36 725 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 725acaccugaug gcaugcacua ugcgcgaucu agaacc 36 726 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 726aaagaugaug gcaugcacua ugcgcgaccu aucuag 36 727 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 727aaaauugaug gcaugcacua ugcgcgagag uccuaa 36 728 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 728guccuugaug gcaugcacua ugcgcgaaaa ucagag 36 729 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 729uuuaaugaug gcaugcacua ugcgcgauga agaaau 36 730 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 730aaucaugaug gcaugcacua ugcgcgauag uguaaa 36 731 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 731uaaauugaug gcaugcacua ugcgcgacau agugua 36 732 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 732uggaaugaug gcaugcacua ugcgcgauaa aucaca 36 733 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 733auccuugaug gcaugcacua ugcgcgaugu aaaugg 36 734 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 734aagugugaug gcaugcacua ugcgcgaucc uuaugu 36 735 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 735cuugaugaug gcaugcacua ugcgcgaaau aagugu 36 736 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 736auuuaugaug gcaugcacua ugcgcgagau ugugcu 36 737 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 737uguaaugaug gcaugcacua ugcgcgauag guuaaa 36 738 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 738acuggugaug gcaugcacua ugcgcgacug aagaug 36 739 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 739uugcaugaug gcaugcacua ugcgcgaauu uugccc 36 740 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 740ucuugugaug gcaugcacua ugcgcgacaa uuuugc 36 741 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 741aacuuugaug gcaugcacua ugcgcgaccu cuugca 36 742 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 742ucaaaugaug gcaugcacua ugcgcgauaa acuuca 36 743 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 743auauuugaug gcaugcacua ugcgcgaaau auaaac 36 744 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 744auggaugaug gcaugcacua ugcgcgauuc aaauau 36 745 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 745acuaaugaug gcaugcacua ugcgcgaugg aagaag 36 746 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 746gaugaugaug gcaugcacua ugcgcgacua auaugg 36 747 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 747ggaggugaug gcaugcacua ugcgcgaaga ugacac 36 748 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 748uggggugaug gcaugcacua ugcgcgaugu ggaagg 36 749 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 749caaguugaug gcaugcacua ugcgcgaugg ggcaug 36 750 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 750ugcauugaug gcaugcacua ugcgcgaagu cauggg 36 751 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 751aacugugaug gcaugcacua ugcgcgauca agucau 36 752 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 752acaagugaug gcaugcacua ugcgcgauua aaacug 36 753 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 753aauuaugaug gcaugcacua ugcgcgaagu auuaaa 36 754 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 754aaucuugaug gcaugcacua ugcgcgaugg uuaggg 36 755 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 755agcagugaug gcaugcacua ugcgcgagua aaucuu 36 756 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 756cacagugaug gcaugcacua ugcgcgagca guaaau 36 757 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 757auccaugaug gcaugcacua ugcgcgagca gcagua 36 758 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 758ggagaugaug gcaugcacua ugcgcgaucc acagca 36 759 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 759aacuuugaug gcaugcacua ugcgcgaugg agauau 36 760 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 760ugacuugaug gcaugcacua ugcgcgagug ggaaaa 36 761 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 761uagggugaug gcaugcacua ugcgcgauuu cugaug 36 762 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 762ucuguugaug gcaugcacua ugcgcgagau ucucuu 36 763 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 763uauggugaug gcaugcacua ugcgcgaucu gucaga 36 764 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 764cccuuugaug gcaugcacua ugcgcgaugg uaucug 36 765 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 765uagguugaug gcaugcacua ugcgcgaaau cccuuu 36 766 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 766agcauugaug gcaugcacua ugcgcgagcc accacc 36 767 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 767caaagugaug gcaugcacua ugcgcgauca gccacc 36 768 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 768auguuugaug gcaugcacua ugcgcgaaag caucag 36 769 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 769ggcagugaug gcaugcacua ugcgcgaaag agaugu 36 770 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 770uugggugaug gcaugcacua ugcgcgagca aagaga 36 771 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 771acuguugaug gcaugcacua ugcgcggcua auggau 36 772 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 772cuauuugaug gcaugcacua ugcgcgauac cagggu 36 773 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 773cugucugaug gcaugcacua ugcgcgauuc auacca 36 774 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 774aucuuugaug gcaugcacua ugcgcgauua aauucu 36 775 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 775ugcacugaug gcaugcacua ugcgcgaucu uuauua 36 776 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 776uucugugaug gcaugcacua ugcgcgacua ucuuua 36 777 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 777cuaguugaug gcaugcacua ugcgcgauag auuacc 36 778 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 778gaaugugaug gcaugcacua ugcgcgauua cuguua 36 779 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 779uaaaaugaug gcaugcacua ugcgcgaaug gaaugu 36 780 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 780cauugugaug gcaugcacua ugcgcgauga agauuu 36 781 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 781uuuuuugaug gcaugcacua ugcgcgauug caugaa 36 782 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 782uaaagugaug gcaugcacua ugcgcgauuu uucauu 36 783 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 783agcuuugaug gcaugcacua ugcgcgauga auuaaa 36 784 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 784ucugaugaug gcaugcacua ugcgcgacca aaaaaa 36 785 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 785aagagugaug gcaugcacua ugcgcggaga cucuga 36 786 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 786ggugaugaug gcaugcacua ugcgcgaaga gcgaga 36 787 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 787cacugugaug gcaugcacua ugcgcgauuc cagccu 36 788 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 788gauggugaug gcaugcacua ugcgcggcca cugcau 36 789 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 789gguugugaug gcaugcacua ugcgcgagug agcuga 36 790 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 790agaauugaug gcaugcacua ugcgcggcuu gaaccu 36 791 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 791cgaggugaug gcaugcacua ugcgcgacga gaaucg 36 792 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 792cuacuugaug gcaugcacua ugcgcgagga ggccga 36 793 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 793gugcaugaug gcaugcacua ugcgcgacgc cuguaa 36 794 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 794uagugugaug gcaugcacua ugcgcgacac gccugu 36 795 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 795aaauaugaug gcaugcacua ugcgcgaaaa auuagu 36 796 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 796gccaaugaug gcaugcacua ugcgcgaggu gaaacc 36 797 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 797gaguuugaug gcaugcacua ugcgcggaga ccagcc 36 798 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 798gagguugaug gcaugcacua ugcgcgagga guucga 36 799 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 799ugaauugaug gcaugcacua ugcgcgacuu gagguc 36 800 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 800agguuugaug gcaugcacua ugcgcgauga ggccaa 36 801 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 801caaaaugaug gcaugcacua ugcgcgaggu uuauga 36 802 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 802uucugugaug gcaugcacua ugcgcgaaaa cagguu 36 803 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 803auaaaugaug gcaugcacua ugcgcgauuu gcugaa 36 804 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 804gcacuugaug gcaugcacua ugcgcgaaua aauauu 36 805 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 805guaggugaug gcaugcacua ugcgcgacuc aauaaa 36 806 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 806acuggugaug gcaugcacua ugcgcgaucu gguagg 36 807 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 807uugugugaug gcaugcacua ugcgcgggug acuggc 36 808 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 808uaccaugaug gcaugcacua ugcgcgauac ccagug 36 809 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 809gauacugaug gcaugcacua ugcgcgauau acccag 36 810 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 810gggauugaug gcaugcacua ugcgcgaugu cucuug 36 811 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 811acuagugaug gcaugcacua ugcgcgagua ccuaag 36 812 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 812gaccaugaug gcaugcacua ugcgcgacua gcagua 36 813 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 813uauuaugaug gcaugcacua ugcgcgagac cacacu 36 814 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 814uaagaugaug gcaugcacua ugcgcgauua cagacc 36 815 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 815ggucgugaug gcaugcacua ugcgcgauac caaagg 36 816 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 816uggguugaug gcaugcacua ugcgcgguau accaaa 36 817 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 817cguguugaug gcaugcacua ugcgcgaucu cugggu 36 818 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 818cgcauugaug gcaugcacua ugcgcggugu uaucuc 36 819 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 819auacgugaug gcaugcacua ugcgcgaucg uguuau 36 820 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 820cuuugugaug gcaugcacua ugcgcgaaaa cuaaaa 36 821 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 821uggcaugaug gcaugcacua ugcgcgagag accaaa 36 822 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 822gcuggugaug gcaugcacua ugcgcgacag agacca 36 823 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 823acaauugaug gcaugcacua ugcgcgauag agcugg 36 824 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 824caaaaugaug gcaugcacua ugcgcgaauu auagag 36 825 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 825cguagugaug gcaugcacua ugcgcgaaaa caauua 36 826 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 826ggaauugaug gcaugcacua ugcgcgguag caaaac 36 827 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 827aguuuugaug gcaugcacua ugcgcgagug gaaucg 36 828 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 828uugauugaug gcaugcacua ugcgcggaag aguuuc 36 829 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 829auuuaugaug gcaugcacua ugcgcgauaa aguagc 36 830 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 830uaaaaugaug gcaugcacua ugcgcgaaug aaguga 36 831 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 831aaguuugaug gcaugcacua ugcgcgauuc cuuuaa 36 832 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 832auaauugaug gcaugcacua ugcgcgaagu uuauuc 36 833 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 833aacaaugaug gcaugcacua ugcgcgauaa ucaagu 36 834 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 834aaaaaugaug gcaugcacua ugcgcgaaua uaauca 36 835 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 835acaguugaug gcaugcacua ugcgcgaugc caaaua 36 836 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 836aaucaugaug gcaugcacua ugcgcgaguu augcca 36 837 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 837agaauugaug gcaugcacua ugcgcgacag uuaugc 36 838 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 838guguaugaug gcaugcacua ugcgcgagua auuguc 36 839 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 839acauaugaug gcaugcacua ugcgcgaccu uaaugu 36 840 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 840ucugaugaug gcaugcacua ugcgcgauac accuua 36 841 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 841augaaugaug gcaugcacua ugcgcgaucu gacaua 36 842 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 842gucaaugaug gcaugcacua ugcgcgauga auaucu 36 843 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 843uggguugaug gcaugcacua ugcgcgaaua ugaaua 36 844 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 844uuacaugaug gcaugcacua ugcgcgauuu ggguca 36 845 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 845uauuaugaug gcaugcacua ugcgcgacau uugggu 36 846 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 846uggaaugaug gcaugcacua ugcgcgauua cacauu 36 847 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 847uuaugugaug gcaugcacua ugcgcgagag aaaacu 36 848 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 848uuacuugaug gcaugcacua ugcgcgaugc agagaa 36 849 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 849aaguaugaug gcaugcacua ugcgcgauuu uaauua 36 850 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 850uuaagugaug gcaugcacua ugcgcgauau uuuaau 36 851 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 851aaaacugaug gcaugcacua ugcgcgauua auuuuu 36 852 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 852cuguuugaug gcaugcacua ugcgcgauuu guaccc 36 853 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 853ucaggugaug gcaugcacua ugcgcgacug uuuauu 36 854 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 854uaguuugaug gcaugcacua ugcgcgaggc acuguu 36 855 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 855uuuuaugaug gcaugcacua ugcgcgauag aaguuu 36 856 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 856gaaauugaug gcaugcacua ugcgcgauag ugauuu 36 857 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 857caauuugaug gcaugcacua ugcgcgagaa aucaua 36 858 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 858cauagugaug gcaugcacua ugcgcgaauu cagaaa 36 859 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 859uuucaugaug gcaugcacua ugcgcgauag caauuc 36 860 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 860aguuuugaug gcaugcacua ugcgcgacau agcaau 36 861 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 861cuaaaugaug gcaugcacua ugcgcgagug uuccaa 36 862 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 862cuuaaugaug gcaugcacua ugcgcgaccc uaccua 36 863 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 863uguguugaug gcaugcacua ugcgcgaagu cuuaac 36 864 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 864auggcugaug gcaugcacua ugcgcgauuu cuuucu 36 865 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 865ugaagugaug gcaugcacua ugcgcgaugg ccauuu 36 866 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 866cacugugaug gcaugcacua ugcgcgaguu ccugaa 36 867 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 867auaagugaug gcaugcacua ugcgcgacug caguuc 36 868 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 868ccccuugaug gcaugcacua ugcgcgauaa gcacug 36 869 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 869cuaaaugaug gcaugcacua ugcgcgaucc ccucau 36 870 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 870aaauuugaug gcaugcacua ugcgcgaaga ggccua 36 871 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 871uacauugaug gcaugcacua ugcgcgaaaa auucaa 36 872 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 872aucuaugaug gcaugcacua ugcgcgauca aaaauu 36 873 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 873augccugaug gcaugcacua ugcgcgaucu acauca 36 874 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 874guucaugaug gcaugcacua ugcgcgauaa agguaa 36 875 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 875aaguuugaug gcaugcacua ugcgcgacau aaaggu 36 876 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 876ccauuugaug gcaugcacua ugcgcgaaag uucaca 36 877 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 877uaaacugaug gcaugcacua ugcgcgauuc aaaguu 36 878 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 878aaaaaugaug gcaugcacua ugcgcgaaau cuuuug 36 879 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 879cucuaugaug gcaugcacua ugcgcgaaaa acaaau 36 880 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 880acauuugaug gcaugcacua ugcgcgauuu cuagaa 36 881 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 881gguaaugaug gcaugcacua ugcgcgauuu auuucu 36 882 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 882uucaaugaug gcaugcacua ugcgcgaagg auuuuu 36 883 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 883aacuuugaug gcaugcacua ugcgcgaaca aggauu 36 884 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 884aagucugaug gcaugcacua ugcgcgaugu aauuua 36 885 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 885acaaaugaug gcaugcacua ugcgcgaugu uaaugc 36 886 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 886uuccaugaug gcaugcacua ugcgcgaaac auguua 36 887 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 887ugcuaugaug gcaugcacua ugcgcgauuc uuccac 36 888 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 888ucugcugaug gcaugcacua ugcgcgauau ucuucc 36 889 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 889uacaaugaug gcaugcacua ugcgcgauac gucugc 36 890 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 890ugauaugaug gcaugcacua ugcgcgaaua uacguc 36 891 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 891ucacuugaug gcaugcacua ugcgcgaaau gauaca 36 892 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 892acauuugaug gcaugcacua ugcgcgacuc aaauga 36 893 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 893gggaaugaug gcaugcacua ugcgcgauuc acucaa 36 894 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 894ugacuugaug gcaugcacua ugcgcgaguu aaauag 36 895 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 895cuaugugaug gcaugcacua ugcgcgagug ugacuc 36 896 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 896auuccugaug gcaugcacua ugcgcgaugc agugug 36 897 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 897uaaccugaug gcaugcacua ugcgcgauaa aaguua 36 898 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 898gacaaugaug gcaugcacua ugcgcgaguu uugaua 36 899 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 899ggugaugaug gcaugcacua ugcgcgaaca guuuug 36 900 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 900uugugugaug gcaugcacua ugcgcgaaug gugaca 36 901 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 901uaggaugaug gcaugcacua ugcgcgaaaa uugugc 36 902 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 902guauaugaug gcaugcacua ugcgcgauua ggacaa 36 903 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 903auguaugaug gcaugcacua ugcgcgauau uaggac 36 904 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 904cuaugugaug gcaugcacua ugcgcgauau auuagg 36 905 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 905guuucugaug gcaugcacua ugcgcgaugu auauau 36 906 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 906ccccaugaug gcaugcacua ugcgcgaaag uuucua 36 907 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 907cuuaaugaug gcaugcacua ugcgcgaugc cccaca 36 908 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 908uugugugaug gcaugcacua ugcgcgaaac uguaac 36 909 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 909gaauaugaug gcaugcacua ugcgcgaaau gagaug 36 910 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 910aaaauugaug gcaugcacua ugcgcgaaug gaauac 36 911 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 911uuauaugaug gcaugcacua ugcgcgauac uguuuu 36 912 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 912aguuaugaug gcaugcacua ugcgcgauau acuguu 36 913 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 913aaaguugaug gcaugcacua ugcgcgauau auacug 36 914 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 914aucuuugaug gcaugcacua ugcgcgagau aguuuu 36 915 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 915uuugaugaug gcaugcacua ugcgcgaaau ggaaau 36 916 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 916gaaauugaug gcaugcacua ugcgcgauua cuuuuu 36 917 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 917auuauugaug gcaugcacua ugcgcgaaga aaucau 36 918 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 918acaauugaug gcaugcacua ugcgcgauca agaaau 36 919 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 919cuacaugaug gcaugcacua ugcgcgaauu aucaag 36 920 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 920cacuaugaug gcaugcacua ugcgcgacaa uuauca 36 921 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 921acauuugaug gcaugcacua ugcgcgacua cacaau 36 922 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 922aaaaaugaug gcaugcacua ugcgcgauuc acuaca 36 923 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 923gcuuuugaug gcaugcacua ugcgcgaagg uaacug 36 924 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 924aaauuugaug gcaugcacua ugcgcgagcu uucaag 36 925 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 925cuaaaugaug gcaugcacua ugcgcgauaa auucag 36 926 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 926uaacaugaug gcaugcacua ugcgcgagaa guuacu 36 927 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 927auuaaugaug gcaugcacua ugcgcgacag aaguua 36 928 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 928uccagugaug gcaugcacua ugcgcgauua acacag 36 929 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 929caugcugaug gcaugcacua ugcgcgaucc aguauu 36 930 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 930gaauuugaug gcaugcacua ugcgcgaugc uaucca 36 931 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 931caaugugaug gcaugcacua ugcgcgagaa uucaug 36 932 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 932uuucuugaug gcaugcacua ugcgcgaaug cagaau 36 933 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 933cuauuugaug gcaugcacua ugcgcgaguu ucucaa 36 934 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 934acagcugaug gcaugcacua ugcgcgauuc aguuuc 36 935 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 935uaugaugaug gcaugcacua ugcgcgagcu auucag 36 936 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 936cauuuugaug gcaugcacua ugcgcgauga cagcua 36 937 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 937gaaagugaug gcaugcacua ugcgcgauuu uaugac 36 938 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 938gugagugaug gcaugcacua ugcgcgaucu uucuuu 36 939 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 939gaacuugaug gcaugcacua ugcgcgaugu gaguau 36 940 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 940uucuuugaug gcaugcacua ugcgcgaaga acucau 36 941 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 941augacugaug gcaugcacua ugcgcgauuc uucaag 36 942 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 942cuaguugaug gcaugcacua ugcgcgauga cuauuc 36 943 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 943aaacaugaug gcaugcacua ugcgcgagau cuuaau 36 944 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 944uaaaaugaug gcaugcacua ugcgcgacag aucuua 36 945 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 945caaacugaug gcaugcacua ugcgcgauua aacuaa 36 946 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 946cacuuugaug gcaugcacua ugcgcgaaac uauuaa 36 947 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 947acaggugaug gcaugcacua ugcgcgacuu caaacu 36 948 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 948ccaaaugaug gcaugcacua ugcgcgaggc acuuca 36 949 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 949aucauugaug gcaugcacua ugcgcgaucc caaaca 36 950 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 950ccuauugaug gcaugcacua ugcgcgauua ucccaa 36 951 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 951uuaccugaug gcaugcacua ugcgcgauca uuaucc 36 952 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 952aaauuugaug gcaugcacua ugcgcgaucu aaauua 36 953 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 953aacugugaug gcaugcacua ugcgcgagau aacuuu 36 954 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 954cucaaugaug gcaugcacua ugcgcgauaa cugcag 36 955 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 955gcccuugaug gcaugcacua ugcgcgaaca uaacug 36 956 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 956uaaaaugaug gcaugcacua ugcgcgacug uaaccc 36 957 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 957acuuuugaug gcaugcacua ugcgcgggau aaaaca 36 958 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 958caagaugaug gcaugcacua ugcgcgagug gaauug 36 959 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 959aaacaugaug gcaugcacua ugcgcgaaga cagugg 36 960 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 960gaaaaugaug gcaugcacua ugcgcgacaa gacagu 36 961 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 961uucaaugaug gcaugcacua ugcgcgauga aaacac 36 962 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 962auuuuugaug gcaugcacua ugcgcgaaca ugaaaa 36 963 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 963aaaagugaug gcaugcacua ugcgcgauuu ucaaca 36 964 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 964aaaugugaug gcaugcacua ugcgcgaaaa guauuu 36 965 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 965gcacuugaug gcaugcacua ugcgcgaaag gaaaaa 36 966 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 966auuggugaug gcaugcacua ugcgcgacuc aaagga 36 967 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 967uguuaugaug gcaugcacua ugcgcgauua agaaau 36 968 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 968guaaaugaug gcaugcacua ugcgcgaugu uacauu 36 969 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 969aaagaugaug gcaugcacua ugcgcgaggc caggua 36 970 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 970cuauaugaug gcaugcacua ugcgcgaaaa auaguu 36 971 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 971uacacugaug gcaugcacua ugcgcgauac aaaaau 36 972 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 972guuuaugaug gcaugcacua ugcgcgacua uacaaa 36 973 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 973uguuuugaug gcaugcacua ugcgcgaguu uacacu 36 974 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 974augugugaug gcaugcacua ugcgcgaugu uucagu 36 975 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 975auguaugaug gcaugcacua ugcgcgaaaa ugugca 36 976 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 976aagcaugaug gcaugcacua ugcgcgaaug uacaaa 36 977 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 977gaaagugaug gcaugcacua ugcgcgacaa uguaca 36 978 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 978acccaugaug gcaugcacua ugcgcgaaaa gaaagc 36 979 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 979cugcaugaug gcaugcacua ugcgcgauga cccaca 36 980 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 980cacugugaug gcaugcacua ugcgcgauau gaccca 36 981 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 981gaucaugaug gcaugcacua ugcgcgacug cauaug 36 982 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 982uggauugaug gcaugcacua ugcgcgacac ugcaua 36 983 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 983gaaaaugaug gcaugcacua ugcgcgaacu ggauca 36 984 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 984cagcgugaug gcaugcacua ugcgcgaacc aaauga 36 985 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 985gucagugaug gcaugcacua ugcgcggcaa ccaaau 36 986 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 986uagguugaug gcaugcacua ugcgcgagcg caacca 36 987 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 987accaaugaug gcaugcacua ugcgcgauuc cuaggu 36 988 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 988uuugaugaug gcaugcacua ugcgcgauga ccaaca 36 989 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 989gugguugaug gcaugcacua ugcgcgauuu uuaaug 36 990 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 990aauuuugaug gcaugcacua ugcgcgauua aaagag 36 991 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 991auaaaugaug gcaugcacua ugcgcgauuu aaaagu 36 992 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 992acuccugaug gcaugcacua ugcgcgauaa acauuu 36 993 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 993cagcaugaug gcaugcacua ugcgcgauac uccuau 36 994 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 994cacagugaug gcaugcacua ugcgcgacau acuccu 36 995 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 995cuucaugaug gcaugcacua ugcgcgagca cauacu 36 996 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 996cacuuugaug gcaugcacua ugcgcgacag cacaua 36 997 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 997uagauugaug gcaugcacua ugcgcgacuu cacagc 36 998 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 998uauuaugaug gcaugcacua ugcgcgaaau uuuaga 36 999 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 999aaaaaugaug gcaugcacua ugcgcgauua caaauu 36 1000 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1000caugaugaug gcaugcacua ugcgcgaaaa auauua 36 1001 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1001caguuugaug gcaugcacua ugcgcgauga caaaaa 36 1002 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1002uaguaugaug gcaugcacua ugcgcgaguu caugac 36 1003 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1003cauuaugaug gcaugcacua ugcgcgaaua auuagg 36 1004 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1004uauuaugaug gcaugcacua ugcgcgauua caauaa 36 1005 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1005auuuuugaug gcaugcacua ugcgcgauua cauuac 36 1006 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1006guaacugaug gcaugcacua ugcgcgauuu uuauua 36 1007 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1007auaguugaug gcaugcacua ugcgcgacug uaacua 36 1008 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1008acacuugaug gcaugcacua ugcgcgauag ucacug 36 1009 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1009auacaugaug gcaugcacua ugcgcgacuc auaguc 36 1010 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1010aaauaugaug gcaugcacua ugcgcgacac ucauag 36 1011 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1011auuugugaug gcaugcacua ugcgcgauga auaaau 36 1012 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1012caguuugaug gcaugcacua ugcgcgaaau uugcau 36 1013 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1013gcaaaugaug gcaugcacua ugcgcgaguu caaauu 36 1014 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1014cggggugaug gcaugcacua ugcgcgaaac aguuca 36 1015 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1015cauuuugaug gcaugcacua ugcgcggggg caaaca 36 1016 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1016auaucugaug gcaugcacua ugcgcgauuu cggggc 36 1017 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1017auccaugaug gcaugcacua ugcgcgaucc auuucg 36 1018 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1018guaucugaug gcaugcacua ugcgcgauau ccauuu 36 1019 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1019uaaagugaug gcaugcacua ugcgcgaucc auaucc 36 1020 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1020uggcuugaug gcaugcacua ugcgcgauaa aguauc 36 1021 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1021gugucugaug gcaugcacua ugcgcgaugg cuuaua 36 1022 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1022uauacugaug gcaugcacua ugcgcgauag ugucua 36 1023 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1023acuggugaug gcaugcacua ugcgcgauac uauagu 36 1024 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1024agauuugaug gcaugcacua ugcgcgacug guauac 36 1025 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1025agcugugaug gcaugcacua ugcgcgauaa aagauu 36 1026 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1026ucuaaugaug gcaugcacua ugcgcgaagc ugcaua 36 1027 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1027cacagugaug gcaugcacua ugcgcgaccu uuuaga 36 1028 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1028auccaugaug gcaugcacua ugcgcgagca ccuuuu 36 1029 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1029cauaaugaug gcaugcacua ugcgcgaucc acagca 36 1030 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1030cuuuaugaug gcaugcacua ugcgcgauaa uaucca 36 1031 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1031gcaaaugaug gcaugcacua ugcgcgacgc cuuuac 36 1032 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1032uuaagugaug gcaugcacua ugcgcgaaac acgccu 36 1033 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1033cuaaaugaug gcaugcacua ugcgcgaugg aaaauu 36 1034 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1034uuuugugaug gcaugcacua ugcgcgaucu acuucu 36 1035 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1035aaaggugaug gcaugcacua ugcgcgagau uuguuu 36 1036 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1036uuuguugaug gcaugcacua ugcgcgauaa aggcag 36 1037 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1037uauccugaug gcaugcacua ugcgcgauuu uuuugu 36 1038 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1038aauguugaug gcaugcacua ugcgcgaucc uauuuu 36 1039 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1039uaccuugaug gcaugcacua ugcgcgauug auaaaa 36 1040 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1040uguauugaug gcaugcacua ugcgcgaauu accuua 36 1041 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1041uugugugaug gcaugcacua ugcgcgauca auuacc 36 1042 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1042caaguugaug gcaugcacua ugcgcgaccu guugug 36 1043 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1043uccauugaug gcaugcacua ugcgcgauua auguug 36 1044 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1044auuucugaug gcaugcacua ugcgcgauua uuaaug 36 1045 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1045ucaauugaug gcaugcacua ugcgcgauuu ccauua 36 1046 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1046cuauuugaug gcaugcacua ugcgcgaauu auuucc 36 1047 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1047cuaacugaug gcaugcacua ugcgcgauuc aauuau 36 1048 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1048acauaugaug gcaugcacua ugcgcgauaa cuaacu 36 1049 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1049auuaaugaug gcaugcacua ugcgcgauac auaacu 36 1050 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1050acuggugaug gcaugcacua ugcgcgauua acauac 36 1051 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1051ggaguugaug gcaugcacua ugcgcgauua cuucug 36 1052 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1052auaugugaug gcaugcacua ugcgcgaugg agucau 36 1053 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1053aauaaugaug gcaugcacua ugcgcgaugu auggag 36 1054 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1054guaguugaug gcaugcacua ugcgcgauag aaauaa 36 1055 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1055aacguugaug gcaugcacua ugcgcgaugg cuaggc 36 1056 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1056aacggugaug gcaugcacua ugcgcgaugg cuaggc 36 1057 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1057aacguugaug gcaugcacua ugcgcggugg cuaggc 36 1058 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1058aacguugaug gcaugcacua ugcgcguugg cuaggc 36 1059 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1059aacgaugaug gcaugcacua ugcgcgaugg cuaggc 36 1060 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1060aacgaugaug gcaugcacua ugcgcggugg cuaggc 36 1061 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1061aacggugaug gcaugcacua ugcgcggugg cuaggc 36 1062 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1062aacggugaug gcaugcacua ugcgcguugg cuaggc 36 1063 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1063aacgaugaug gcaugcacua ugcgcguugg cuaggc 36 1064 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1064aacgcugaug gcaugcacua ugcgcggugg cuaggc 36 1065 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1065aacgcugaug gcaugcacua ugcgcgaugg cuaggc 36 1066 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1066aacguugaug gcaugcacua ugcgcgcugg cuaggc 36 1067 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1067aacggugaug gcaugcacua ugcgcgcugg cuaggc 36 1068 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1068aacgcugaug gcaugcacua ugcgcguugg cuaggc 36 1069 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1069aacgaugaug gcaugcacua ugcgcgcugg cuaggc 36 1070 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1070aacgcugaug gcaugcacua ugcgcgcugg cuaggc 36 1071 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1071agcugugaug gcaugcacua ugcgcgaucg ucaaggn 37 1072 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1072gaucaugaug gcaugcacua ugcgcgauuc guccacn 37 1073 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1073uucucugaug gcaugcacua ugcgcgauca auuacun 37 1074 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1074gagaaugaug gcaugcacua ugcgcgaucc aagagan 37 1075 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1075ucccuugaug gcaugcacua ugcgcgauug cacugun 37 1076 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1076guccuugaug gcaugcacua ugcgcgaugu acuggun 37 1077 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1077aguauugaug gcaugcacua ugcgcgauuu auggcan 37 1078 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1078agguaugaug gcaugcacua ugcgcgaucu ucagagn 37 1079 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1079aggacugaug gcaugcacua ugcgcgauag guacaun 37 1080 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1080aaucaugaug gcaugcacua ugcgcgauuu auuuccn 37 1081 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1081aauucugaug gcaugcacua ugcgcgauaa cuucuun 37 1082 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1082ggcauugaug gcaugcacua ugcgcgauca acacccn 37 1083 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1083gaaggugaug gcaugcacua ugcgcgauca ucaacan 37 1084 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1084uaaugugaug gcaugcacua ugcgcgauag aaggcan 37 1085 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1085uuuacugaug gcaugcacua ugcgcgaucu uugcucn 37 1086 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1086auaagugaug gcaugcacua ugcgcgauuu aagguan 37 1087 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1087acaggugaug gcaugcacua ugcgcgauug cuaguun 37 1088 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1088aacugugaug gcaugcacua ugcgcgaugc accaaan 37 1089 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1089accaaugaug gcaugcacua ugcgcgauuc acacuun 37 1090 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1090agcuuugaug gcaugcacua ugcgcgauua auuugun 37 1091 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1091uaaucugaug gcaugcacua ugcgcgauuu augugan 37 1092 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1092aagccugaug gcaugcacua ugcgcgauaa auuugun 37 1093 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1093aucauugaug gcaugcacua ugcgcgauca ggaagcn 37 1094 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1094agaauugaug gcaugcacua ugcgcgauca ucaggan 37 1095 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1095acauuugaug gcaugcacua ugcgcgauca gggaugn 37 1096 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1096cuuuaugaug gcaugcacua ugcgcgauuc aucaggn 37 1097 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1097guuucugaug gcaugcacua ugcgcgauug ccuugun 37 1098 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1098ggccuugaug gcaugcacua ugcgcgauaa uaguuun 37 1099 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1099aaagcugaug gcaugcacua ugcgcgauua ggagucn 37 1100 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1100aauccugaug gcaugcacua ugcgcgauuc auacugn 37 1101 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1101guugcugaug gcaugcacua ugcgcgauaa uaauccn 37 1102 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1102uaagcugaug gcaugcacua ugcgcgauaa cuggccn 37 1103 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1103cucucugaug gcaugcacua ugcgcgauga aagcucn 37 1104 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1104cagucugaug gcaugcacua ugcgcgaugc ugugaan 37 1105 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1105caaugugaug gcaugcacua ugcgcgaucg uacaacn 37 1106 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1106ugagcugaug gcaugcacua ugcgcgaucc aaacugn 37 1107 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1107cacuuugaug gcaugcacua ugcgcgauug uuuaaan 37 1108 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1108guguuugaug gcaugcacua ugcgcgaugc aauguun 37 1109 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1109uuaaaugaug gcaugcacua ugcgcgaugg aucagan 37 1110 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1110caugcugaug gcaugcacua ugcgcgaucu cacuucn 37 1111 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1111cucacugaug gcaugcacua ugcgcgaugc caucucn 37 1112 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1112acaccugaug gcaugcacua ugcgcgaucu agaaccn 37 1113 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1113uuuaaugaug gcaugcacua ugcgcgauga agaaaun 37 1114 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1114uggaaugaug gcaugcacua ugcgcgauaa aucacan 37 1115 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1115auccuugaug gcaugcacua ugcgcgaugu aaauggn 37 1116 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1116aacugugaug gcaugcacua ugcgcgauca agucaun 37 1117 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1117aaucuugaug gcaugcacua ugcgcgaugg uuagggn 37 1118 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1118ggagaugaug gcaugcacua ugcgcgaucc acagcan 37 1119 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1119aacuuugaug gcaugcacua ugcgcgaugg agauaun 37 1120 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1120uagggugaug gcaugcacua ugcgcgauuu cugaugn 37 1121 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1121cccuuugaug gcaugcacua ugcgcgaugg uaucugn 37 1122 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1122caaagugaug gcaugcacua ugcgcgauca gccaccn 37 1123 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1123cuauuugaug gcaugcacua ugcgcgauac cagggun 37 1124 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1124cauugugaug gcaugcacua ugcgcgauga agauuun 37 1125 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1125agcuuugaug gcaugcacua ugcgcgauga auuaaan 37 1126 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1126cacugugaug gcaugcacua ugcgcgauuc cagccun 37 1127 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1127agguuugaug gcaugcacua ugcgcgauga ggccaan 37 1128 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1128auaaaugaug gcaugcacua ugcgcgauuu gcugaan 37 1129 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1129acuggugaug gcaugcacua ugcgcgaucu gguaggn 37 1130 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1130uaccaugaug gcaugcacua ugcgcgauac ccagugn 37 1131 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1131gauacugaug gcaugcacua ugcgcgauau acccagn 37 1132 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1132gggauugaug gcaugcacua ugcgcgaugu cucuugn 37 1133 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1133ggucgugaug gcaugcacua ugcgcgauac caaaggn 37 1134 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1134cguguugaug gcaugcacua ugcgcgaucu cugggun 37 1135 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1135auacgugaug gcaugcacua ugcgcgaucg uguuaun 37 1136 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1136acaauugaug gcaugcacua ugcgcgauag agcuggn 37 1137 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1137aaguuugaug gcaugcacua ugcgcgauuc cuuuaan 37 1138 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1138acaguugaug gcaugcacua ugcgcgaugc caaauan 37 1139 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1139uuacaugaug gcaugcacua ugcgcgauuu gggucan 37 1140 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1140uggaaugaug gcaugcacua ugcgcgauua cacauun 37 1141 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1141uuacuugaug gcaugcacua ugcgcgaugc agagaan 37 1142 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1142cuguuugaug gcaugcacua ugcgcgauuu guacccn 37 1143 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1143uuucaugaug gcaugcacua ugcgcgauag caauucn 37 1144 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1144auggcugaug gcaugcacua ugcgcgauuu cuuucun 37 1145 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1145ugaagugaug gcaugcacua ugcgcgaugg ccauuun 37 1146 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1146augccugaug gcaugcacua ugcgcgaucu acaucan 37 1147 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1147guucaugaug gcaugcacua ugcgcgauaa agguaan 37 1148 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1148uaaacugaug gcaugcacua ugcgcgauuc aaaguun 37 1149 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1149acaaaugaug gcaugcacua ugcgcgaugu uaaugcn 37 1150 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1150ugcuaugaug gcaugcacua ugcgcgauuc uuccacn 37 1151 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1151ucugcugaug gcaugcacua ugcgcgauau ucuuccn 37 1152 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1152uacaaugaug gcaugcacua ugcgcgauac gucugcn 37 1153 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1153gggaaugaug gcaugcacua ugcgcgauuc acucaan 37 1154 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1154auuccugaug gcaugcacua ugcgcgaugc agugugn 37 1155 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1155caugcugaug gcaugcacua ugcgcgaucc aguauun 37 1156 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1156gaauuugaug gcaugcacua ugcgcgaugc uauccan 37 1157 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1157acagcugaug gcaugcacua ugcgcgauuc aguuucn 37 1158 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1158aucauugaug gcaugcacua ugcgcgaucc caaacan 37 1159 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1159ccuauugaug gcaugcacua ugcgcgauua ucccaan 37 1160 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1160cucaaugaug gcaugcacua ugcgcgauaa cugcagn 37 1161 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1161augugugaug gcaugcacua ugcgcgaugu uucagun 37 1162 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1162cugcaugaug gcaugcacua ugcgcgauga cccacan 37 1163 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1163cacugugaug gcaugcacua ugcgcgauau gacccan 37 1164 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1164accaaugaug gcaugcacua ugcgcgauuc cuaggun 37 1165 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1165uuugaugaug gcaugcacua ugcgcgauga ccaacan 37 1166 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1166cagcaugaug gcaugcacua ugcgcgauac uccuaun 37 1167 56 DNA Artificial Sequence Description of Artificial Sequence Selection Primer 1 1167tggtgcaagc ttaatacgac tcactatagg gagactgtct agatcatgag gatgct 56 1168 59 DNA Artificial Sequence Description of Artificial Sequence Selection Primer 2 1168tctcggatcc tgcagatcat nnnnnnnnnn nnnnnnnnnn nnaggattag catcctcat 59 1169 20 DNA Artificial Sequence Description of Artificial Sequence Reverse transcription primer 1169tctcggatcc tgcagatcat 20 1170 23 DNA Artificial Sequence Description of Artificial Sequence PCR primer 1170tggtgcaagc ttaatacgac tca 23 1171 11 RNA Artificial Sequence Description of Artificial Sequence Miscellaneous substrate 1171nnnnuhnnnn n 11 1172 28 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1172nnnnncugan gagnnnnnnc gaaannnn 28 1173 47 RNA Artificial Sequence Description of Artificial Sequence Self-cleaving Enzymatic Nucleic Acid 1173agaucgucnn nngucuaauc cucugaugag cgcaagcgaa acgaucu 47 1174 51 RNA Artificial Sequence Description of Artificial Sequence Self-cleaving Enzymatic Nucleic Acid 1174agaucaugag gagucuaauc cunnnnnnnn nnnnnnnnnn nnnnaugauc u 51 1175 69 RNA Artificial Sequence Description of Artificial Sequence Self-cleaving Enzymatic Nucleic Acid 1175gggagacugu cuagaucaug aggagucuaa uccunnnnnn nnnnnnnnnn nnnnnnauga 60ucugcagga 69 1176 18 RNA Artificial Sequence Description of Artificial Sequence Self-cleaving Enzymatic Nucleic Acid 1176cugaugagcg caagcgaa 18 1177 22 RNA Artificial Sequence Description of Artificial Sequence Self-cleaving Enzymatic Nucleic Acid 1177ggaaucagcc ugacaccggc cc 22 1178 22 RNA Artificial Sequence Description of Artificial Sequence Self-cleaving Enzymatic Nucleic Acid 1178ggcauccccg gcauggugcg cg 22 1179 22 RNA Artificial Sequence Description of Artificial Sequence Self-cleaving Enzymatic Nucleic Acid 1179agcauuaccc ggcuggugcg cg 22 1180 22 RNA Artificial Sequence Description of Artificial Sequence Self-cleaving Enzymatic Nucleic Acid 1180gcaucacggg gcaaucugcg cg 22 1181 22 RNA Artificial Sequence Description of Artificial Sequence Self-cleaving Enzymatic Nucleic Acid 1181agcaucaccc ggauggugcg cg 22 1182 22 RNA Artificial Sequence Description of Artificial Sequence Self-cleaving Enzymatic Nucleic Acid 1182agcaucaccc ggcuggugcg cg 22 1183 22 RNA Artificial Sequence Description of Artificial Sequence Self-cleaving Enzymatic Nucleic Acid 1183abcguccacg gcaucgagcg cg 22 1184 21 RNA Artificial Sequence Description of Artificial Sequence Self-cleaving Enzymatic Nucleic Acid 1184ugauggcuug cacuaagcgc g 21 1185 21 RNA Artificial Sequence Description of Artificial Sequence Self-cleaving Enzymatic Nucleic Acid 1185ugauggcaug cacuaugcgc g 21 1186 21 RNA Artificial Sequence Description of Artificial Sequence Self-cleaving Enzymatic Nucleic Acid 1186ugauggcaug caggaugcgc g 21 1187 21 RNA Artificial Sequence Description of Artificial Sequence Self-cleaving Enzymatic Nucleic Acid 1187ugauggcaug caccaugcgc g 21 1188 21 RNA Artificial Sequence Description of Artificial Sequence Self-cleaving Enzymatic Nucleic Acid 1188ugaucggaug caccaugcgc g 21 1189 21 RNA Artificial Sequence Description of Artificial Sequence Self-cleaving Enzymatic Nucleic Acid 1189ugggccgauc gcaagggcgc g 21 1190 75 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1190gggagacugu cuagaucaug aggaugcuaa uccuugaugg caugcacuau gcgcgaugau 60cugcaggauc cgaga 75 1191 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1191auccuugaug gcaugcacua ugcgcgauga ucugca 36 1192 16 RNA Artificial Sequence Description of Artificial Sequence Substrate Nucleic Acid for SEQ ID NO 1191 1192ugcagaucau gaggau 16 1193 35 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1193auccuugaug gcaugcacua ugcgcgauga cgcug 35 1194 15 RNA Artificial Sequence Description of Artificial Sequence Substrate Nucleic Acid for SEQ ID NO 1193 1194cagcgucaug aggau 15 1195 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1195auccuugaug gcaugcacua ugcgcgauga cgcuga 36 1196 16 RNA Artificial Sequence Description of Artificial Sequence Substrate Nucleic Acid for SEQ ID NO 1195 1196ucagcgucau gaggau 16 1197 29 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1197cccuugaugg caugcacuau gcgcgauga 29 1198 9 RNA Artificial Sequence Description of Artificial Sequence Substrate Nucleic Acid for SEQ ID NO 1197 1198ucaugaggg 9 1199 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1199auccuugaug gcaugcacua ugcgcgauga cgcugan 37 1200 16 RNA Artificial Sequence Description of Artificial Sequence Substrate Nucleic Acid for SEQ ID NO 1199 1200ucagcgucau gaggau 16 1201 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1201auccuugaug gcaugcacua ugcgcgauga cgcugan 37 1202 16 RNA Artificial Sequence Description of Artificial Sequence Substrate Nucleic Acid for SEQ ID NO 1201 1202ucagcgucau gaggau 16 1203 36 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1203auccuugaug gcaugcacua ugcgcgauga cgcuga 36 1204 16 RNA Artificial Sequence Description of Artificial Sequence Substrate Nucleic Acid for SEQ ID NO 1203 1204ucagcgucau gaggau 16 1205 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1205auccuugaug gcaugcacua ugcgcgauga cgcugan 37 1206 16 RNA Artificial Sequence Description of Artificial Sequence Substrate Nucleic Acid for SEQ ID NO 1205 1206ucagcgucau gaggau 16 1207 37 RNA Artificial Sequence Description of Artificial Sequence Enzymatic Nucleic Acid 1207nnnnuugaug gcaugcacua ugcgcgannn nnnnnnn 37 1208 16 RNA Artificial Sequence Description of Artificial Sequence Substrate Nucleic Acid for SEQ ID NO 1207 1208nnnnnnnnnu gannnn 16

Claims

1. A nucleic acid molecule with endonuclease activity to cleave a substrate RNA having the formula V: wherein, X and Y are independent oligonucleotides comprising 3 or more nucleotides; L is a linker which may be present or absent, wherein said linker, when present, is independently or in combination a nucleotide linker, or a non-nucleotide linker; Z is independently a nucleotide which is complementary to a nucleotide in the substrate RNA and C, G, A, and U represent cytidine, guanosine, adenosine, and uridine nucleotides, respectively, wherein each of said X and Y oligonucleotides independently comprises a sequence complementary to a portion of the substrate RNA.

2. The nucleic acid molecule with endonuclease activity of claim 1, wherein said L is a nucleotide linker.

3. The nucleic acid molecule with endonuclease activity of claim 2, wherein said nucleotide linker is a sequence selected from the group consisting of 5′-GCACU-3′, 5′-GAACU-3′, 5′-GCACC-3′, 5′-GNACU-3′, 5′-GNGCU-3′, 5′-GNCCU-3′, 5′-GNUCU-3′, 5′-GNGUU-3′, 5′-GNCUU-3′, 5′-GNUUU-3′, 5′-GNAUU-3′, 5′-GNACA-3′, 5′-GNGCA-3′, 5′-GNCCA-3′, and 5′-GNUCA-3′, whereby N can be selected from the group consisting of A, G, C, or U.

4. The nucleic acid molecule with endonuclease activity of claim 2, wherein said nucleotide linker is a nucleic acid aptamer.

5. The nucleic acid molecule with endonuclease activity of claim 4, wherein said aptamer is an ATP aptamer.

6. The nucleic acid molecule with endonuclease activity of claim 1, wherein said L is non-nucleotide linker.

7. The nucleic acid molecule with endonuclease activity of claim 1, wherein said chemical linkage is independently or in combination selected from the group consisting of phosphate ester, amide, phosphorothioate, phosphorodithioate, arabino, and arabinofluoro linkages.

8. The nucleic acid molecule with endonuclease activity of claim 1, wherein said nucleic acid molecule is chemically synthesized.

9. The nucleic acid molecule with endonuclease activity of claim 1, wherein said nucleic acid molecule comprises at least four ribonucleotide residues.

10. The nucleic acid molecule with endonuclease activity of claim 1, wherein said nucleic acid molecule comprises at least five ribonucleotide residues.

11. The nucleic acid molecule with endonuclease activity of claim 1, wherein said nucleic acid molecule comprises at least one sugar modification.

12. The nucleic acid molecule with endonuclease activity of claim 1, wherein said nucleic acid molecule comprises at least one nucleic acid base modification.

13. The nucleic acid molecule with endonuclease activity of claim 1, wherein said nucleic acid molecule comprises at least one phosphate backbone modification.

14. The nucleic acid molecule with endonuclease activity of claim 11, wherein said sugar modification is selected from the group consisting of 2′-H, 2′-O-methyl, 2′-O-allyl, 2′-C-allyl, and 2′-deoxy-2′-amino.

15. The nucleic acid molecule with endonuclease activity of claim 13, wherein said phosphate backbone modification is selected from the group consisting of phosphorothioate, phosphorodithioate, and amide.

16. The nucleic acid molecule with endonuclease activity of claim 1, wherein said nucleic acid molecule comprises a 5′-cap or a 3′-cap or both a 5′-cap and a 3′-cap.

17. The nucleic acid molecule with endonuclease activity of claim 16, wherein said 5′-cap is a phosphorothioate modification of at least one 5′-terminal nucleotide in said nucleic acid molecule.

18. The nucleic acid molecule with endonuclease activity of claim 16, wherein said 5′-cap is a phosphorothioate modification of at least two 5′-terminal nucleotides in said nucleic acid molecule.

19. The nucleic acid molecule with endonuclease activity of claim 16, wherein said 5′-cap is a phosphorothioate modification of at least three 5′-terminal nucleotides in said nucleic acid molecule.

20. The nucleic acid molecule with endonuclease activity of claim 16, wherein said 5′-cap is a phosphorothioate modification of at least four 5′-terminal nucleotides in said nucleic acid molecule.

21. The nucleic acid molecule with endonuclease activity of claim 16, wherein said 3′-cap is a 3′-3′ inverted riboabasic moiety.

22. The nucleic acid molecule with endonuclease activity of claim 16, wherein said 3′-cap is a 3′-3′ inverted deoxyriboabasic moiety.

23. The nucleic acid molecule with endonuclease activity of claim 1, wherein said nucleic acid molecule with endonuclease activity cleaves a separate nucleic acid molecule.

24. The nucleic acid molecule with endonuclease activity of claim 23, wherein said separate nucleic acid molecule is RNA.

25. The nucleic acid molecule with endonuclease activity of claim 23, wherein said nucleic acid molecule with endonuclease activity comprises between 12 and 100 bases complementary to said separate nucleic acid molecule.

26. The nucleic acid molecule with endonuclease activity of claim 23, wherein said nucleic acid molecule with endonuclease activity comprises between 14 and 24 bases complementary to said separate nucleic acid molecule.

27. The nucleic acid molecule with endonuclease activity of claim 1, wherein the length of said X is equal to the length of said Y.

28. The nucleic acid molecule with endonuclease activity of claim 1, wherein the length of said X is not equal to the length of said Y.

29. The nucleic acid molecule with endonuclease activity of claim 28, wherein the length of said X is 10 nucleotides and the length of said Y is 5 nucleotides.

30. The nucleic acid molecule with endonuclease activity of claim 1, wherein said Z is selected from the group consisting of Adenosine, Uridine, Guanosine, Cytidine and Inosine.

31. A cell including the nucleic acid molecule with endonuclease activity of claim 1.

32. The cell of claim 31, wherein said cell is a mammalian cell.

33. The cell of claim 32, wherein said cell is a human cell.

34. An expression vector comprising nucleic acid sequence encoding at least one of the nucleic acid molecule with endonuclease activity of claim 1, in a manner which allows expression of that nucleic acid molecule with endonuclease activity.

35. A cell including the expression vector of claim 34.

36. The cell of claim 35, wherein said cell is a mammalian cell.

37. The cell of claim 36, wherein said cell is a human cell.

38. A method of cleaving a separate nucleic acid comprising, contacting the nucleic acid molecule of claim 1 with said separate nucleic acid molecule to achieve the cleavage of said separate nucleic acid molecule.

39. The method of claim 38, wherein said cleavage is carried out in the presence of a divalent cation.

40. The method of claim 39, wherein said divalent cation is Mg2+.

41. The expression vector of claim 34, wherein said vector comprises:a) a transcription initiation region; b) a transcription termination region; c) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

42. The expression vector of claim 34, wherein said vector comprises:a) a transcription initiation region; b) a transcription termination region; c) an open reading frame; d) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said gene is operably linked to the 3′-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

43. The expression vector of claim 34, wherein said vector comprises:a) a transcription initiation region; b) a transcription termination region; c) an intron; d) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region, said intron and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

44. The expression vector of claim 34, wherein said vector comprises:a) a transcription initiation region; b) a transcription termination region; c) an intron; d) an open reading frame; e) a nucleic acid sequence encoding at least one said nucleic acids molecule, wherein said sequence is operably linked to the 3′-end, of said open reading frame; and wherein said sequence is operably linked to said initiation region, said intron, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

45. The nucleic acid molecule of claim 23, wherein said nucleic acid molecule comprises at least five ribose residues; a phosphorothioate, phosphorodithioate, or 2′-C-allyl modification at position 6 of said nucleic acid; at least ten 2′-O-alkyl modifications, and a 3′- cap structure.

46. The nucleic acid molecule of claim 45, wherein said 2′-O-alkyl modifications is selected from the group consisting of 2′-O-methyl and 2′-O-allyl.

47. The nucleic acid molecule of claim 45, wherein said 3′-cap is 3′-3′ inverted riboabasic moiety.

48. The nucleic acid molecule of claim 45, wherein said 3′-cap is 3′-3′ inverted deoxyriboabasic moiety.

49. The nucleic acid molecule of claim 45, wherein said 3′-cap is 3′-3′ inverted nucleotide.

50. The nucleic acid molecule of claim 45, wherein said nucleic acid comprises phosphorothioate linkages in at least two of the 5′ terminal nucleotides.