AU770076B2 - Alpha-conotoxin peptides - Google Patents

Description

TITLE OF THE INVENTION ALPHA-CONOTOXN PEPTIDES This invention was made with Government support under Grant No. PO1 GM48677 awarded by the National Institute of General Medical Sciences, National Institutes of Health, Bethesda, Maryland. The United States Government has certain rights in the invention.

BACKGROUND OF THE INVENTION Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

The invention relates to relatively short peptides (termed a-conotoxins herein), about 10-30 residues in length, which are naturally available in minute amounts in the venom of the cone snails or analogous to the naturally available peptides, and which preferably include two disulfide bonds.

The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference, and for convenience are referenced in the following text by author and date and are listed alphabetically by author in the appended bibliography.

The predatory cone snails (Conus) have developed a unique biological strategy.

Their venom contains relatively small peptides that are targeted to various oneuromuscular receptors and may be equivalent in their pharmacological diversity to the I: alkaloids of plants or secondary metabolites of microorganisms. Many of these peptides are among the smallest nucleic acid-encoded translation products having defined conformations, and as such, they are somewhat unusual. Peptides in this size range Vnormally equilibrate among many conformations. Proteins having a fixed conformation are generally much larger.

The cone snails that produce these peptides are a large genus of venomous gastropods comprising approximately 500 species. All cone snail species are predators .30 that inject venom to capture prey, and the spectrum of animals that the genus as a whole can envenomate is broad. A wide variety of hunting strategies are used, however, every Conus species uses fundamentally the same basic pattern of envenomation.

Several peptides isolated from Conus venoms have been characterized. These include the t- and co-conotoxins which target nicotinic acetylcholine receptors, muscle-sodium-channels, and neuronal calcium channels, respectively (Olivera et al., 1985). Conopressins, which are vasopressin analogs, have also been identified (Cruz et al., 1987). In addition, peptides named conantokins have been isolated from Conus geographus and Conus tulipa (Mena et al., 1990; Haack et al., 1990).

The a-conotoxins are small peptides highly specific for neuromuscular junction nicotinic acetylcholine receptors (Gray et al., 1981; Marshall and Harvey, 1990; Blount et al., 1992; Jacobsen et al., 1997) or highly specific for neuronal nicotinic acetylcholine receptors (Fainzilber et al., 1994); Johnson et al., 1995; Cartier et al., 1996; Luo et al., 1998). The a-conotoxins with specificity for neuromuscular junction nicotinic acetylcholine receptors are used as neuromuscular blocking agents for use in conjunction with surgery, as disclosed in U.S. patent Serial No. 6,268,473 filed 21 January 2000 and international patent No. WO 00/43409, filed 21 January 2000, each incorporated by reference herein. Additional a-conotoxins and uses for them have been described in U.S. Patent Nos. 4,447,356 (Olivera et al., 1984); 5,432,155; 5,514,774, each incorporated herein by reference.

Additional uses for a-conotoxins are described in WO 99/33482 filed 22 December 1998, incorporated herein by reference. In this application, a-conotoxins with specificity for neuronal nicotinic acetylcholine receptors are used for treating disorders regulated at neuronal nicotinic acetylcholine receptors. Such disorders include, but are not limited to, cardiovascular disorders, gastric motility disorders, urinary incontinence, nicotine addiction, mood disorders (such as bipolar disorder, unipolar depression, dysthymia and seasonal effective disorder) and small cell lung 25 carcinoma, as well as the localization of small cell lung carcinoma.

It is desired to provide additional a-conotoxin peptides having uses as described herein.

o SUMMARY OF THE INVENTION The invention relates to relatively short peptides (termed a-conotoxins herein), about 10-30 residues in length, which are naturally available in minute amounts in the -3venom of the cone snails or analogous to the naturally available peptides, and which preferably include two disulfide bonds.

More specifically, the present invention is directed to a-conotoxin peptides having the general formula I: Xaal -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Cys-Cys-Xaa-Xaa 7 -Xaa 8 -Xaa 9 -Cys- Xaalo-Xaal 1- Xaal 2 Cys-Xaal 3 (SEQ ID NO:1), wherein Xaaj is des-Xaal, Ile, Leu or Val; Xaa 2 is des-Xaa 2 Ala or Gly; Xaa 3 is des-Xaa 3 Gly, Trp (D or neo-Trp, halo-Trp or any unnatural aromatic amino acid; Xaa 4 is des-Xaa 4 Asp, Phe, Gly, Ala, Glu,y-carboxy-Glu (Gla) or any unnatural aromatic amino acid; Xaas is Glu, Gla, Asp, Ala, Thr, Ser, Gly, Ile, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 6 is Ser, Thr, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 7 is Asp, Glu, Gla, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaas is Ser, Thr, Asn, Ala, Gly, Arg, Lys, ornithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid; His, halo-His, Pro or hydroxy-Pro; Xaa 9 is Thr, Ser, Ala, Asp, Asn, Pro, hydroxy-Pro, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaao is Gly, Ser, Thr, Asn, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; XaalI is Gin, Leu, His, halo-His, Trp (D or halo-Trp, neo-Trp, Tyr, nor- Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid or any unnatural aromatic amino acid; Xaa 12 is Asn, His, 25 halo-His, Ile, Leu, Val, Gin, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,Ndimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 13 is des- Xaal 3 Val, Ile, Leu, Arg, omrnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl- Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid. The C-terminus may contain a free carboxyl group or an amide group. The halo is chlorine, bromine or iodine, preferably iodine for Tyr and His and preferably bromine for Trp. The Cys residues may be in D or L configuration and may optionally be substituted with **homocysteine (D or The Tyr residues may be substituted with the 3-hydroxyl or 2hydroxyl isomers and corresponding O-sulpho- and O-phospho-derivatives. The acidic 3aamino acid residues may be substituted with any synthetic acidic bioisoteric amino acid surrogate, tetrazolyl derivatives of Gly and Ala.

More specifically, the present invention is directed to ct-conotoxin peptides having the general formnula 11: Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Cys-Cys-Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Cys-Xaa-Xaa 0 -Xaa 11 Xaa 1 2 -Xaal 3 -Xaa 14 -Cys-Xaa 5 -Xaal 6 -Xaa 7 (SEQ ID NO:2), wherein Xaa 1 is des-Xaa 1 Asp, Glu or 7-carboxy-Glu (Gla); Xaa 2 is des-Xaa 2 Gln, Ala, Asp, Glu, Gla; Xaa 3 is des- Xaa 3 Gly, Ala, Asp, Glu, Gla, Pro or hydroxy-Pro; Xaa 4 is des-Xaa 4 Gly, Glu, Gla, Gln, Asp, Asn, Pro or hydroxy-Pro; Xaa 5 is Ser, Thr, Gly, Glu, Gla, Asn, Trp (D or neo- Trp, halo-Trp, Arg, omnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, dihalo-Tyr, O-sulpho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing.

WO 00/44776 PCT/US00/01979 4 amino acid; Xaa 6 is Asp, Asn, His, halo-His, Thr, Ser, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa, is Pro or hydroxy-Pro; Xaag is Ala, Ser, Thr, Asp, Val, lie, Pro, hydroxy-Pro, Tyr, nor-Tyr, mono-halo- Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa, is Gly, lie, Leu, Val, Ala, Thr, Ser, Pro, hydroxy-Pro, Phe, Trp (D or neo-Trp, halo-Trp, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, NN-dimethyl-Lys, N,N,N-trimethyl- Lys, any unnatural basic amino acid or any unnatural aromatic amino acid; Xaao is Ala, Asn, Phe, Pro, hydroxy-Pro, Glu, Gla, Gin, His, halo-His, Val, Ser, Thr, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, NN,N-trimethyl-Lys or any unnatural basic amino acid; Xaa I is Thr, Ser, His, halo-His, Leu, lie, Val, Asn, Met, Pro, hydroxy-Pro, Arg, omrnithine, homoarginine, Lys, N-methyl-Lys, NN-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa, 2 is Asn, Pro, hydroxy-Pro, Gin, Ser, Thr, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, NN-dimethyl-Lys N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 3 is des-Xaa 3 Gly, Thr, Ser, Pro, hydroxy-Pro, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 4 is des-Xaa 4 lie, Val, Asp, Leu, Phe, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,NN-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; and Xaa 5 is des-Xaa 15 Gly, Ala, Met, Ser, Thr, Trp (D or neo-Trp, halo-Trp, any unnatural aromatic amino acid, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa, 6 is des-Xaa 1 6 Trp (D or neo-Trp, halo-Trp, any unnatural aromatic amino acid, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 7 is des-Xaa,7, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl- Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid. The C-terminus may contain a free carboxyl group or an amide group. The halo is preferably bromine, chlorine or iodine, more preferably iodine for His or Tyr and bromine for Trp. The Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or The Tyr residues may be substituted with the 3-hydroxyl or 2-hydroxyl isomers and corresponding O-sulpho- and 0phospho-derivatives. The acidic amino acid residues may be substituted with any synthetic acidic bioisoteric amino acid surrogate, tetrazolyl derivatives of Gly and Ala.

More specifically, the present invention is directed to a-conotoxin peptides having the general formula III: Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Cys-Cys-Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Cys-Xaai o-Xaa 11 Xaa 1 2 -Xaa 1 3 -Xaal 4 -Xaa 1 5 -Xaa 1 6 -Cys-Xaa 1 7 -Xaa 1 g-Xaa 1 9 -Xaa 2 o-Xaa 2 1 -Xaa 22 -Xaa 23 -Xaa 24 (SEQ ID NO:3), wherein Xaaj is des-Xaa 1 Ser or Tbr; Xaa 2 is des-Xaa 2 Asp, Glu, ycarboxy-Glu (Gla), Asn, Ser or Thr; Xaa 3 is des-Xaa 3 Ala, Gly, Asn, Ser, Thr, Pro, hydroxy-Pro, Arg, omnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 1 is des-Xaa 4 Ala, Val, Leu, Ile, Gly, Glu, Gla, Gln, Asp, Asn, Phe, Pro, hydroxy-Pro or any unnatural aromatic amino acid; Xaa 5 is des-Xaa 5 Thr, Ser, Asp, Glu, Gla, Gln, Gly, Val, Asp, Asn, Ala, Pro, hydroxy-Pro, Arg, omnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 6 is Tbr, Ser, Asp, Asn, Met, Val, Ala, Gly, Leu, Ile, Phe, any unnatural aromatic amino acid, Pro, hydroxy-Pro, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa.

7 is Ile, Leu, Val, Ser, Thr, Gln, Asn, Asp, Arg, His, halo-His, Phe, any unnatural aromatic amino acid, homoarginine, omnithine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural ~:basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, 0-phospho- Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 8 is Pro, hydroxy- Pro, Ser, Thr, Ile, Asp, Leu, Val, Gly, Ala, Phe, any unnatural aromatic amino acid, Arg, *ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 9 is Val, Ala, Gly, Ile, Leu, Asp, Ser, Thr, Pro, hydroxy-Pro, Arg, omnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaaj 0 is His, halo-His, Arg, homoarginine, ornithine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Asn, Ser, Thr, Phe, Ile, Leu, Gly, Trp (D or neo-Trp, halo-Trp, any unnatural aromatic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaaj I is Leu, Gln, Val, Ile, Gly, Met, Ala, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, Ser, Thr, Arg, homoarginine, ornithine, any unnatural basic amino acid, Asn, Giu, Gia, Gin, Phe, Trp (D or neo-Trp, halo-Trp or any unnatural aromatic amino acid; Xaa 12 is Glu, Gla, Gin, Asn, Asp, Pro, hydroxy-Pro, Ser, Gly, Thr, Lys, Nmethyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, Arg, homoarginine, ornithine, any unnatural basic amino acid, Phe, His, halo-His, any unnatural aromatic amino acid, Leu, Met, Gly, Ala, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 13 is His, halo-His, Asn, Thr, Ser, lie, Val, Leu, Phe, any unnaturai aromatic amino acid, Arg, homoarginine, omnithine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho- Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa1 4 is Ser, Thr, Ala, Gin, Pro, hydroxy-Pro, Gly, Ilie, Leu, Arg, ornithine, homoarginine, Lys, N-methyi-Lys, N,N-dimethyl-Lys, N,N,N-trimethyi-Lys or any unnatural basic amino acid; Xaa 15 is Asn, Giu, Gia, Asp, Gly, His, halo-His, Ala, Leu, Gln, Arg, omnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyi-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 16 is Met, Ilie, Thr, Ser, Val, Leu, Pro, hydroxy-Pro, Phe, any unnatural aromatic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr, nitro-Tyr, any unnatural hydroxy containing amino acid, Glu, Gla, Ala, His, halo-His, Mrg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 17 is des-Xaa 17 Gly, Asp, Asn, Ala, Ile, Leu, Ser, Thr, His, halo-His, Mrg, omnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 1 8 is des-Xaa, 8 Gly, Giu, Gla, Gin, Trp (D or neo-Trp, halo-Trp, any unnatural aromatic amino acid, Arg, omnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyi-Lys, N,N,N-trimethyi-Lys or any unnatural basic amino acid; Xaaj 9 is des-Xaa 1 9 Ser, Thr, Val, Ilie, Ala, Mrg, omnithine, homoarginine, Lys, N-methyi-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 2 0 is des-Xaa 2 o, Val, Asp, His, halo-His, Arg, omnithine, homoarginine, Lys, N-methyi-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 2 l is des-Xaa 21 Asn, Pro or hydroxy-Pro; Xaa 22 is des-Xaa 22 Mrg, omnithine, homoarginine, Lys, N-methyi-Lys, N,N-dimethyi-Lys, N,N,N-trimethyi-Lys or any unnatural basic amino acid; Xaa 23 is des-Xaa23, Ser or Thr; Xaa 24 is des-Xaa 24 Leu, Ilie or Val; with the proviso that Xaa 5 is not Gly, when Xaaj -7is des-Xaal, Xaa 2 is des-Xaa 2 Xaa 3 is des-Xaa 3 Xaa 4 is des-Xaa 4 Xaa 6 is Ser, Xaa 7 is His, Xaa 8 is Pro, Xaa 9 is Ala, Xaajo is Ser, Xaall is Val, Xaa 12 is Asn, Xaa 13 is Asn, Xaa 14 is Pro, Xaa 1 5 is Asp, Xaa 16 is le, Xaa 17 is des-Xaal 7 Xaa 1 8 is des-Xaa 18 Xaaj 9 is des-Xaa 19 Xaa 20 is des-Xaa 2 o, Xaa 2 l is des-Xaa 2 l, Xaa 22 is des-Xaa 22 Xaa 23 is des- Xaa 23 and Xaa 24 is des-Xaa 24 The C-terminus may contain a free carboxyl group or an amide group. The halo is preferably bromine, chlorine or iodine, more preferably iodine for His and Tyr and bromine for Trp. The Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or The Tyr residues may be substituted with the 3-hydroxyl or 2-hydroxyl isomers and corresponding O-sulpho- and 0-phospho-derivatives. The acidic amino acid residues may be substituted with any synthetic acidic bioisoteric amino acid surrogate, tetrazolyl derivatives of Gly and Ala.

The present invention is also directed to novel specific a-conotoxin peptides of general formula I having the formulas: Asp-Xaa 1 -Cys-Cys-Ser-Asp-Ser-Arg-Cys-Gly-Xaa 2 -Asn-Cys-Leu (SEQ ID NO:4); Ala-Cys-Cys-Ser-Asp-Arg-Arg-Cys-Arg-Xaa 3 -Arg-Cys (SEQ ID Phe-Thr-Cys-Cys-Arg-Arg-Gly-Thr-Cys-Ser-Gln-His-Cys (SEQ ID NO:6); Asp-Xaa 1 -Cys-Cys-Arg-Arg-His-Ala-Cys-Thr-Leu-Ile-Cys (SEQ ID NO:7); *20 Asp-Xaat-Cys-Cys-Arg-Arg-Xaa 5 -Xaa 5 -Cys-Tbr-Leu-Ile-Cys (SEQ ID NO:8); Gly-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Arg-Xaa 4 -Arg-Cys-Arg (SEQ ID NO:9); (SQGly-Gly-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Ala-Xaa 3 -Arg-Cys (SEQ ID NO: Ile-Ala-Xaa 3 -Asp-Ile-Cys-Cys-Ser-Xaa -Xaa 5 -Asp-Cys-Asn-His-Xaa 2 -Cys-Va *SE ID NO: 11); and Gly-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Xaa 2 -His-Gln-Cys (SEQ ID NO: 12), ~.wherein Xaaj is Glu or y-carboxy-Glu (Gla); Xaa 2 is Lys, N-methyl-Lys, N,N-dimethyl- Lys or N,N,N-trimethyl-Lys; Xaa 3 is Trp (D or halo-Trp or neo-Trp; Xaa 4 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, 0-phospho-Tyr or nitro-Tyr; and Xaa 5 is Pro or hydroxy-Pro; and the C-terminus contains a carboxyl or amide group.

0 0. 30 The halo is preferably bromine, chlorine or'iodine, more preferably iodine for Tyr and bromine for Trp. In addition, the His residues may be substituted with halo-His; the Arg residues may be substituted by Lys, omnithine, homoarginine, N-methyl-Lys, N,Ndimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Lys residues 7a may be substituted by Arg, ornithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Tyr residues may be substituted with any unnatural hydroxy containing amino acid; the Ser residues may be substituted with Thr; the Thr residues may be substituted with Ser; and the Phe and Trp residues may be substituted with any unnatural aromatic amino acid. The Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or The Tyr residues may be substituted with the 3-hydroxyl or 2-hydroxyl isomers and corresponding O-sulpho- and O-phospho-derivatives. The acidic amino acid residues may be substituted with any synthetic acidic bioisoteric amino acid surrogate, tetrazolyl derivatives of Gly and Ala.

oo WO 00/44776 WO 0044776PCT/USOO/01979 8 More specifically, the present invention is directed to the following a-conotoxin peptides of general formula 1: Imi SEQ ID NO:4, wherein Xaa, is Glu and Xaa, is Lys; Iml.2: SEQ ID NO:5, wherein Xaa 3 is Trp; Rgl.2: SEQ ID NO:6; Rgl SEQ ID NO:7, wherein Xaa 4 is Tyr; Rg1 .6A: SEQ ID NO:8, wherein Xaa 4 is Tyr and Xaa 5 is Pro; Rgl.7: SEQ ID NO:9, wherein Xaa 4 is Tyr and Xaa 5 is Pro; Rgl.9: SEQ ID NO: 10, wherein Xaa 3 is Trp and Xaas is Pro; Rgl.10: SEQ ID NO:l 11, wherein Xaaj is Glu, Xaa 2 is Lys, Xaa 3 is Trp and Xaa, is Pro; and Rg1. 11: SEQ ID NO: 12, wherein Xaa 2 is Lys and Xaa 5 is Pro.

The C-terminus of Iml.l, Rgl.7 an Rgl.10 preferably contains a free carboxyl group. The Cterminus of Iml.2, Rgl.2, Rgl.6, Rg1.6A, Rgl.9 and Rgl.1 1 preferably contains an amide group.

The present invention is further directed to novel specific a-conotoxin peptides of general formula II having the formulas: Cys-Cys-Ser-Asp-Xaa 5 -Ala-Cys-Xaa 2 -Gln-Thr-Xaa 5 -Gly-Cys-Arg (SEQ ID NO: 13); Cys-Cys-Xaaj -Asn-Xaas-Ala-Cys-Arg-His-Thr-Gln-Gly-Cys (SEQ ID NO: 14); Gly-Cys-Cys-Xaa 3 -His-Xaa 5 -Ala-Cys-Gly-Arg-His-Xaa 4 -Cys (SEQ ID NO: Ala-Xaa 5 -Cys-Cys-Asn-Asn-Xaa 5 -Ala-Cys-Val-Xaa 2 -His-Arg-Cys (SEQ ID NO: 16); Ala-Xaa 5 -Gly-Cys-Cys-Asn-Asn-Xaa 5 -Ala-Cys-Val-Xaa 2 -His-Arg-Cys (SEQ ID NO: 17); Xaa 5 -Xaa 5 -Cys-Cys-Asn-Asn-Xaas-Ala-Cys-Val-Xaa 2 -His-Arg-Cys (SEQ ID NO: 18); Asp-Xaa 1 -Asn-Cys-Cys-Xaa 3 -Asn-Xaa 5 -Ser-Cys-Xaas-Arg-Xaa 5 -Arg-Cys-Thr (SEQ ID NO:19); Gly-Cys-Cys-Ser-Thr-Xaa 5 -Xaa 5 -Cys-Ala-Val-Leu-Xaa 4 -Cys (SEQ ID NO Gly-Cys-Cys-Gly-Asn-Xaa 5 -Asp-Cys-Thr-Ser-H-is-Ser-Cys (SEQ ID NO:2 1); Gly-Cys-Cys-Ser-Asn-Xaa 5 -Xaa 5 -Cys-Ala-His-Asn-Asn-Xaa 5 -Asp-Cys-Arg (SEQ ID NO:42); Gly-Cys-Cys-Xaa 4 -Asn-Xaa-Val-Cys-Xaa 2 -Xaa-Xaa 4 -Xaa 4 -Cys-Xaa 3 -Xaa, (SEQ ID NO: 154); Xaa 6 -Xaa 1 .Xaa 5 -Gly- Cys-Cys-Arg-His-Xaa 5 Ala-Cys-Gly-Xaa 2 -Asn-Arg-Cys (SEQ ID NO:155); -9-

ID

NO: 156); Gl-y-y-a4AnXa-e-y-a3Xa-a2TrXa-y-e-a3 Xaa 2 (SEQ ID NO: 15 7); Cys-Cys-Ser-Asn-Xaa 5 -Thr-Cys-Xaa2-Xaal -Thr-Xaa4-Gly-Cys (SEQ ID NO: 15 8); Cys-Cys-Ala-Asn-Xaa 5 -Ile-Cys-Xaa 2 -Asn-Thr-Xaa5-Gly-Cys (SEQ ID NO: 159); Cys-Cys-Asn-Asn-Xaa 5 -Thr-Cys-Xaa2-Xaal -Thr-Xaa 4 -Gly-Cys (SEQ lID NO: 160); Cys-Cys-Ser-Asn-Xaa 5 -Val-Cys-Xaa2-Xaal -Tbr-Xaa 4 -Gly-Cys (SEQ ID NO: 16 1); Gly-Gly-Cys-Cys-Ser-Xaa 4 -Xaa 5 -Xaa 5 -Cys-Ile-Ala-Ser-Asn-Xaa5-Xaa2-Cys-Gly (SEQ lID NO: 162); Gly-Cys-Cys-Ser-His-Xaa 5 -Val-Cys-Ser-Ala-Met-Ser-Xaa5-Ile-Cys (SEQ ID NO: 163); Gly-Cys-Cys-Xaa 2 -Asn-Xaa 5 -Xaa 4 -Cys-Gly-Ala-Ser-Xaa2-Thr-Xaa4-Cys

(SEQ

ID NO: 164); Gly-Cys-Cys-Ser-Xaat-Xaa 5 -Xaa 5 -Cys-Phe-Ala-Thr-Asn-Xaa5-Asp-Cys

(SEQ

ID NO: 165); .*(SEQ lID NO: 166); (SEQ lID NO: 167); (SEQ lBD NO: 168); and (SEQ ]ED NO: 169), wherein Xaa 1 is Glu or y-carboxy-Glu (Gla); Xaa2 is Lys, N-methyl-Lys, N,N-dimethyl- Lys or N,N,N-trimethyl-Lys; Xaa 3 is Trp (D or halo-Trp or neo-Trp; Xaa 4 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-suipho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa 5 is Pro or hydroxy-Pro; and the C-terminus contains a carboxyl or amide group.

The halo is preferably bromine, chlorine or iodine, more preferably iodine for Tyr and bromine for Tip. In addition, the His residues may be substituted with halo-His; the Arg 9aresidues may be substituted by Lys, ornithine, homoarginine, N-methyl-Lys, N,Ndimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Lys residues may be substituted by Arg, ornithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Tyr residues may be substituted with any unnatural hydroxy containing amino acid; the Ser residues may be substituted with Thr; the Thr residues may be substituted with Ser; and the Phe and Trp residues may be substituted with any unnatural aromatic amino acid. The Cys residues may be in D or L configuration and may So WO 00/44776 PCT/US00/01979 optionally be substituted with homocysteine (D or The Tyr residues may be substituted with the 3-hydroxyl or 2-hydroxyl isomers and corresponding O-sulpho- and O-phospho-derivatives. The acidic amino acid residues may be substituted with any synthetic acidic bioisoteric amino acid surrogate, tetrazolyl derivatives of Gly and Ala.

More specifically, the present invention is directed to the following a-conotoxin peptides of general formula II: Snl.l: Snl.2: S11.3: A1.2: Bul.l: Bul.2: Bul.3: Bul.4: Crl.3: Dil.l: Msl.7: P1.7: SEQ ID NO:13, wherein Xaa 2 is Lys and Xaas is Pro; SEQ ID NO:14, wherein Xaa, is Glu and Xaa 5 is Pro; SEQ ID NO: 15, wherein Xaa 3 is Trp, Xaa 4 is Tyr and Xaa, is Pro; SEQ ID NO:16, wherein Xaa 2 is Lys and Xaa 5 is Pro; SEQ ID NO:17, wherein Xaa 2 is Lys and Xaa 5 is Pro; SEQ ID NO: 18, wherein Xaa 2 is Lys and Xaa 5 is Pro; SEQ ID NO:19, wherein Xaa, is Glu, Xaa 3 is Trp and Xaa 5 is Pro; SEQ ID NO:20, wherein Xaa 4 is Tyr and Xaa 5 is Pro; SEQ ID NO:21, wherein Xaa 5 is Pro; SEQ ID NO:42 wherein Xaa 5 is Pro; SEQ ID NO:154, wherein Xaa 2 is Lys, Xaa 3 is Trp, Xaa 4 is Tyr and Xaa 5 is Pro; SEQ ID NO:155, wherein Xaa, is Glu, Xaa 2 is Lys, Xaa 5 is Pro and Xaa 6 is Gin; SEQ ID NO:156, wherein Xaa 5 is Pro; SEQ ID NO:157, wherein Xaa 2 is Lys, Xaa 3 is Trp, Xaa 4 is Tyr and Xaa 5 is Pro; SEQ ID NO:158, wherein Xaa, is Glu, Xaa 2 is Lys, Xaa 4 is Tyr and Xaa 5 is Pro; SEQ ID NO:159, wherein Xaa 2 is Lys and Xaa, is Pro; SEQ ID NO:160, wherein Xaa, is Glu, Xaa 2 is Lys, Xaa 4 is Tyr and Xaa 5 is Pro; SEQ ID NO:161, wherein Xaa, is Glu, Xaa 2 is Lys, Xaa 4 is Tyr and Xaa 5 is Pro; SEQ ID NO:162, wherein Xaa 2 is Lys, Xaa 4 is Tyr and Xaa 5 is Pro; SEQ ID NO:163, wherein Xaa 5 is Pro; Msl.2: Msl.3: Msl.4: Msl.8: Msl.9: Btl.7: WO 00/44776 WO 0044776PCTIUSOO/01979 MS.1: EQIDNO 64 werinXaisLy, aa i Tran Xa. i1Po Oms1. 1: SEQ ID NO: 165, wherein Xa Ls Xaa 4 is Tyr and Xaa 5 is Pro; I .1 SEQ ID NO:l166, wherein Xaa 4 is Tyr and Xaa 5 is Pro; R1.7: SEQ ID NO: 167, wherein Xaa 4 is Tyr and Xaa, is Pro; r1.7: SEQ ID NO: 168, wherein Xaa 4 is Tr and Xa sPo Vrl SEQ ID NO: 168, wherein Xaa 5 is Pro;.n The C-terminus preferably contains a carboxyl group for the peptides Snl.l, Snl.2, Cr1.3, Dil.1, Msl.2, Msl.4, Msl.5, Msl.8, Msl.9, Vrl.1 and Vrl.2. Th e C-terminus of the other peptides preferably contains an amide group.

The present invention is also directed to novel specific a-conotoxin peptides of general formula III having the formulas: Gly-Cys-Cys-Ser-Asn-Xaas-Val.Cys-His-Leu-Xaa 1 -His-Ser-Asn-Met-Cys (SEQ IDNO :22); Gly-Cys-Cys-Ser-Asn-Xaa-Va-Cys-Arg-Gn-Asn-Asn-Ala-Xaa,-Xaa 4 -Cys-rg (SEQ ID NO:23); Xaas-Gln-Cys-Cys-Ser-I-is-Xaas-Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Xaa -Ile-Cys-Arg (SEQ ID NO:24); Xaas-Xaal-Cys-Cys-Ser-His-Xaas-Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Xaa,-Ile-CyspArg (SEQ ID Xaa 5 -Gln-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Xaa -Ile-Cys-Asp (SEQ ID NO:26);

(SEQ

ID NO:27); Xaas-Gln-Cys-Cys-Ser-His-Xaas-Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Gly-Ile-Cys-Arg (SEQ ID NO:28); Xaa5-Gln-Cys-Cys-Ser-His-Xaa-Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Xaa,-Thr-Cys-Arg (SEQ ID NO:29); Xaas-Gln-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Xaal-val-Cys-Arg (SEQ ID NO:3 0); Xaas-Gln-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Ile-Asp-His-Xaa 5 -Xaa,-Ile-Cys-Arg (SEQ ID NO:3 1); Xaa 5 -Gln-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaa-Xaa -Ile-Cys-Arg-Arg- Arg-Arg (SEQ ID NO:32); WO 00/44776 PCTIUSOO/01979 12 -Leu-Cys (SEQ ID NO:33); Gly-CysCys-SerHisXaaAaCysSerVa1AsnHisXaasXaa)-Leu-Cys(SEQIDNO: 3 4 s-i-a5Xa-i-y(SEQ IDNO Gly-CysCys-SerHisXaa 5 AaCysSerGly-Xaa 2 -Thr-Gln-Xaa -Xaa,-Cys-Arg-Xaa1 -Ser (SEQ ID NO:36);

(SEQ

ID NO:3 7); Gl-y-y-e-i-asAaCy-e- -s-s-a5Xa-Phe-Cys-Arg-Gln

(SEQ

ID NO:38); a-y (SEQ ID NO:39); (SEQ ID Gl-y-y-e-s-a5Xa-y-l-l-a2AnXa-i-e-y-l (SEQ ID NO:41);

(SEQ

ID NO:43); Gl-y-y-e-r-aa-l-y l-l-snAnXa-s-e-y(SEQ IDNO:44); Arg (SEQ ID Gl-l-y-y-e-h-a5AaCsAg-a2Xa-r-a5Xa-e-y-l(E ID NO:46); ID NO:47); ID NO:48); Xa6VlCsCsSrApXa-r-y-s-a-l-i-asXa-l-y-l

(SEQ

ID NO:49); (SEQ ID WO 00/44776 WO 0044776PCT/USOO/OI 979 13 Xaa 5 -Gln-Cys-Cys-Ser-His-Leu-Ala-Cys-Asn-Val-Asp-His-Xaas-Xaa -lle-Cys-Arg (SEQ ID NO:5 1); Gly-Cys-Cys-Ser-Xaa 4 -Phe-Asp-Cys-Arg-Met-Met-Phe-Xaa 5 -Xaal-Met-Cys-Gly-Xaa 3 -Arg (SEQ ID NO:52); Gly-Gly-Cys-Cys-Ser-Phe-Ala-Ala-Cys-Arg-Xaa 2 -Xaa 4 -Arg-Xaa 5 -Xaa -Met-Cys-Gly (SEQ ID NO:53); Gly-Gly-Cys-Cys-Phe-His-Xaa 5 -Val-Cys-Xaa 4 -Ile-Asn-Leu-Leu-Xaa -Met-Cys-Arg-Gln- Arg (SEQ ID NO:54); Ser-Ala-Thr-Cys-Cys-Asn-Xaa 4 -Xaa-Xaa 5 -Cys-Xaa 4 -Xaa -Thr-Xaa 4 -Xaa 5 -Xaa 1 -Ser-Cys- Leu (SEQ ID Ala-Cys-Cys-Ala-Xaa 4 -Xaas-Xaa 5 -Cys-Phe-Xaa 1 -Ala-Xaa 4 -Xaa 5 -Xaa 1 -Arg-Cys-Leu (SEQ ID NO:56); Asn-Ala-Xaa,-Cys-Cys-Xaa 4 -Xaa 4 -XaaS-Xa 5 -Cys-Xaa 4 -Xaa-Ala-Xaa 4 -Xaa 5 -Xaa-Ile-Cys- Leu (SEQ ID NO:57); Xaa 1 -Cys-Cys-Thr-Asn-Xaa 5 -Val-Cys-His-Ala-Xaa 1 -His-Gln-Xaa 1 -Leu-Cys-Ala-Arg-Arg- Arg (SEQ ID NO: 170); Gly-Cys-Cys-Ser-Asn-Xaa 5 -VaI-Cys-His-Leu-Xaa 1 -His-Ser-Asfl-Leu-Cys (SEQ ID NO: 17 1); Xaa,-Cys-Cys-Thr-Asn-Xaa 5 -Val-Cys-His-Val-Xaa-THis-Gln-Xaa -Leu-Cys-Ala-Arg-Arg- Arg (SEQ ID NO: 172); Xaa 6 -Xaa 1 -Cys-Cys-Ser-Xaa 4 -Xaa 5 -Ala-Cys-Asn-Leu-Asp-His-Xaa 5 -Xaal-Leu-Cys (SEQ ID NO: 173); Xaa 5 -Xaa,-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Asn-Ser-Thr-His-Xaa 5 -Xaa,-Leu-Cys-Gly(SEQ ID NO: 174); Leu-Asn-Cys-Cys-Met-Ile-Xaa 5 -Xaa-Cys-Xaa 3 -Xaa 2 -Xaa 2 -Xaa 4 -Gly-Asp-Arg-Cys-Ser- Xaa 1 -Val-Arg (SEQ ID NO: 175); Ala-Phe-Gly-Cys-Cys-Asp-Leu-Ile-Xaa 5 -Cys-Leu-Xaa -Arg-Xaa 4 -Gly-Asn-Arg-Cys-Asn- Xaa 1 -Val-His (SEQ ID NO: 176); Leu-Gly-Cys-Cys-Asn-Val-Thr-Xaa-Cys-Xaa 3 -Xaa -Xaa 2 -Xaa 4 -Gly-Asp-Xaa 2 -Cys-Asn- Xaa 1 -Val-Arg (SEQ ID NO: 177); Asp-Xaa 1 Arg (SEQ ID NO: 178); WO 00/44776 WO 0044776PCTIUSOO/01979 14 Leu-Asn-Cys-Cys-Ser-Ile-Xaa 5 -Gly-Cys-Xaa 3 -Asn-Xaa,-Xaa 4 -Xaa 2 -Asp-Arg-Cys-Ser-Xaa 2 Val-Arg (SEQ ID NO: 179); Gly-Gly-Cys-Cys-Ser--is-Xaa 5 -Val-Cys-Xaa 4 -Phe-Asn-Asn-Xaas-Gln-Met-Cys-Arg (SEQ ID NO: 180); Gly-Gly-Cys-Cys-Ser-His-Xaa 5 -Val-Cys-Asn-Leu-Asn-Asn-Xaa 5 -Gln-Met-Cys-Arg (SEQ ID NO: 18 1); Gly-Cys-Cys-Ser-His-Xaa 5 -Xaas-Cys-Xaa 4 -Ala-Asn-Asn-Gln-Ala-Xaa 4 -Cys-Asn (SEQ ID NO: 182); Gly-Gly-Cys-Cys-Ser-His-Xaas-Ala-Cys-Ser-Val-Thr-His-Xaa 5 -Xaa -Leu-Cys (SEQ ID NO: 183); Gly-Gly-Cys-Cys-Ser-Xaa 4 -Xaa 5 -Ala-Cys-Ser-VaI-Xaa 1 -His-Gln-Asp-Leu-Cys-Asp (SEQ ID NO: 184); Val-Ser-Cys-Cys-Val-Val-Arg-Xaa-Cys-Xaa 3 -Ile-Arg-Xaa 4 -Gln-Xaa 1 -Xaal-Cys-Leu-Xaa 1 Ala-Asp-Xaa 5 -Arg-Thr-Leu (SEQ ID NO: 185); Xaa 6 -Asn-Cys-Cys-Ser-Ile-Xaa 5 -Gly-Cys-Xaa 3 -Xaa-Xaa-Xaa 4 -Gly-Asp-Xaa 2 -Cys-Ser- Xaa 1 -Val-Arg (SEQ ID NO: 186); Gly-Cys-Cys-Ser-Asn-Xaa 5 -Val-Cys-His-Leu-Xaa 1 -His-Xaa 5 -Asn-Ala-Cys (SEQ ID NO: 187); Gl-y-y-e-s-a5IeCsXa4PeAnAnXa-r-i-y-r (SEQ ID NO: 188); Xaa,-Cys-Cys-Ser-Gln-Xaa 5 -Xaa 5 -Cys-Arg-Xaa 3 -Xaa 2 -His-Xaa 5 -Xaal-Leu-Cys-Ser (SEQ ID NO: 189); Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ala-Gly-Asn-Asn-Gln-His-Ile-Cys (SEQ ID NO: 190); Gly-Cys-Cys-AlaVal-Xaa 5 -Ser-Cys-Arg-Leu-Arg-Asn-Xaa 5 -Asp-Leu-Cys-Gly-Gly (SEQ ID NO: 19 1); Gly-Cys-Cys-Ser-His-Xaas-Ala-Cys-Asn-Val-Asn-Asn-Xaas-His-Ile-Cys(SEQIDNO:1 9 2); Thr-Xaas-Xaa 1 -Xaa 1 -Cys-Cys-Xaa 5 -Asn-Xaa 5 -Xaa 5 -CYs-Phe-Ala-Thr-Asn-Ser-Asp-le-Cys- Gly (SEQ ID NO: 193); Asp-Ala-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Ser-Gy-Xaa 2 -His-Gln-Asp-Leu-Cys (SEQ ID NO:194); Xaa 1 -Asp-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Ser-Val-Gy-His-Gln-Asp-Leu-Cys (SEQ ID NO:195); WO 00/44776 WO 0044776PCT[USOO/01979 Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ala-Gly-Ser-Asn-Ala-His-Ile-Cys (SEQ ID NO: 196); Xaa -Asp- Cys-Cys-Ser-Asp-Xaa5-Arg-Cys-Ser-VaI-Gly-Hi s-Gln-Asp-Met-Cys (SEQ ID NO: 197); Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ala-Gly-Asn-Asn-Xaa 5 -His-Ile-Cys (SEQ IDNO: 198); Gly-Cys-Cys-Gly-Asn-Xaas-Ser-Cys-Ser-Ile-His-Ile-Xaa 5 -Xaa 4 -Val-Cys-Asn (SEQ ID NO: 199); Thr-Asp-Ser-Xaa 1 -Xaa-Cys-Cys-Leu-Asp-Ser-Arg-Cys-Ala-Gly-Gln-His-Gln-Asp-Leu- Cys-Gly (SEQ ID NO:200); Gly-Cys-Cys-Ser-Asn-Xaa 5 -Xaas-Cys-Xaa 4 -Ala-Asn-Asn-Gln-Ala-Xaa 4 -Cys-Asn (SEQ ID NO:201); Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ser-Val-Asn-Asn-Xaa 5 -Asp-Ile-Cys (SEQ IDNO:202); Gly-Xaa,-Cys-Cys-Ile-Asn-Asp-Ala-Cys-Arg-Ser-Xaa,-His-Xaa 5 -Gln-Xaa 4 -CYS-Ser (SEQ ID NO:203); Gly-Cys-Cys-Xaa 4 -Asn-Ile-Ala-Cys-Arg-Ile-Asn-Asn-Xaa 5 -Arg-Xaa 4 -Cys-Arg (SEQ ID NO:204); Gly-Cys-Cys-Ser-His-Xaa -Val-Cys-Arg-Phe-Asn-Xaa 4 -Xaa 5 -Xaa 2 -Xaa 4 -Cys-Gly (SEQ ID NO:205); Asp-Xaa 1 -Cys-Cys-Ala-Ser-Xaa 5 -Xaa 5 -Cys-Arg-Leu-Asn-Asn-Xaa 5 -Xaa 4 -Val-Cys-His (SEQ ID NO :206); Gly-Cys-Cys-Ser-Asn-Xaa 5 -Val-Cys-Xaa 3 -Gln-Asn-Asn-Ala-Xaa 1 -Xaa 4 -Cys-Arg-Xaa -Ser (SEQ ID NO:207); Gly-Cys-Cys-Ser-His-Xaa 5 -Xaa 5 -Cys-Ala-Gln-Asn-Asn-Gln-Asp-Xaa 4 -Cys (SEQ ID NO:208); Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ser-Gly-Asn-Asn-Arg-Xaa 1 -Xaa 4 -Cys-Arg-Xaa,-Ser (SEQ ID NO:209); Asp-Xaa 5 -Cys-Cys-Ser-Xaa 4 -Xaas-Asp-Cys-Gly-Ala-Asn-His-Xaa 5 -Xaa-Ile-Cys-Gly(SEQ ID NO:2 Xaal-Cys-Cys-Ser-Gln-Xaa 5 -Xaa 5 -Cys-Arg-Xaa 3 -Xaa,-His-Xaa 5 -Xaa -Leu-Cys-Ser (SEQ ID NO:21 1); Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ala-Gly-Asn-Asn-Xaa 5 -His-Ile-Cys (SEQ IDNO:2 12); 5 -Asp-Xaa 4 -CYS (SEQ ID NO:2 13); WO 00/44776 WO 0044776PCT/USOO/01979 16 XaXa-y-y-e-s-asAgCs-e-a-l-i-l-s-e-y-r

(SEQ

ID NO:2 14); Gly-Gly-Cys-Cys-Ser-Asn-Xaa 5 -Ala-Cys-Leu-Va-Asn-His-Leu-Xaa -Met-Cys (SEQ ID NO:21 Ar-s-a5CsCsPeAnXa-l-CsAnVlAnAnXa-l-l-y

(SEQ

ID NO:216); Arg (SEQ ID NO:217); Cys-Cys-Thr-Asn-Xaas-Ala-Cys-Leu-VaI-Asn-Asn-Ile-Arg-Phe-Cys-Gy(SEQIDNO:2 18); As-alCsCsSrApXa-r-y-i-l-s-s-r-s-i-y-l

(SEQ

ID NO:219); Asp-Cys-Cys-Ser-His-Xaa 5 -Leu-Cys-Arg-Leu-Phe-Val-Xaa 5 -GlyLeuCys-lle (SEQ ID NO:220); Gly-Cys-Cys-Ser-His-Xaa-Val-Cys-Xaa 2 -Val-Arg-Xaa 4 -Xaa 5 -Asp-Leu-.Cys.Arg (SEQ ID NO:221); Gl-y-y-e-i-a5AaCsAnVl-s-s-a1-i-l-y(EIN:2) Gly-Cys-Cys-Ser-His-Xaa 5 -Val-Cys-Xaa 2 -Val-Arg-Xaa 4 -Ser-Asp-Met-Cys (SEQ ID NO:223); Gly-Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Xaa 2 -VaI-His-Phe-Xaa 5 -His-Ser.Cys (SEQ ID NO:224); Val-Cys-Cys-Ser-Asn-Xaa 5 -Val-Cys-His-Val-Asp-His-Xaa 5 -Xaa -Leu-Cys-Arg-Arg-Arg- Arg (SEQ ID NO:225); Gly-Cys-Cys-Ser-His-Xaa 5 -Val-Cys-Asn-Leu-Ser-Asn-Xaa 5 -Gln-Ile-Cys-Arg (SEQ ID NO:226); Xaa 6 -Xaa 1 y-y-e-i-Xa-l-y-s-VlApHsXa-Xa-l-y-r

(SEQ

ID NO:227); Gly-Cys-Cys-Ser-Asn-Xaa 5 -Ala-Cys-Leu-Val-Asn-His-Ile-Arg-Phe-Cys-Gly (SEQ ID NO:228); Asp-Cys-Cys-Asp-Asp-Xaa 5 -Ala-Cys-Thr-Val-Asn-Asn-Xaa 5 -Gly.Leu.Cys-Thr (SEQ ID NO:229); and Gly-Cys-Cys-Ser-Asn-Xaa-Xaa-Cys-Ile-Ala-Xaa 2 -Asn-Xaa 5 -His-Met-Cys-Gly-Gly..rg.

Arg (SEQ ID NO:230), -17wherein Xaal is Glu or y-carboxy-Glu (Gla); Xaa 2 is Lys, N-methyl-Lys, N,N-dimethyl- Lys or N,N,N-trimethyl-Lys; Xaa 3 is Trp (D or halo-Trp or neo-Trp; Xaa 4 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa 5 is Pro or hydroxy-Pro; Xaa 6 is Gin or pyro-Glu; and the C-terminus contains a carboxyl or amide group. The halo is preferably bromine, chlorine or iodine, more preferably iodine for Tyr and bromine for Trp. In addition, the His residues may be substituted with halo-His; the Arg residues may be substituted by Lys, ornithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Lys residues may be substituted by Arg, omithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Tyr residues may be substituted with any unnatural hydroxy containing amino acid; the Ser residues may be substituted with Thr; the Thr residues may be substituted with Ser; and the Phe and Trp residues may be substituted with any unnatural aromatic amino acid. The Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or The Tyr residues may be substituted with the 3hydroxyl or 2-hydroxyl isomers and corresponding O-sulpho- and O-phosphoderivatives. The acidic amino acid residues may be substituted with any synthetic acidic bioisoteric amino acid surrogate, tetrazolyl derivatives of Gly and Ala.

More specifically, the present invention is directed to the following a-conotoxin 20 peptides of general formula III: SmI: SEQ ID NO:22, wherein Xaal is Glu and Xaa 5 is Pro; OB-29: SEQ ID NO:23, wherein Xaal is Glu, Xaa 3 is Tyr and Xaa 5 is Pro; SEQ ID NO:2, wherein Xaa is Glu and Xaa is Pro TxR1.1: SEQ ID NO:24, wherein Xaal is Glu and Xaa 5 is Pro; RL.1A: SEQ ID NO:26, wherein Xaal is Glu and Xaa5 is Pro; 25 R. Om-: SEQ ID NO:27, wherein Xaal is Glu and Xaa5 is Pro; Om-1: SEQ ID NO:28, wherein Xaas is Pro; Om-21: SEQ ID NO:29, wherein Xaai is Glu and Xaa 5 is Pro; S* Om-51: SEQ ID NO:30, wherein Xaa5 is Glu and Xaas is Pro; 3 3Om-27: SEQ ID NO:31, wherein Xaal is Glu and Xaa 5 is Pro;

S**

Om-28: SEQ ID NO:32, wherein Xaal is Glu and Xaa5 is Pro; B. t3.Om-2: SEQ ID NO:33, wherein Xaal is Glu and Xaa 5 is Pro; Bt.4Om-2: SEQ ID NO:34, wherein Xaal is Glu and Xaa 5 is Pro; Btl.2: SEQ ID NO:33, wherein Xaa is Glu and Xaa 5 is Pro; Btl.4: SEQ ID NO:34, wherein Xaal is Glu and Xaa 5 is Pro; 17a Dal.1: SEQ ED NO:35, wherein Xaal is Glu and Xaa 5 is Pro; -21- Rgl.3, Rgl.4, Sml.5, Txl.5 and Vrl.3. The C-terminus of the other peptides preferably contains an amide group.

The present invention is also directed to the novel specific a-conotoxin peptides having the formulas: Cys-Cys-Thr-Ile-Xaa 5 -Ser-Cys-Xaa4-Xaal-Xaa 2 -Xaa 2 -Xaa 2 -Ile-Xaa 2 -Ala-Cys- Val-Phe (SEQ ID NO:231) and Gly-Cys-Cys-Gly-Asn-Xaas-Ala-Cys-Ser-Gly-Ser-Ser-Xaa 2 -Asp-Ala-Xaas-Ser- Cys (SEQ ID NO:232), wherein Xaal is Glu or y-carboxy-Glu (Gla); Xaa 2 is Lys, N-methyl-Lys, N,N-dimethyl- Lys or N,N,N-trimethyl-Lys; Xaa 4 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaas is Pro or hydroxy-Pro; and the Cterminus contains a carboxyl or amide group. The halo is preferably bromine, chlorine or iodine, more preferably iodine for Tyr. In addition, the His residues may be substituted with halo-His; the Arg residues may be substituted by Lys, ornithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Lys residues may be substituted by Arg, omithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Tyr residues may be substituted with any unnatural hydroxy containing amino acid; the Ser residues may be substituted with Thr; the Thr residues may be substituted with Ser; and the Phe residues may be substituted with any unnatural aromatic amino acid. The Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or The Tyr residues may be substituted with the 3hydroxyl or 2-hydroxyl isomers and corresponding O-sulpho- and O-phospho- S. :i derivatives. The acidic amino acid residues may be substituted with any synthetic acidic bioisoteric amino acid surrogate, tetrazolyl derivatives of Gly and Ala.

More specifically, the present invention is directed to the following a-conotoxin peptides: Gl.2: SEQ ID NO:231, wherein Xaal is Glu, Xaa 2 is Lys, Xaa 4 is Tyr and Xaa 5 is Pro; and Rg1.12: SEQ ID NO:232, wherein Xaa 2 is Lys and Xaa 5 is Pro.

.The C-terminus of G1.2 preferably contains a carboxyl group, and the C-terminus of Rgl.12 preferably contains an amide group.

-22- Examples of unnatural aromatic amino acid include, but are not limited to, such as nitro-Phe, 4-substituted-Phe wherein the substituent is C 1

-C

3 alkyl, carboxyl, hydroxymethyl, sulphomethyl, halo, phenyl, -CHO, -CN, -SO 3 H and -NHAc. Examples of unnatural hydroxy containing amino acid, include, but are not limited to, such as 4hydroxymethyl-Phe, 4-hydroxyphenyl-Gly, 2,6-dimethyl-Tyr and Examples of unnatural basic amino acids include, but are not limited to, N-1-(2pyrazolinyl)-Arg, 2-(4-piperinyl)-Gly, 2-(4-piperinyl)-Ala, 2-[3-(2S)pyrrolininyl)-Gly and 2-[3-(2S)pyrrolininyl)-Ala. These and other unnatural basic amino acids, unnatural hydroxy containing amino acids or unnatural aromatic amino acids are described in Building Block Index, Version 3.0 (1999 Catalog, pages 4-47 for hydroxy containing amino acids and aromatic amino acids and pages 66-87 for basic amino acids; see also http://www.amino-acids.com), incorporated herein by reference, by and available from RSP Amino Acid Analogues, Inc., Worcester, MA.

Optionally, in the peptides of general formulas I, II and III and the specific peptides described above, the Asn residues may be modified to contain an N-glycan and the Ser and Thr residues may be modified to contain an O-glycan. In accordance with the present invention, a glycan shall mean any S- or O-linked mono-, di-, tri-, polyor oligosaccharide that can be attached to any hydroxy, amino or thiol group of natural or modified amino acids by synthetic or enzymatic methodologies known in the art. The monosaccharides making up the glycan can include D-allose, D-altrose, D-glucose, Dmannose, D-gulose, D-idose, D-galactose, D-talose, D-galactosamine, D-glucosamine, S* D-N-acetyl-glucosamine (GlcNAc), D-N-acetyl-galactosamine (GalNAc), D-fucose or o* :i D-arabinose. These saccharides may be structurally modified, with one or more Osulfate, O-phosphate, O-acetyl or acidic groups, such as sialic acid, including combinations thereof. The glycan may also include similar polyhydroxy groups, such as D-penicillamine 2,5 and halogenated derivatives thereof or polypropylene glycol derivatives. The glycosidic linkage is beta and 1-4 or 1-3, preferably 1-3. The linkage .between the glycan and the amino acid may be alpha or beta, preferably alpha and is 1-.

Core O-glycans have been described by Van de Steen et al. (1998), incorporated herein by reference. Mucin type O-linked oligosaccharides are attached to Ser or Thr (or other hydroxylated residues of the present peptides) by a GalNAc residue. The -23monosaccharide building blocks and the linkage attached to this first GalNAc residue define the "core glycans," of which eight have been identified. The type of glycosidic linkage (orientation and connectivities) are defined for each core glycan. Suitable glycans and glycan analogs are described furtherin U.S. Serial No. 6,369,193, filed 19 October 1999 and in Australian Patent No. 766294, both incorporated herein by reference. A preferred glycan is Gal(P 1-3)GalNAc(al-).

Optionally, in the peptides of general formulas I and II and the specific peptides described above, pairs of Cys residues may be replaced pairwise with Ser/(Glu or Asp) or Lys/(Glu or Asp) combinations. Sequential coupling by known methods (Barnay et al., 2000; Hruby et al., 1994; Bitan et al., 1997) allows replacement of native Cys bridges with lactam bridges.

The present invention is further directed to propeptides and nucleic acid sequences encoding the propeptides or peptides as described in further detail herein.

According to a first aspect, the present invention provides a substantially pure aconotoxin peptide having the generic formula I: Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaas-Cys-Cys- Xaa 6 -Xaa 7 -Xaa-Xaa 9 -Cys-Xaalo-Xaali-Xaal 2 -Cys-Xaal 3 (SEQ ID NO1:), wherein Xaal is des-Xaa 1 Ile, Leu or Val; Xaa 2 is des-Xaa 2 Ala or Gly; Xaa 3 is des-Xaa 3 Gly, Trp (D or neo-Trp, halo-Trp or any unnatural aromatic amino acid; Xaa 4 is des-Xaa4, Asp, Phe, Gly, Ala, Glu,y-carboxy-Glu (Gla) or any unnatural aromatic amino acid; Xaa is :Glu, Gla, Asp, Ala, Thr, Ser, Gly, Ile, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, Osulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 6 is Ser, Thr, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 7 is Asp, Glu, Gla, Arg, omrnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaas is Ser, Thr, Asn, Ala, Gly, Arg, Lys, ornithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid; His, halo-His, Pro or hydroxy-Pro; Xaa 9 is Thr, Ser, Ala, Asp, Asn, Pro, hydroxy-Pro, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaalo is Gly, Ser, Thr, Asn, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl- Lys or any unnatural basic amino acid; Xaa I is Gin, Leu, His, halo-His, Trp (D or L), halo-Trp, neo-Trp, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O- 23a phospho-Tyr, nitro-Tyr, Arg, omnithine, homoarginine, Lys, N-methyl-Lys, N,Ndimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid or any unnatural aromatic amino acid; Xaa 12 is Asn, His, halo-His, le, Leu, Val, Gin, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 13 is des-Xaa 13 Val, lie, Leu, Arg, omithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; and the C-terminus contains a free carboxyl group or an amide group.

According to a second aspect, the present invention provides a substantially pure a-conotoxin peptide of generic formula I selected from the group consisting of: Asp- Xaaj, -Cys-Cys-Ser-Asp-Ser-Arg-Cys-Gly-Xaa 2 -Asn-Cys-Leu (SEQ ID NO:4); Ala-Cys-Cys-Ser-Asp-Arg Arg-Cys-Arg-Xaa 3 -Arg-Cys SEQ ID Phe-Thr-Cys-Cys-Arg-Arg-Gly-Thr-Cys-Ser-Gln-His-Cys (SEQ lID NO:6); Asp-Xaa 4 -Cys-Cys-Arg-Arg-His-Ala-Cys-Thr-Leu-Ile-Cya (SEQ ID NO:7); Asp-Xaa 4 -Cys-Cys-Arg-Arg-Xaa 5 -Xaa 5 -Cys-Thr-Leu-Iie-Cys (SEQ lID NO:8); Gly-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Arg-Xaa 4 -Arg-Cys-Arg (SEQ ED NO Gly-Gly-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Ala-Xaa 3 -Arg-Cys (SEQ ID NO: Ile-Aia-Xaa 3 -Asp-Ile-Cys-Cys-Ser-Xaa 1 -Xaa 5 -Asp-Cys-Asn-His-Xaa 2 -Cys-Val (SEQ ID NO:l11); and Gly-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Xaa 2 -His-Gln-Cys (SEQ ID NO: 12), wherein Xaaj is Glu or y-carboxy-Giu (Gla); Xaa 2 is Lys, N-methyl-Lys, N, N-dimethyl- 9 Lys or N,N,N-trimethyi-Lys; Xaa 3 is Trp (D or halo-Trp or neo-Trp; Xaa 4 isTyr, nor- Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr or nitro-Tyr; and Xaa is Pro or hydroxy-Pro; and the C-terminus contains a carboxyl or amide group, or According to a third aspect, the present invention provides a substantially pure ccconotoxin peptide having the generic formula II: Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Cys-Cys-Xaa 5 Xaa6-Xaa 7 -Xaa 8 -Cys-Xaa-Xaalo-Xaa 1 i-Xaa 1 2 -Xaa 1 3 -Xaal 4 -Cys-Xaai 5 -Xaai 6 -Xaai 7 (SEQ ID NO:2), wherein Xaa 1 is des-Xaal, Asp, Glu or y-carboxy-Giu (Gla); Xaa 2 is des-Xaa 2 Gln, Ala, Asp, Giu, Gia; Xaa 3 is des-Xaa 3 Gly, Ala, Asp, Glu, Gla, Pro or hydroxy-Pro; Xaa 4 is des-Xaa 1 Gly, Glu, Gla, Gin, Asp, Asn, Pro or hydroxy-Pro; Xaa is Ser, Thr, Gly, Giu, Gia, Asn, Trp (D or neo-Trp, halo-Trp, Arg, omnithine, 23b homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 6 is Asp, Asn, His, halo-His, Thr, Ser, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-supho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 7 is Pro or hydroxy-Pro; Xaa8 is Ala, Ser, Thr, Asp, Val, Ile, Pro, hydroxy-Pro, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 9 is Gly, Ile, Leu, Val, Ala, Thr, Ser, Pro, hydroxy- Pro, Phe, Trp (D or neo-Trp, halo-Trp, Arg, omnithine, homnoarginine, Lys, N-methyl- Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid or any unnatural aromatic amino acid; XaajO is Ala, Asn, Phe, Pro, hydroxy-Pro, Glu, Gla, Gln, His, halo-His, Val, Ser, Thr, Arg, omnithine, homoarginine, Lys, N-methyl-Lys, N,Ndimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaaj I is Thr, Ser, His, halo-His, Leu, Ile, Val, Asn, Met, Pro, hydroxy-Pro, Arg, omnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr, nitro- Tyr or any unnatural hydroxy containing amino acid; Xaa 12 is Asn, Pro, hydroxy-Pro, Gln, Ser, Thr, Arg, omnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, dihalo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 13 is des-Xaa 13 Gly, Thr, Ser, Pro, hydroxy-Pro, Tyr, nor-Tyr, monohalo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 14 is des-Xaal 4 Ile, Val, Asp, Leu, Phe, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho- Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; and Xaa, 5 is des-Xaa, 5 Gly, Ala, Met, Ser, Thr, Trp (D or neo-Trp, halo-Trp, any unnatural aromatic amino acid, Arg, omnithine, homoarginine, Lys, N-methyl-Lys, N,Ndimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa16 is des- Xaa 16 Trp (D or neo-Trp, halo-Trp, any unnatural aromatic amino acid, Arg, omnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 17 is des-Xaa 17 Arg, ornithine, homoarginine, 23c Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; and the C-terminus contains a free carboxyl group or an amide group.

According to a fourth aspect, the present invention provides a substantially pure ac-conotoxin peptide of generic formula 11 selected from the group consisting of: Cys- Cys-Ser-Asp-Xaa 5 -Ala-Cys-Xaa 2 -Gln-Thr-Xaa5-Gly-Cys-Arg (SEQ lID NO: 13); Cys-Cys-Xaal -Asn-Xaa 5 -Ala-Cys-Arg-His-Thr-Gln-Gly-Cys (SEQ ID NO: 14); Gly-Cys-Cys-Xaa 3 -His-Xaa 5 -Ala-Cys-Gly-Arg-His-Xaa 4 -Cys (SEQ ED NO: Ala-Xaa 5 -Cys-Cys-Asn-Asn-Xaa 5 -Ala-Cys-Val-Xaa 2 -His-Arg-Cys (SEQ ID NO: 16); Ala-Xaa 5 -Gly-Cys-Cys-Asn-Asn-Xaa 5 -Ala-Cys-Val-Xaa2-His-Arg-Cys (SEQ II) NO: 17); Xaa 5 Xaa 5 -Cys-Cys-Asn-Asn-Xaa 5 -Ala-Cys-Val-Xaa2-His-Arg-Cys (SEQ ID NO: 18); Asp-Xaa 1 -Asn-Cys-Cys-Xaa 3 -Asn-Xaa 5 -Ser-Cys-Xaaj-Arg-Xaa5-Mrg-Cys-Thr (SEQ ID NO: 19); Gly-Cys-Cys-Ser-Thr-Xaa 5 -Xaa 5 -Cys-Ala-Val-Leu-Xaa4-Cys (SEQ ED NO Gly-Cys-Cys-Gly-Asn-Xaa 5 -Asp-Cys-Tbr-Ser-His-Ser-Cys (SEQ lID NO:2 1); Gly-Cys-Cys-Ser-Asn-Xaa 5 -Xaa 5 -Cys-Ala-His-Asn-Asn-Xaa5-Asp-Cys-Arg (SEQ ID NO:42); Gly-Cys-Cys-Xaa 4 -Asn-Xaa 5 -Val-Cys-Xaa 2 -Xaa 2 -Xaa 4 -Xaa4-Cys-Xaa3-Xaa2 (SEQ ID NO: 154); Xaa6-Xaa 1 -Xaa 5 -Gly-Cys-Cys-Arg-His-Xaa 5 -Ala-Cys-Gly-Xaa2-Asn-Arg-Cys (SEQ ID :NO: 15 Cys-Cys-Ala-Asp-Xaa 5 -Asp-Cys-Arg-Phe-Arg-Xaa 5 -Gly-Cys (SEQ ID NO: 156); Gly-Cys-Cys-Xaa 4 -Asn-Xaas-Ser-Cys-Xaa 3 -Xaa 5 -Xaa 2 -Thr-Xaa4-Cys-Ser-Xaa3-Xaa2 (SEQ ID NO: 15 Cys-Cys-Ser-Asn-Xaa 5 -Thr-Cys-Xaa 2 -XaaI -Thr-Xaa4-Gly-Cys (SEQ lID NO: 15 8); Cys-Cys-Ala-Asn-Xaa 5 -Ile-Cys-Xaa 2 -Asn-Thr-Xaa 5 -Gly-Cys (SEQ ID NO: 15 9); Cys-Cys-Asn-Asn-Xaa 5 -Thr-Cys-Xaa 2 -Xaal-Thr-Xaa 1 -Gly-Cys (SEQ ID NO: 160); Cys-Cys-Ser-Asn-Xaa 5 -Val-Cys-Xaa 2 -Xaai-Thr-Xaat-Gly-Cys (SEQ lID NO: 16 1); OV94: (SEQ ID NO: 162); Gly-Cys-Cys-Ser-His-Xaa 5 -Val-Cys-Ser-Ala-Met-Ser-Xaa 5 -Ile-Cys (SEQ ID NO: 163); 23d Gly-Cys-Cys-Xaa 2 -Asn-Xaa 5 -Xaa 4 -Cys-Gly-Ala-Ser-Xaa 2 -Thr-Xaa4-Cys (SEQ ID NO: 164); Gly-Cys-Cys-Ser-Xaa 4 -Xaa 5 -Xaa 5 -Cys-Phe-Ala-Thr-Asn-Xaa5-Asp-Cys (SEQ ID NO: 165); Gly-Gly-Cys-Cys-Ser-Xaa 4 -Xaa 5 -Xaas-Cys-Ile-Ala-Asn-Asn-Xaa 5 -Leu-Cys-Ala (SEQ ID NO: 166); Gly-Gly-Cys-Cys-Ser-Xaa 4 -Xaa 5 -Xaa 5 -Cys-Ile-Ala-Asn-Asn-Xaa5-Phe-Cys-Ala (SEQ ID NO: 167); Asp-Cys-Cys-Ser-Asn-Xaa 5 -Xaa 5 -Cys-Ser-Gln-Asn-Asn-Xaa 5 -Asp-Cys-Met (SEQ ID NO: 168); Asp-Cys-Cys-Ser-Asn-Xaa 5 -Xaa 5 -Cys-Ala-His-Asn-Asn-Xaa 5 -Asp-Cys-Arg (SEQ ID NO: 169); wherein Xaaj is Glu or y-caroboxy-Glu (Gla); Xaa 2 is Lys, N-methyl-Lys, N,Ndimethyl-Lys or N,N,N-trimethyl-Lys; Xaa 3 is Trp (D or halo-Trp or neo-Trp; Xaa 4 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-supho-Tyr, 0-phospho-Tyr or nitro- Tyr; and Xaa 5 is Pro or hydroxy-Pro; and the C-terminus contains a carboxyl or amide group, or derivatives thereof.

According to a fifth aspect, the present invention provides a substantially pure occonotoxin peptide having the generic formula III: Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Cys-Cys- Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Cys-Xaalo-Xaa 1 -Xaal 2 -Xaai 3 -Xaal 4 -Xaai 5 -Xaa 1 6 -Cys-Xaal 7 Xaa 1 8 -Xaa 19 -Xaa 2 o-Xaa 2 1 -Xaa 22 -Xaa 23 -Xaa 24 (SEQ ED NO:3), wherein Xaaj is des-Xaa 1 Ser or Thr; Xaa 2 is des-Xaa 2 Asp, Giu, y-carboxy-Glu (Gia), Asn, Ser or Thr; Xaa 3 is des-Xaa 3 Ala, Gly, Asn, 5cr, Thr, Pro, hydroxy-Pro, Arg, omnithine, homoarginine, Lys, N-methyi-Lys, N,N-dimethyi-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 4 is des-Xaa 4 Ala, Val, Leu, le, Gly, Giu, Gia, Gin, Asp, Asn, Phe, Pro, hydroxy-Pro or any unnatural aromatic amino acid; Xaa 5 is des-Xaa 5 Thr, Ser, Asp, Glu, Gia, Gin, Gly, Val, Asp, Asn, Ala, Pro, hydroxy-Pro, Arg, omnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 6 is Thr, Ser, Asp, Asn, Met, Val, Ala, Gly, Leu, Ile, Phe, any unnatural *:Goa:aromatic amino acid, Pro, hydroxy-Pro, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0suipho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnaturai hydroxy containing amino acid; Xaa 7 is le, Leu, Val, Ser, Thr, Gin, Asn, Asp, Arg, His, haio-His, Phe, any unnatural -23earomatic amino acid, homoarginine, omrnithine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, dihalo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaas is Pro, hyroxy-Pro, Ser, Thr, Ile, Asp, Leu, Val, Gly, Ala, Phe, any unnatural aromatic amino acid, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,Ndimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 9 is Val, Ala, Gly, Ile, Leu, Asp, Ser, Thr, Pro, hydroxy-Pro, Arg, omrnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaalo is His, halo-His, Arg, homoarginine, ornithine, Lys, N-methyl-Lys, N,Ndimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Asn, Ala, Ser, Thr, Phe, lie, Leu, Gly, Trp (D or neo-Trp, halo-Trp, any unnatural aromatic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaal 1 is Leu, Gin, Val, Ile, Gly, Met, Ala, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, Ser, Thr, Arg, homoarginine, ornithine, any unnatural basic amino acid, Asn, Glu, Gla, Gin, Phe, Trp (D or neo-Trp, halo-Trp or any unnatural aromatic amino acid; Xaa 12 is Glu, Gla, Gin, Asn, Asp, Pro, hydroxy-Pro, Ser, Gly, Thr, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, Arg, homoarginine, ornithine, any unnatural basic amino acid, Phe, His, halo-His, any unnatural aromatic amino acid, Leu, Met, Gly, Ala, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 13 is His, halo-His, Asn, Thr, Ser, Ile, Val, Leu, Phe, any unnatural aromatic amino acid, Arg, homoarginine, ornithine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 14 is Ser, Thr, Ala, Gin, Pro, hydroxy-Pro, Gly, Ile, Leu, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,Ntrimethyl-Lys or any unnatural basic amino acid; Xaas 5 is Asn, Glu, Gla, Asp, Gly, His, halo-His, Ala, Leu, Gin, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N- .dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 1 6 is Met, Ile, Thr, Ser, Val, Leu, Pro, hydroxy-Pro, Phe, any unnatural aromatic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O- -23f suipho-Tyr, 0-phospho-Tyr, nitro-Tyr, any unnatural hydroxy containing amino acid, Glu, Gla, Ala, His, halo-His, Arg, omnithine, homoarginine, Lys, N-methyl-Lys, N,Ndimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 1 is des- Xaa 17 Gly, Asp, Asn, Ala, Ile, Leu, Ser, Thr, His, halo-His, Arg, omnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,NN-trimethyl-Lys or any unnatural basic amino acid; Xaa 18 is des-Xaa 1 8, Gly, Glu, Gla, Gin, Trp (D or neo- Trp, halo-Trp, any unnatural aromatic amino acid, Arg, omnithine, homoarginine, Lys, Nmethyl-Lys, N,N-dimethyl-Lys, N,N,N-trimiethyl-Lys or any unnatural basic amino acid;, Xaa, 19 is des-Xaal 9 Ser, Thr, Val, le, Ala, Arg, ormthine, homoarginine, Lys, N-methyl- Lys, N,N-dimethyl-Lys, N,NN-trimethyl-Lys or any unnatural basic amino acid; Xaa 2 o is des-Xaa 2 o, Val, Asp, His, halo-His, Arg, ornithine, homoarginine, Lys, N.-methyl-Lys, N,N-dimihyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 2 1 is des-Xaa 21 Asn, Pro or hydroxy-Pro; Xaa 22 is des-Xaa 22 Arg, omnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 23 is des-Xaa 23 Ser or Thr; Xaa 24 is des-Xaa 24 Leu, Ile or Val; and the C-terminus contains a free carboxyl group or an anmide group,. with the proviso that (a) Xaa.

5 is not Gly, when Xaaj is des-Xaal, Xaa 2 is des-Xaa 2 Xaa 3 is des-Xaa 3 Xaa 4 is des- Xaa 4 Xaa.

6 is Ser, Xaa, 7 is His, Xaa.

8 is Pro, Xaa 9 is Ala, Xaajo is Ser, Xaal I is Val, Xaa.

12 is Asn, Xaa 13 is Asn, Xaa, 14 is Pro, Xaa, 1 5 is Asp, Xaa 16 is Ie, Xaa.

17 is des-Xaal7, Xaa,18 is des-Xaal 8 Xaaj 9 is des-Xaa 19 Xaa 2 o is des-Xaa 2 o, Xaa 2 l is des-Xaa 2 l, Xaa.

22 is des- Xaa 2 2 Xaa.

23 is des-Xaa 23 and Xaa 24 is des-Xaa 24 According to a sixth aspect, the present invention provides a substainally pure aconotoxin peptide of generic formula 111I selected from the group consisting Of: A substantially pure u-conotoxin peptide of generic forumula Iit selected from the group consis5ting of: (SE (SE fl:3 NO:2M2) O24) (SEQ MD NO:23); -23g Xaa;i-Gin-Cys-Cys-Ser-Hs-Xaa-Aa-Cys-Asn-Va-Asp-Is-Xaa.Xaa, 1 fe-Cys-Asp (SEQ MD NO:26); AaCsAnVlApIi-~a-alI-y-r (SEQ MD NO:27); XaarGn-Cys-Cys-Ser-Hs-Xaas-a-Cys-Asn-Va-Asp-His-Xaas-Gly-Ile-Cys-Arg (SEQ IDNO:28); Xaas-Gn-Cys-Cys-Sr-His-Xaa-Ala-Cys-Asn-Val-Ap-H-is-Xaa- 5 -Xaa,-Thr-Cys-Arg (SEQ ID NO:29); 5 -Aa-Cys-Asn-Va-Asp-His-aa 1 -Xaa,-Va-Cys-Arg (SEQ MD Xa.ai-Gln-Cys-Cys-Ser-His-Xaa-Ala-Cys-Asn-le-Asp-His-Xaa-Xaa -Ile-Cys-Arg (SEQ IM NO:3 1); Xaas-Gln-Cys-Cys-Ser-His-Xaas-Ala-Cys-Asn-Va-Asp-His-Xaa 5 -Xaa-Ile.-Cys-Arg- Arg-Arg-Arg (SEQ ID NO:32);~ Gly-Gly-Cys-Cys-Ser-His-XaaAaCysAaVaAsnHis.X-X -Leu-Cys (SEQ ID NO:33); Gl-y-y-e-i-asAaCsSe-a-s-i-a- Xa-e-y (SEQ ID NO:34); AaCsAnVlAp JsXa-ajl-y (SEQ MD NO:3 Xaal-Ser (SEQ ID NO:36); (SEQ'ID NO:37); (SEQ ED NO:38); ID NO:39); Gl-y-y-e-~-a ,a-y-PeLuAnAnXApXa-y

(SEQ

ID Gl-y-y-e-s-asXa-y-leAaXa-s-asHsMtCs-l (SEQ ID NO:41); -23h (SEQ ID NO:43); sIl-l-s-s-a -s-e-y (SEQ ID Gl-y-y-e-s-a VlCsFsVlXa-His-Xaas-Xaa 1 -Leu-Cys-Arg.

Arg-Arg-Arg (SEQ ID GlY (SEQ ID PJOA4Q) CsAnSe-e-i-a-sXa-Leu-Cys- GlY (SEQ ID NO:47); Xa GnCsCsSrApX,-r-y-s-a-l-sXi-alLuCs Gly (SEQ ID NO:48); (SEQ ID NO:49); Gl-y-y-e-r-" -a CY-l-l-s-siX i-s-e-y

(SEQ

ID Xa _l-y- (SEQ ID NO:5 1); Xa3Ag(SEQ MD NO:52) Gly (SEQ ID NO:53); Gln-Arg (SEQ IDNO:54); r se-l-h-~-~-s-a4Xa-a5Cy-a4Xaha4Xa XaSr Cys-Leu (SEQ EID (SEQ ID NO:56); *Ile-Cys-.Leu (SEQ MD NO:57);4 AaXa Xaa 1 y-CsTr-mYa VlCYs-Hs-AlaXaa -His-Gln-XaalLeu-C(ys-Ala- Arg-Arg-Arg (SEQ. MD NO:1i7o); -23i GI-Y-y-e-s-a_-a-yHi-e-a,.-i-e-s-e-y (S]EQ I]D NO:171); XalCsCsTrAnXa-a-y-i-a-alHsGln aa -Leu-Cy-s-Ala.

Arg-Arg-Arg (SEQ MD NO: 172); Xa6Xa-y-y-e-a4-&i-l-y-s-e-S-i-asX a LuC s (SEQ ID NO: 173); XaralCsCsSrAs-asAgCs-s-e-h-i-asXaLuCs Gly (SEQID NO: 174); Ser-Xaa 1 -VaI...g (SEQ MD NO: 175); CYS-AsnXa ValHis (SEQ ID NO: 176); Asn-Xaa 1 -Val-Arg (SEQ ID NO:107); Asp -Xaa 1 y-y-e-s-aa AaCsAgvlAn-s-asHsVlCs Arg-Arg-Arg (SEQ ID NO: 178); Le.AnCsCsSrIeXa-l-y'a3AnXa-a a ApAgCs Ser-Xaa 2 -Val-Arg (SEQ MD NO: 179); (SEQ ID NO: 180); (SEQ ID NO: IS1); **Gly-Cys-Cys-Se-His-XaaXaB3-Cys-Xaa Ala-AsnAsnGln I aXaa4-CyAs (SEQ ID NO: 182); 0 IDDNO: 183); (SEQ MD NO: :184); Va-e-y-CsV VlAr-a CsXa3IeAgX *GnXa-Xaa, Cs LCu-XaaI-AaAsp-Xa Arg-.ThrLeu (SEQ ID NO: 185);.

Ser-Xaa 1 -Val-Arg (SEQ ID NO:I 86); -23j Gly-Cys-Cys-Ser-Asn-Xaa 5 -Val-Cys-His-Leu-Xaa 1 -His-Xa.- 5 -Asn-Ala-Cys (SEQ MDNO: 187); Gly-Cys-Cys-Ser-Asn-Xaa 5 -fle-Cys-Xaa 4 -Phe-Asn-Asn-Xaa 5 -Arg-Ile-Cys-Arg(SEQ ID NO: 188); Xaa,-Cys-Cys-Ser-Gln-Xaas-Xaa 5 -Cys-Arg-Xaa 3 -Xaa 2 -His-Xaas-Xaa 1 -Leu-Cys-Ser (SEQ -ID NO: 189); Gly-Cys-Cys-Ser-His-Xaai 5 -Ala-Cys-Ala-Gly-Asn-Asn-GIn-His-Ile-Cys (SEQ MD NO: 190); Gly-Cys-Cys-Ala-Val-Xaas-Ser-Cys-Arg-Leu-Arg-Asn-Xaa 5 -Asp-Leu-Cys-Gy-Gly (SEQ MDNO: 19 1); Gly-Cys-Cys-Ser-H-is-Xaa, 5 -Ala-Cys-Asn-Val-Asn-Asn-Xaa 5 -His-Ile-Cys (SEQ IID NO:192); Tr-Xaa-i-Xaa,-Xaa 1 -Cys-Cys-Xaa5-Asn-Xaas-Xaa 5 -Cys-Phe-Ala-Thr-Asn-Ser-Asp- Ile-Cys-Gly (SEQ MD NO: 193); As-l-y-y-e-s.Xa~gCsSrGyXa-i-l-s-e-y(E MD NO: 194); XalApCsCsSxApX~sAgCsSrVlGyE-l-s-e-y(E ID NO: 195); l-erAnAaHi-l-y (SEQ, Ib NO: 196); Xaa 1 -Asp-Cys-Cys-Ser-Asp-Xaa4-Arg-Cys-Ser-Val Gly is- Gln-Asp..Met..Cys S(SEQ IDNO19) NO:198); Gly-Cys-Cys-Gly-Asn-Xasi-Ser-Cys-Ser-Ie-His.fle.Xaas-Xaa4..ValCys.Asn

(SEQ

ED NO: 199); *Tbr-As-Ser-Xaa,-Xaa-Cys-Cys.Leu-AspSerAgCysaGyGn.1is-GlnAp Leu-Cys-Gly (SEQ ID NO:200); (SEQ ID NO:201); -23k Gl-y-y-e- SX ,i-l-y-e-a-s-s a -s-l-y (SEQ MD NO:202); Gl-akCsCsIeAnApAaCsAgSrXa-i-a GnXa-y-e (SEQ MD NO:203); MD N0:204);' Gl-y-y-lrHsX i-a-y-r-h-s-a-4X a-a2Xa-y-l (SEQ MD NO:205); As-alCsCsAaSrXa~a5CsAgLuAnAnXra4VlCs His (SEQ MD NO :206); Gl-y-y-e-s-a-.-a-y-aGnAnAnAaXa-a4CsAg Xaal-Ser (SEQ MD N0:207); Gly-Cys-Cys-Ser-His-Xaa-Xa-i-Cys-Ala-Gln-AsnAsnGnAspXaa 4 .Cys (SEQ ID NO:208); Gl-y-y-e-i-a-i-l-y-erGyAnAnAgXa-a4CsAg Xaa 1 -Ser (SEQ MD NO:209);i As-a5CsCsSr-a4Xa-s-y GyAaAnHsa-Xalie-Cys- GIly (SEQ MD NO:2 0 (SEQ MDNO:21 1);(SQI G*-y -y sX a-l-y -l-l-s -s -a-slsH -y (SEQ NO:2 12); Gly-Cys-Cys-Ser-Asp-Xa i-e-y-s-a-s-AnXa5ApXa-y

(SEQ

ID NO:213); (SEQ ID NO:214); Gl~y-Gly-Cys-CysSer-Asn-Xaa 5 -Ala-Cys-Leu-.ValAsn-His-Leu-Xaal-Met-Cys (SEQ ID NO:215); (SEQ ID NO:216); VaI-Asn-Arg (SEQ ID NO:217); -231- Cys-Cys-Tr-Asn-Xa-i-Aa-Cys-Leu-Va-Asn-Asn-Ie-Arg-Phe-Cys-Gly (SEQ MD NO:218); Asp-Xaa,-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Es-Gy-An-Asn-Ag-Asp4sCys-Ala (SEQ MD NO:219); MD NO:220); (SEQ ID NO:22 1); Gly-Cys-Cys-Ser-H-is-Xaa 5 -Ala-Cys-Asn-Val-Asn-Asn-Xaa 5 -His-fle-Cys (SEQ MD *NO 222).

Gly-Cys-Cys-Se-I-is-Xaa-a-Cys-Xaa 2 -Val-Arg-Xaa 4 -Ser-Asp-Met-Cys (SEQMI NO:223); Gly-Gly-Cys-Cys-Ser-Hs-Xaa-Ala-Cys-Xaa 2 -Val-His-Phe-Xa 5 i-His-Ser-CysgSEQ MD NO :224);.

Arg-Arg (SEQ ID NO :225); Gly-Cys-Cys-Scr-Hs-Xaa -VaI-Cys-Asn-Leu-Se-Asn-Xaa-Gln-fle-Cys-Arg

(SEQ

MD NO:226); (SQXaa 6 ,-Xaa,-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-VaI-Asp-His-XCaa 5 -Xaa 1 -Ile-Cys-Arg (S D NO:227); :Gly-Cys-Cys-Ser-sn-aa 5 -Ala-Cys-Leu-Val-Asn-His-Ile-Arg-Phe-Cys-Gly

(SEQ.

*00 ED NO:228); C0 *Asp-Cys-Cys-Asp-Asp-Xaas-Ala-Cy~i-Thr-Val-Asn-Asn-Xaas-Gly-Leu-Cys-Tr (SEQ ID NO:229); and Gly-Cys-Cys-Ser-An-Xaa-a-Cys-le-Ala-Xaa 2 -Asn-Xaas-His-Met-Cys-Gly- Gly-Arg-Arg (SEQ ID NO:230), :.:wherein Xaa, is Glu or y-carboxy-Glu (Gla);'Xaa 2 is Lys, N-methyl-Lys, NN-dimnethyl-Lys *ses:or NN,N-trixnethyl-Lys; Xaa 3 is Trp (D or halo-Trp or neo-Trp; Xaa. is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-T)r, 0-phospho-Tyr or nitro-Tyr, and Xaa is Pro or* ::::*hydroxy-Pro; Xaa is Gin or pyro-Glu; and the C-terminus contains a carboxyl or amnide group, or derivatives thereof.

23m According to a seventh aspect, the present invention provides a susbtanially pure a-coxotoxin peptide selected from the group consisting of: Cys-Cys-Thr-Ile-Xaa 5 -Ser-Cys-Xaa4-Xaal-Xaa 2 -Xaa 2 -Xaa 2 -Ile-Xaa 2 -Ala-Cys-Val-Phe (SEQ ID NO:231) and Gly-Cys-Cys-Gly-Asn-Xaa 5 (SEQ ID NO:232), wherein Xaal is Glu or y-carboxy-Glu (Gla); Xaa 2 is Lys, N-methyl-Lys, N,N-dimethyl- Lys or N,N,N-trimethyl-Lys; Xaa 4 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa 5 is Pro or hydroxy-Pro; and the Cterminus contains a carboxyl or amide group, or derivatives thereof.

According to an eighth aspect, the present invention provides an isolated nucleic acid comprising a nucleic acid coding for an a-conotoxin precursor comprising an amino acid sequence selected from the group of amino acid sequences set forth in Tables 1-134.

According to a ninth aspect, the present invention provides a substantially pure a-conotoxin protein precursor comprising an amino acid sequence selected from the group of amino acid sequences set forth in Tables 1-134.

Unless the context clearly requires otherwise, throughout the description and the claims, the words 'comprise', 'comprising', and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".

DETAILED DESCRIPTION OF THE INVENTION The invention relates to relatively short peptides (termed a-conotoxins herein), about 10-30 residues in length, which are naturally available in minute amounts in the venom of the cone snails or analogous to the naturally available peptides, and which o* preferably include two disulfide bonds.

The present invention, in another aspect, relates to a pharmaceutical composition comprising an effective amount of an a-conotoxin peptide. Such a pharmaceutical composition has the capability of acting as antagonists for nicotinic acetylcholine receptors. In one aspect, the a-conotoxins with specificity for neuromuscular junction nicotinic acetylcholine receptors are used as neuromuscular blocking agents for use in conjunction with surgery, as disclosed in U.S. patent Serial No. 6,268,473, filed 21 January 2000 and international patent No.WO 00/43409, filed 21 January 2000 each January 2000 and international patent No.WO 00/43409, filed 21 January 2000 each 23n incorporated by reference herein. In a second aspect, additional a-conotoxins and uses for them have been described in U.S. Patent Nos. 4,447,356 (Olivera et al., 1984); 5,432,155; 5,514,774, each incorporated herein by reference.

In another aspect additional uses for a-conotoxins are described in U.S. Serial No.WO 99/33482, filed 22 December 1998, incorporated herein by reference. In this application, a-conotoxins with specificity for neuronal nicotinic acetylcholine receptors are used for treating disorders regulated at neuronal nicotinic acetylcholine receptors.

Such disorders include, but are not limited to, cardiovascular disorders, gastric motility disorders, urinary incontinence, nicotine addiction, mood disorders (such as bipolar disorder, unipolar depression, dysthymia and seasonal effective disorder) and small cell lung carcinoma, as well as the localization of small cell lung carcinoma.

The a-conotoxin peptides described herein are sufficiently small to be chemically synthesized. General chemical syntheses for preparing the foregoing aconotoxin peptides are described hereinafter. Various ones of the a-conotoxin peptides can also be obtained by isolation a **a *a o• WO 00/44776 PCT/US00/01979 24 and purification from specific Conus species using the technique described in U.S. Patent No.

4,447,356 (Olivera et al., 1984), the disclosure of which is incorporated herein by reference.

Although the a-conotoxin peptides of the present invention can be obtained by purification from cone snails, because the amounts of a-conotoxin peptides obtainable from individual snails are very small, the desired substantially pure a-conotoxin peptides are best practically obtained in commercially valuable amounts by chemical synthesis using solid-phase strategy. For example, the yield from a single cone snail may be about 10 micrograms or less of a-conotoxin peptide. By "substantially pure" is meant that the peptide is present in the substantial absence of other biological molecules of the same type; it is preferably present in an amount of at least about 85% purity and preferably at least about 95% purity. Chemical synthesis of biologically active a-conotoxin peptides depends of course upon correct determination of the amino acid sequence.

The a-conotoxin peptides can also be produced by recombinant DNA techniques well known in the art. Such techniques are described by Sambrook et al. (1989). The peptides produced in this manner are isolated, reduced if necessary, and oxidized to form the correct disulfide bonds.

One method of forming disulfide bonds in the conantokin peptides of the present invention is the air oxidation of the linear peptides for prolonged periods under cold room temperatures or at room temperature. This procedure results in the creation of a substantial amount of the bioactive, disulfide-linked peptides. The oxidized peptides are fractionated using reverse-phase high performance liquid chromatography (HPLC) or the like, to separate peptides having different linked configurations. Thereafter, either by comparing these fractions with the elution of the native material or by using a simple assay, the particular fraction having the correct linkage for maximum biological potency is easily determined. However, because of the dilution resulting from the presence of other fractions of less biopotency, a somewhat higher dosage may be required.

The peptides are synthesized by a suitable method, such as by exclusively solid-phase techniques, by partial solid-phase techniques, by fragment condensation or by classical solution couplings.

In conventional solution phase peptide synthesis, the peptide chain can be prepared by a series of coupling reactions in which constituent amino acids are added to the growing peptide chain in the desired sequence. Use of various coupling reagents, dicyclohexylcarbodiimide or diisopropylcarbonyldimidazole, various active esters, esters of N-hydroxyphthalimide or Nhydroxy-succinimide, and the various cleavage reagents, to carry out reaction in solution, with subsequent isolation and purification of intermediates, is well known classical peptide methodology.

WO 00/44776 PCT/US00/01979 Classical solution synthesis is described in detail in the treatise, "Methoden der Organischen Chemie (Houben-Weyl): Synthese von Peptiden," (1974). Techniques of exclusively solid-phase synthesis are set forth in the textbook, "Solid-Phase Peptide Synthesis," (Stewart and Young, 1969), and are exemplified by the disclosure of U.S. Patent 4,105,603 (Vale et al., 1978). The fragment condensation method of synthesis is exemplified in U.S. Patent 3,972,859 (1976). Other available syntheses are exemplified by U.S. Patents No. 3,842,067 (1974) and 3,862,925 (1975). The synthesis of peptides containing y-carboxyglutamic acid residues is exemplified by Rivier et al.

(1987), Nishiuchi et al. (1993) and Zhou et al. (1996).

Common to such chemical syntheses is the protection of the labile side chain groups of the various amino acid moieties with suitable protecting groups which will prevent a chemical reaction from occurring at that site until the group is ultimately removed. Usually also common is the protection of an a-amino group on an amino acid or a fragment while that entity reacts at the carboxyl group, followed by the selective removal of the a-amino protecting group to allow subsequent reaction to take place at that location. Accordingly, it is common that, as a step in such a synthesis, an intermediate compound is produced which includes each of the amino acid residues located in its desired sequence in the peptide chain with appropriate side-chain protecting groups linked to various ones of the residues having labile side chains.

As far as the selection of a side chain amino protecting group is concerned, generally one is chosen which is not removed during deprotection of the ca-amino groups during the synthesis.

However, for some amino acids, His, protection is not generally necessary. In selecting a particular side chain protecting group to be used in the synthesis of the peptides, the following general rules are followed: the protecting group preferably retains its protecting properties and is not split off under coupling conditions, the protecting group should be stable under the reaction conditions selected for removing the a-amino protecting group at each step of the synthesis, and the side chain protecting group must be removable, upon the completion of the synthesis containing the desired amino acid sequence, under reaction conditions that will not undesirably alter the peptide chain.

It should be possible to prepare many, or even all, of these peptides using recombinant DNA technology. However, when peptides are not so prepared, they are preferably prepared using the Merrifield solid-phase synthesis, although other equivalent chemical syntheses known in the art can also be used as previously mentioned. Solid-phase synthesis is commenced from the C-terminus of the peptide by coupling a protected a-amino acid to a suitable resin. Such a starting material can WO 00/44776 PCT/US00/01979 26 be prepared by attaching an a-amino-protected amino acid by an ester linkage to a chloromethylated resin or a hydroxymethyl resin, or by an amide bond to a benzhydrylamine (BHA) resin or paramethylbenzhydrylamine (MBHA) resin. Preparation of the hydroxymethyl resin is described by Bodansky et al. (1966). Chloromethylated resins are commercially available from Bio Rad Laboratories (Richmond, CA) and from Lab. Systems, Inc. The preparation of such a resin is described by Stewart and Young (1969). BHA and MBHA resin supports are commercially available, and are generally used when the desired polypeptide being synthesized has an unsubstituted amide at the C-terminus. Thus, solid resin supports may be any of those known in the art, such as one having the formulae -O-CH 2 -resin support, -NH BHA resin support, or -NH-MBHA resin support. When the unsubstituted amide is desired, use of a BHA or MBHA resin is preferred, because cleavage directly gives the amide. In case the N-methyl amide is desired, it can be generated from an N-methyl BHA resin. Should other substituted amides be desired, the teaching of U.S. Patent No. 4,569,967 (Kornreich et al., 1986) can be used, or should still other groups than the free acid be desired at the C-terminus, it may be preferable to synthesize the peptide using classical methods as set forth in the Houben-Weyl text (1974).

The C-terminal amino acid, protected by Boc or Fmoc and by a side-chain protecting group, if appropriate, can be first coupled to a chloromethylated resin according to the procedure set forth in K. Horiki et al. (1978), using KF in DMF at about 60 0 C for 24 hours with stirring, when a peptide having free acid at the C-terminus is to be synthesized. Following the coupling of the BOCprotected amino acid to the resin support, the a-amino protecting group is removed, as by using trifluoroacetic acid (TFA) in methylene chloride or TFA alone. The deprotection is carried out at a temperature between about 0°C and room temperature. Other standard cleaving reagents, such as HC1 in dioxane, and conditions for removal of specific a-amino protecting groups may be used as described in Schroder Lubke (1965).

After removal of the a-amino-protecting group, the remaining a-amino- and side chainprotected amino acids are coupled step-wise in the desired order to obtain the intermediate compound defined hereinbefore, or as an alternative to adding each amino acid separately in the synthesis, some of them may be coupled to one another prior to addition to the solid phase reactor.

Selection of an appropriate coupling reagent is within the skill of the art. Particularly suitable as a coupling reagent is N,N'-dicyclohexylcarbodiimide (DCC, DIC, HBTU, HATU, TBTU in the presence of HoBt or HoAt).

WO 00/44776 PCT/US00/01979 27 The activating reagents used in the solid phase synthesis of the peptides are well known in the peptide art. Examples of suitable activating reagents are carbodiimides, such as N,N'diisopropylcarbodiimide and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide. Other activating reagents and their use in peptide coupling are described by Schroder Lubke (1965) and Kapoor (1970).

Each protected amino acid or amino acid sequence is introduced into the solid-phase reactor in about a twofold or more excess, and the coupling may be carried out in a medium of dimethylformamide

(DMF):CH

2 C1 2 or in DMF or CH 2 Cl 2 alone. In cases where intermediate coupling occurs, the coupling procedure is repeated before removal of the a-amino protecting group prior to the coupling of the next amino acid. The success of the coupling reaction at each stage of the synthesis, if performed manually, is preferably monitored by the ninhydrin reaction, as described by Kaiser et al. (1970). Coupling reactions can be performed automatically, as on a Beckman 990 automatic synthesizer, using a program such as that reported in Rivier et al. (1978).

After the desired amino acid sequence has been completed, the intermediate peptide can be removed from the resin support by treatment with a reagent, such as liquid hydrogen fluoride or TFA (if using Fmoc chemistry), which not only cleaves the peptide from the resin but also cleaves all remaining side chain protecting groups and also the a-amino protecting group at the N-terminus if it was not previously removed to obtain the peptide in the form of the free acid. If Met is present in the sequence, the Boc protecting group is preferably first removed using trifluoroacetic acid (TFA)/ethanedithiol prior to cleaving the peptide from the resin with HF to eliminate potential Salkylation. When using hydrogen fluoride or TFA for cleaving, one or more scavengers such as anisole, cresol, dimethyl sulfide and methylethyl sulfide are included in the reaction vessel.

Cyclization of the linear peptide is preferably affected, as opposed to cyclizing the peptide while a part of the peptido-resin, to create bonds between Cys residues. To effect such a disulfide cyclizing linkage, fully protected peptide can be cleaved from a hydroxymethylated resin or a chloromethylated resin support by ammonolysis, as is well known in the art, to yield the fully protected amide intermediate, which is thereafter suitably cyclized and deprotected. Alternatively, deprotection, as well as cleavage of the peptide from the above resins or a benzhydrylamine

(BHA)

resin or a methylbenzhydrylamine (MBHA), can take place at 0°C with hydrofluoric acid (HF) or TFA, followed by oxidation as described above.

The peptides are also synthesized using an automatic synthesizer. Amino acids are sequentially coupled to an MBHA Rink resin (typically 100 mg of resin) beginning at the C- -28terminus using an Advanced Chemtech 357 Automatic Peptide Synthesizer. Couplings are carried out using 1,3-diisopropylcarbodimide in N-methylpyrrolidinone (NMP) or by 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and diethylisopropylethylamine (DIEA). The FMOC protecting group is removed by treatment with a 20% solution of piperidine in dimethylformamide(DMF). Resins are subsequently washed with DMF (twice), followed by methanol and NMP.

Pharmaceutical compositions containing a compound of the present invention or its pharmaceutically acceptable salts as the active ingredient can be prepared according to conventional pharmaceutical compounding techniques. See, for example, Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, PA). Typically, an antagonistic amount of the active ingredient will be admixed with a pharmaceutically acceptable carrier. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, intravenous, oral or parenteral. The compositions may further contain antioxidizing agents, stabilizing agents, preservatives and the like.

For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions or emulsions. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, suspending agents, and the like in the case of oral liquid preparations (such as, for example, suspensions, elixirs and solutions); or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (such as, S for example, powders, capsules and tablets). Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques. The active agent can be encapsulated to make it stable to passage through the gastrointestinal tract while at the same time allowing for passage across the blood brain barrier. See for example, WO 96/11698.

•For parenteral administration, the compound may be dissolved in a pharmaceutical carrier and administered as either a solution or a suspension. Illustrative o -29of suitable carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative or synthetic origin. The carrier may also contain other ingredients, for example, preservatives, suspending agents, solubilizing agents, buffers and the like. When the compounds are being administered intrathecally, they may also be dissolved in cerebrospinal fluid.

The active agent is preferably administered in an therapeutically effective amount. The actual amount administered, and the rate and time-course of administration, will depend on the nature and severity of the condition being treated.

Prescription of treatment, e.g. decisions on dosage, timing, etc., is within the responsibility of general practitioners or specialists, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of techniques and protocols can be found in Remington's Pharmaceutical Sciences.

Typically the conopeptides of the present invention exhibit their effect at a dosage range from about 0.001 mg/kg to about 250 mg/kg, preferably from about 0.05 mg/kg to about 100 mg/kg of the active ingredient, more preferably from about 0.1 mg/kg to about mg/kg. A suitable dose can be administered in multiple sub-doses per day. Typically, a dose or sub-dose may contain from about 0.1 mg to about 500 mg of the active ingredient per unit dosage form. A more preferred dosage will contain from about mg to about 100 mg of active ingredient per unit dosage form. Dosages are generally initiated at lower levels and increased until desired effects are achieved.

Alternatively, targeting therapies may be used to deliver the active agent more specifically to certain types of cell, by the use of targeting systems such as antibodies or cell specific ligands. Targeting may be desirable for a variety of reasons, e.g. if the agent is unacceptably toxic, or if it would otherwise require too high a dosage, or if it Sowould not otherwise be able to enter the target cells.

The active agents, which are peptides, can also be administered in a cell based delivery system in which a DNA sequence encoding an active agent is introduced into cells designed for implantation in the body of the patient, especially in the spinal cord :region. Suitable delivery systems are described in U.S. Patent No. 5,550,050 and published PCT Application Nos. WO 92/19195, WO 94/25503, WO 95/01203, WO 95/05452, WO 96/02286, WO 96/02646, WO 96/40871, WO 96/40959 and WO oooo 97/12635. Suitable DNA sequences can be prepared synthetically for each active agent on the basis of the developed sequences and the known genetic code.

EXAMPLES

The present invention is described by reference to the following Examples, which are offered by way of illustration and are not intended to limit the invention in any manner. Standard techniques well known in the art or the techniques specifically described below were utilized.

EXAMPLE 1 Isolation of a-Conotoxins Crude venom was extracted from venom ducts (Cruz et al., 1976), and the components were purified as previously described (Cartier et al., 1996a). The crude extract from venom ducts was purified by reverse phase liquid chromatography (RPLC) using a Vydac C 1 8 semi-preparative column (10 x 250 mm) and elution with a linear gradient of acetonitrile in 0.1% TFA. Further purification of bioactive peaks was done on a Vydac C 1 8 analytical column (4.6 x 220 mm) eluted with a gradient of acetonitrile in 0.1% TFA. The effluents were monitored at 220 nm. Peaks were collected, and aliquots were assayed for activity. Activity was monitored by assessing block of a334 nAChRs expressed in Xenopus oocytes.

The amino acid sequence of the purified peptides were determined by standard methods. The purified peptides were reduced and alkylated prior to sequencing by automated Edman degradation on an Applied Biosystems 477A Protein Sequencer with a 120A Analyzer (DNA/Peptide Facility, University of Utah) (Martinez et al., 1995; S' Shon et al., 1994).

In accordance with this method, peptides MII, AuIA, AuIB, AuIC, MAR-1, MAR-2, TI, OB-29, EpI, S1.1, Bnl.1, Bnl.2, Cal.1, Cal.2, Cnl.1, Cnl.2 and Sml.3 were obtained.

**EXAMPLE 2 Synthesis of Conopeptides The synthesis of conopeptides, either the mature toxins or the precursor peptides, was separately performed using conventional protection chemistry as described by S Cartier et al. (1996). Briefly, the linear chains were built on Rink amide resin by Fmoc *oo -31 procedures with 2-(1H-benzotriol- -yl)-1,1,3,3,-tetramethyluronium tetrafluoroborated coupling using an ABI model 430A peptide synthesizer with amino acid derivatives purchased from Bachem (Torrance CA). Orthogonal protection was used on cysteines: Cys 3 and Cys 16 were protected as the stable Cys(S-acetamidomethyl), while Cys 2 and Cys 8 were protected as the acid-labile Cys(S-trityl). After removal of the terminal Fmoc protecting group and cleavage of the peptides from the resins, the released peptides were precipitated by filtering the reaction mixture into -10 0 C methyl t-butyl ether, which removed the protecting groups except on Cys 3 and Cys 1 6 The peptides were dissolved in 0.1% TFA and 60% acetonitrile and purified by RPLC on a Vydac C 18 preparative column (22 x 250 mm) and eluted at a flow rate of 20 mL/min with a gradient of acetonitrile in 0.1% TFA.

The disulfide bridges in the three conopeptides were formed as described in Cartier et al. (1996). Briefly, the disulfide bridges between Cys 2 and Cys 8 were formed by air oxidation which was judged to be complete by analytical RPLC. The monocyclic peptides were purified by RPLC on a Vydac C 1 8 preparative column (22 x 250 mm) and eluted with a gradient of acetonitrile in 0.1% TFA. Removal of S-acetamidomethyl groups and closure of the disulfide bridge between Cys 3 and Cys 16 was carried out simultaneously be iodine oxidation. The cyclic peptides were purified by RPLC on a Vydac C 18 preparative column (22 x 250 mm) and eluted with a gradient of acetonitrile in 0.1% TFA.

EXAMPLE 3 Isolation of DNA Encoding a-Conotoxins DNA coding for a-conotoxins was isolated and cloned in accordance with conventional techniques using general procedures well known in the art, such as o described in Olivera et al. (1996). Alternatively, cDNA libraries was prepared from Conus venom duct using conventional techniques. DNA from single clones was amplified by conventional techniques using primers which correspond approximately to Sthe M13 universal priming site and the M13 reverse universal priming site. Clones having a size of approximately 300 nucleotides were sequenced and screened for similarity in sequence to known a-conotoxins. The DNA sequences and encoded propeptide or peptide sequences are set forth in Tables 1-134.

o -31a- TABLE 1 DNA Sequence (SEQ ID NO:58) and Protein Sequence (SEQ ID NO:59) of MII atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc cct tca gat cgt gca tct gat ggc agg aat gcc gca gcc aac gac Phe Pro Ser Asp Arg Ala Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp aaa gcg tct gac gtg atc acg ctg gcc ctc aag gga tgc tgt tcc aac Lys Ala Ser Asp Val Ile Thr Leu Ala Leu Lys Gly Cys Cys Ser Asn cct gtc tgt cac ttg gag cat tca. aac ctt tgt ggt aga aga cgc Pro Val Cys His Leu Glu His Ser Asn Leu Cys Gly Arg Arg Arg 0*00*0 WO 00/44776 WO 0044776PCTIUSOO/O1 979 32 tgatgctcca gqaccctctg aaccacgacg ttcgagca TABLE 2 DNA Sequence (SEQ ID NO:60) and Protein Sequence (SEQ ID NO:61) of AuI1A atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tca gat cgt gca tct gat ggc agg aag gac gca gcg tct gqc Phe Thr Ser Asp Arg Ala Ser Asp Gly Arg Lys Asp Ala Ala Ser Gly ctg atc gct ctg acc atc aag gga tgc tgt tct tat cct ccc tgt ttc Leu Ile Ala Leu Thr Ile Lys Gly Cys Cys Ser Tyr Pro Pro Cys Phe gcg act aat tca gac tat tgt ggt tgacgacgct gatgctccag gaccctctga Ala Thr Asn Ser Asp Tyr Cys Gly accacgacgt TABLE 3 DNA Sequence (SEQ ID NO:62) and Protein Sequence (SEQ ID NO:63) of AuIB atg ttc acc gtg ttt ctg ttg gtc gtc ttg gca acc acc gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tca gat cgt gca tct gat ggc agg aag gac gca gcg tct ggc Phe Thr Ser Asp Arg Ala Ser Asp Gly Arg Lys Asp Ala Ala Ser Gly ctg att. gct ctg acc atg aag gga tgc tgt tct tat cct ccc tgt ttc Leu Ile Ala Leu Thr Met Lys Gly Cys Cys Ser Tyr Pro Pro Cys Phe gcg act aat cca gac tgt ggt cga cga cgc tgatgctcca ggaccctctg Ala Thr Asn Pro Asp Cys Gly Arg Arg Arg aaccacgacg t TABLE 4 DNA Sequence (SEQ ID NO:64) and Protein Sequence (SEQ ID NO:65) of Txl.3 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc tct tca ggt cgt agt aca ttt. cgt ggc agg aat gcc gca gcc aaa Phe Ser Ser Gly Arg Ser Thr Phe Arg Gly Arg Asn Ala Ala Ala Lys gcg tct ggc ctg gtc agt ctg act gac agg aga cca gaa tgc tgt agt Ala Ser Gly Leu Val Ser Leu Thr Asp Arg Arg Pro Glu Cys Cys Ser gat cct cgc tgt aac tcg agt cat cca gaa ctt tgt ggt gga aga cgc Asp Pro Arg Cys Asn Ser Ser His Pro Glu Leu Cys Gly Gly Arg Arg tgatgctcca ggaccctctg aaccacgacg t WO 00/44776 PCT/USOO/01979 33 TABLE DNA Sequence (SEQ ID NO:66) and Protein Sequence (SEQ ID NO:67) of Txl .2 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc gcc gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Ala Val Val Ser ttc act tca gat cgt gca tct gat gac ggg aaa gcc gct gcg tct gac Phe Thr Ser Asp Arg Ala Ser Asp Asp Gly Lys Ala Ala Ala Ser Asp ctg atc act ctg acc atc aag gga tgc tgt tct cgt cct ccc tgt atc Leu Ile Thr Leu Thr Ile Lys Gly Cys Cys Ser Arg Pro Pro Cys Ile gcg aat aat cca gac ttg tgt ggt tgacgacgct gatgctccag aacggtctga Ala Asn Asn Pro Asp Leu Cys Gly accacgacgt tcgagcaatg ttcaccgtgt ttctgttggt tgtctt TABLE 6 DNA Sequence (SEQ ID NO:68) and Protein Sequence (SEQ ID NO:69) ofTx .1 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tca ggt cgt agt aca ttt cgt ggc agg aat gcc gca gcc aaa Phe Thr Ser Gly Arg Ser Thr Phe Arg Gly Arg Asn Ala Ala Ala Lys gcg tct ggc ctg gtc agt ctg act gac agg aga cca caa tgc tgt tct Ala Ser Gly Leu Val Ser Leu Thr Asp Arg Arg Pro Gin Cys Cys Ser cat cct gcc tgt aac gta gat cat cca gaa att tgt cgt tgaagacgct His Pro Ala Cys Asn Val Asp His Pro Glu Ile Cys Arg gatgctccag gaccctctga accacgacgt TABLE 7 DNA Sequence (SEQ ID NO:70) and Protein Sequence (SEQ ID NO:71) of R1.1A atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tca ggt cgt cgt aca ttt cat ggc agg aat gcc gca gcc aaa Phe Thr Ser Gly Arg Arg Thr Phe His Gly Arg Asn Ala Ala Ala Lys gcg tct ggc ctg gtc agt ctg act gac agg aga cca gaa tgc tgt tct Ala Ser Gly Leu Val Ser Leu Thr Asp Arg Arg Pro Glu Cys Cys Ser cat cct gcc tgt aac gta gat cat cca gaa att tgt cgt tgaagacgct His Pro Ala Cys Asn Val Asp His Pro Glu Ile Cys Arg gatgctccag gaccctctga accacgacgt TABLE8 DNA Sequence (SEQ ID NO:72) and Protein Sequence (SEQ ID NO:73) of RL.lB atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser i WO 00/44776 PCTIUSOO/01979 34 ttc act tca ggt cgt agt aca ttt cgt ggc agg aat gcc gca qcc aaa Phe Thr Ser Gly Arg Ser Thr Phe Arg Gly Arg Asn Ala Ala Ala Lys gcg tct ggc ctg gtc agt ctg act gac agg aga cca caa tgc tgt tct Ala Ser Gly Leu Val Ser Leu Thr Asp Arg Arg Pro Gin Cys Cys Ser cat cct gcc tgt aac gta gat cat cca gaa att tgc gat tgaagacgct His Pro Ala Cys Asn Val Asp His Pro Glu Ile Cys Asp gatgctccag gaccctctga accacgacgt TABLE9 DNA Sequence (SEQ ID NO:74) and Protein Sequence (SEQ ID NO:75) of S1.1 atg ttc act gtg ttt ctg ttg gtt gtc ttg gca atc act gtc qtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Ile Thr Val Val Ser ttc cct tta gat cgt gaa tct gat ggc gcg aat gcc gaa qcc cgc acc Phe Pro Leu Asp Arg Glu Ser Asp Gly Ala Asn Ala Glu Ala Arg Thr cac gat cat gag aag cac gca ctg gac cgg aat gga tgc tgt agg aat His Asp His Glu Lys His Ala Leu Asp Arg Asn Gly Cys Cys Arg Asn cct gcc tgt gag agc cac aga tgt ggt tgacgacgct gatgctccag Pro Ala Cys Glu Ser His Arg Cys Gly gaccctctga accacgacgt tcgagca TABLE DNA Sequence (SEQ ID NO:76) and Protein Sequence (SEQ ID NO:77) of Bnl.1 atg ttc acc atg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc Met Phe Thr Met Phe Leu Leu Val Val Leu Ala Thr Thr Val'Val Ser ttc gct tca gat cgt gca tct gat ggc agg aat gcc gca gcc aag gac Phe Ala Ser Asp Arg Ala Ser Asp Gly Arg Asn Ala Ala Ala Lys Asp aaa gcg tct gac ctg gtc gct ctg acc gtc aag gga tgc tgt tct cat Lys Ala Ser Asp Leu Val Ala Leu Thr Val Lys Gly Cys Cys Ser His cct gcc tgt agc gtg aat aat cca gac att tgt ggt tgaagacgct Pro Ala Cys Ser Val Asn Asn Pro Asp Ile Cys Gly gatgctccag gaccctctga accacgacgt tcgagca TABLE 11 DNA Sequence (SEQ ID NO:78) and Protein Sequence (SEQ ID NO:79) of Bn1 .2 aaa gaa tgc tgt act cat cct gcc tgt cac gtg agt cat cca gaa ctc Lys Glu Cys Cys Thr His Pro Ala Cys His Val Ser His Pro Glu Leu tgt ggt tgaaaagcga cgtgacgctc caggaccctc tgaaccacga cgttcgagca Cys Gly WO 00/44776 PCTUSOO/01979 TABLE 12 DNA Sequence (SEQ ID NO:80) and Protein Sequence (SEQ ID NO:81) of Bnl.3 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca act gct gtt ctt cca Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Ala Val Leu Pro gtc act tta gat cgt gca tct gat gga agg aat gca gca gcc aac gcc Val Thr Leu Asp Arg Ala Ser Asp Gly Arg Asn Ala Ala Ala Asn Ala aaa acg cct cgc ctg atc gcg cca ttc atc agg gat tat tgc tgt cat Lys Thr Pro Arg Leu Ile Ala Pro Phe Ile Arg Asp Tyr Cys Cys His aga ggt ccc tgt atg gta tgg tgt ggt tgaagccgct gctgctccag Arg Gly Pro Cys Met Val Trp Cys Gly gaccctctga accac TABLE 13 DNA Sequence (SEQ ID NO:82) and Protein Sequence (SEQ ID NO:83) of Cal.1 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtg gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Vai Ser ttc act tca gat cgt gct tct gat ggc agg aat gcc gca gcc aac gcg Phe Thr Ser Asp Arg Ala Ser Asp Gly Arg Asn Ala Ala Ala Asn Ala ttt gac ctg atc gct ctg atc gcc agg caa aat tgc tgt agc att ccc Phe Asp Leu Ile Ala Leu Ile Ala Arg Gin Asn Cys Cys Ser Ile Pro agc tgt tgg gag aaa tat aaa tgt agt taa Ser Cys Trp Giu Lys Tyr Lys Cys Ser TABLE 14 DNA Sequence (SEQ ID NO:84) and Protein Sequence (SEQ ID NO:85) of Cal.2 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtg gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tca gat cgt gcg tct gaa ggc agg aat gct gca gcc aag gac Phe Thr Ser Asp Arg Ala Ser Giu Gly Arg Asn Ala Ala Ala Lys Asp aaa gcg tct gac ctg gtg gct ctg aca gtc agg gga tgc tgt gcc att Lys Ala Ser Asp Leu Val Ala Leu Thr Val Arg Gly Cys Cys Ala Ile cgt gaa tgt cgc ttg cag aat gca gcg tat tgt ggt gga ata tac Arg Giu Cys Arg Leu Gin Asn Ala Ala Tyr Cys Gly Gly Ile Tyr *tgatgctcca ggaccctctg aaccacgacg TABLE DNA Sequence (SEQ ID NO:86) and Protein Sequence (SEQ ID NO:87) of TIB atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Vai Val Ser WO 00/44776 PCT/US00101979 36 ttc cct tca gat att gca act gag ggc agg aat gcc gca gcc aaa gcg Phe Pro Ser Asp Ile Ala Thr Glu Gly Arg Asn Ala Ala Ala Lys Ala ttt gac ctg ata tct tcg ate gtc aag aaa gga tgc tgt tcc cat cct Phe Asp Leu Ile Ser Ser Ile Val Lys Lys Gly Cys Cys Ser His Pro gcc tgt tcg ggg aat aat cca gaa ttt tgt cgt caa ggt cgc Ala Cys Ser Gly Asn Asn Pro Glu Phe Cys Arg Gln Gly Arg tgatgctcca ggaccctctg aaccacgacg t TABLE 16 DNA Sequence (SEQ ID NO:88) and Protein Sequence (SEQ ID NO:89) of TIA atg ttc acc gtg ttt etg ttg gtt gtc ttg gca ace act gte gtt tee Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc cct tea gat ata gea act gag gge agg aat gee gca gee aaa gcg Phe Pro Ser Asp Ile Ala Thr Glu Gly Arg Asn Ala Ala Ala Lys Ala ttt gac ctg ata tet teg ate gte agg aaa gga tge tgt tee aat ccc Phe Asp Leu Ile Ser Ser Ile Val Arg Lys Gly Cys Cys Ser Asn Pro gee tgt geg ggg aat aat eca cat gtt tgt egt caa ggt cgc Ala Cys Ala Gly Asn Asn Pro His Val Cys Arg Gin Gly Arg tgatgctcca ggaccctctg aaccacgaeg t TABLE 17 DNA Sequence (SEQ ID NO:90) and Protein Sequence (SEQ ID NO:91) of S11.

atg ttc ace gtg ttt etg ttg gtt gte ttg gea ace ace gte gtt tee Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc aat tea gat egt gat cca gca tta ggt gge agg aat get gea gee Phe Asn Ser Asp Arg Asp Pro Ala Leu Gly Gly Arg Asn Ala Ala Ala aaa geg tet gae aag ate get teg ace etc aag aga aga gga tgc tgt Lys Ala Ser Asp Lys Ile Ala Ser Thr Leu Lys Arg Arg Gly Cys Cys tcg tat ttt gac tgt aga atg atg ttt eca gaa atg tgt ggt tgg ega Ser Tyr Phe Asp Cys Arg Met Met Phe Pro Giu Met Cys Gly Trp Arg ggc tgatgetcca ggaccctetg aaccacgaeg t Gly TABLE 18 DNA Sequence (SEQ ID NO:92) and Protein Sequence (SEQ ID NO:93) of S11.2 atg tte ae gtg ttt ctg ttg gtt gte ttg gca ace ace gte gtt tee Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser tte aat tea gat cgt gat eca gea tta ggt gge agg aat get gea gee Phe Asn Ser Asp Arg Asp Pro Ala Leu Gly Gly Arg Asn Ala Ala Ala ata geg tet gac aag ate get teg ace etc agg aga gga gga tge tgt Ile Ala Ser Asp Lys Ile Ala Ser Thr Leu Arg Arg Gly Gly Cys Cys WO 00/44776 PCTIUSOO/01979 37 tct ttt cct gcc tgt aga aag tat cgt cca gaa atg tgt ggt gga cga Ser Phe Pro Ala Cys Arg Lys Tyr Arg Pro Glu Met Cys Gly Gly Arg cgc tgatgctcca ggaccctctg aaccacgacg t Arg TABLE 19 DNA Sequence (SEQ ID NO:94) and Protein Sequence (SEQ ID NO:95) of S11.3 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tca gat cat gaa tct gat cgc ggt gat gcc caa acc atc caa Phe Thr Ser Asp His Giu Ser Asp Arg Gly Asp Ala Gin Thr Ile Gin gaa gtg ttt gag atg ttc gct ctg gac agc gat gga tgc tgt tgg cat Glu Val Phe Glu Met Phe Ala Leu Asp Ser Asp Giy Cys Cys Trp His cct gct tgt ggc aga cac tat tgt ggt cqa aga cgc tgatgctcca Pro Ala Cys Giy Arg His Tyr Cys Gly Arg Arg Arg ggaccctctg aaccacgacg t TABLE DNA Sequence (SEQ ID NO:96) and Protein Sequence (SEQ ID NO:97) of S11.6 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Vai Leu Ala Thr Thr Val Val Ser ttc aat tca gat cgt gat cca gca tta ggt ggc agg aat gct gca gcc Phe Asn Ser Asp Arg Asp Pro Ala Leu Gly Gly Arg Asn Ala Ala Ala ata gcg tct gac aag atc gct tcg acc ctc agg aga gga gga tgc tgt Ile Ala Ser Asp Lys Ile Ala Ser Thr Leu Arg Arg Gly Gly Cys Cys tct ttt gct gcc tgt aga aag tat cgt cca gaa atg tgt ggt gga cga Ser Phe Ala Ala Cys Arg Lys Tyr Arg Pro Glu Met Cys Gly Gly Arg cgc tgatgct Arg TABLE 21 DNA Sequence (SEQ ID NO:98) and Protein Sequence (SEQ ID NO:99) of S11.7 atg ttc acc gtg ttt ctg ttg gtt ctc ttg gca acc acc gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Leu Leu Ala Thr Thr Val Val Ser ttc aat tca gat cgt gca tta ggt ggc agg aat gct gca gcc aaa gcg Phe Asn Ser Asp Arg Ala Leu Gly Gly Arg Asn Ala Aia Ala Lys Ala tct gac aag atc ctt tcg aac ctc agg aga gga gga tgc tgt ttt cat Ser Asp Lys Ile Leu Ser Asn Leu Arg Arg Gly Giy Cys Cys Phe His cct gtc tgt tac atc aat ctt cta gaa atg tgt cgt caa cga ggc Pro Val Cys Tyr Ile Asn Leu Leu Glu Met Cys Arg Gin Arg Gly tgatcgtcca ggaccctctg aaccacgacg t WO 00/44776 PCT/USOO/01979 38 TABLE 22 DNA Sequence (SEQ ID NO:100) and Protein Sequence (SEQ ID NO:101) of Cn 1.1 atg ttc acc gtg ttt ctg ttg gtt gtc ttq aca acc act gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Thr Thr Thr Val Val Ser ttc cct tca gat agt gca tct gat gtc agg gat gac gaa gcc aaa gac Phe Pro Ser Asp Ser Ala Ser Asp Val Arg Asp Asp Glu Ala Lys Asp gaa agg tct gac atg tac aaa tcg aaa cgg aat gga cgc tgt tgc cat Glu Arg Ser Asp Met Tyr Lys Ser Lys Arg Asn Gly Arg Cys Cys His cct gcc tgt ggc aaa cac ttt agt tgt gga cgc tgatgctcca ggaccctctg Pro Ala Cys Gly Lys His Phe Ser Cys Gly Arg aaccacgacg t TABLE 23 DNA Sequence (SEQ ID NO: 102) and Protein Sequence (SEQ ID NO: 103) of SmI atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser tcc cct tca gat cgt gca tct gat ggc agg aat gcc gca gcc aac gag Ser Pro Ser Asp Arg Ala Ser Asp Gly Arg Asn Ala Ala Ala Asn Glu aaa gcg tct gac gtg atc gcg ctg gcc ctc aag gga tgc tgt tcc aac Lys Ala Ser Asp Val Ile Ala Leu Ala Leu Lys Gly Cys Cys Ser Asn cct gtc tgt cac ctg gag cat tca aac atg tgt ggt aga aga cgc Pro Val Cys His Leu Glu His Ser Asn Met Cys Gly Arg Arg Arg tgatgctcca ggaccctctg aaccacgacg TABLE24 DNA Sequence (SEQ ID NO:104) and Protein Sequence (SEQ ID NO:105) of Btl.1 atg ttc tcc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc Met Phe Ser Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser tcc act tca ggt ggt gca tct ggt ggc agg aag gct gca gcc aaa gcg Ser Thr Ser Gly Gly Ala Ser Gly Gly Arg Lys Ala Ala Ala Lys Ala tct aac cgg atc gct ctg acc gtc agg agt gca aca tgc tgt aat tat Ser Asn Arg Ile Ala Leu Thr Val Arg Ser Ala Thr Cys Cys Asn Tyr cct ccc tgt tac gag act tat cca gaa agt tgt ctg taacgtgaat Pro Pro Cys Tyr Glu Thr Tyr Pro Glu Ser Cys Leu catccagagc tttgtggctg aagacactga tgctccagga ccctctgaac cacgacgt TABLE DNA Sequence (SEQ ID NO: 106) and Protein Sequence (SEQ ID NO: 107) of Bt 1.2 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtg gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser WO 00/44776 PCT/USOO/01979 39 ttc act tea ggt cgt gca ttt cgt ggc agg aat cgc gca gcc gac gac Phe Thr Ser Gly Arg Ala Phe Arg Gly Arg Asn Arg Ala Ala Asp Asp aaa agg tct gac ctg gce gct ctg agc gte agg gga gga tgc tgt tcc Lys Arg Ser Asp Leu Ala Ala Leu Ser Val Arg Gly Gly Cys Cys Ser cat ect gec tgt geg gtg aat cat cca gag ctt tgt ggc tgaagacgct His Pro Ala Cys Ala Val Asn His Pro Glu Leu Cys Gly gatgccceag gaccctctga accacgacgt TABLE 26 DNA Sequence (SEQ ID NO: 108) and Protein Sequence (SEQ ID NO: 109) of Btl.3 atg tte ace gtg ttt etg ttg gtt gte ttg gca ace act gte gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tea ggt cgt gca tet ggt ggc agg aat gct gea gec aaa gcg Phe Thr Ser Gly Arg Ala Ser Gly Gly Arg Asn Ala Ala Ala Lys Ala tct aae egg atc gct atg gee ate age agt gga gca tgc tgt gca tat Ser Asn Arg Ile Ala Met Ala Ile Ser Ser Gly Ala Cys Cys Ala Tyr ect ccc tgt tte gag get tat cca gaa aga tgt etg taaegtgaat Pro Pro Cys Phe Glu Ala Tyr Pro Glu Arg Cys Leu eatccagaec tttgtggetg aagacgctga tgccccagga ccctctgaac cacgaegt TABLE 27 DNA Sequence (SEQ ID NO: 1 10) and Protein Sequence (SEQ ID NO:1 11) of Btl.4 atg tte acc gtg ttt etg ttg gtt gte ttg gca acc aet gte gtt tee Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser tte act tea gat egt gca ttt egt gge agg aat tee gca gee aae gae Phe Thr Ser Asp Arg Ala Phe Arg Gly Arg Asn Ser Ala Ala Asn Asp aaa agg tet gae ctg gee get etg age gte agg aga gga tge tge tee Lys Arg Ser'Asp Leu Ala Ala Leu Ser Val Arg Arg Gly Cys Cys Ser eat ccc gce tgt age gtg aat eat cea gag ett tgt ggt aga aga cgc His Pro Ala Cys Ser Val Asn His Pro Glu Leu Cys Gly Arg Arg Arg tgatgcccca ggaccctctg aaccacgaeg t TABLE 28 DNA Sequence (SEQ ID NO:1 12) and Protein Sequence (SEQ ID NO:113) of atg tte ace gtg ttt ctg ttg gtt gte ttg gea acc act gte gtt tee Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tea ggt cgt gca tet ggt gge agg aat get gca gee aaa gcg Phe Thr Ser Gly Arg Ala Ser Gly Gly Arg Asn Ala Ala Ala Lys Ala tct aac egg ate get ctg ate gtc agg aat gca gaa tge tgt tat tat Ser Asn Arg Ile Ala Leu Ile Val Arg Asn Ala Glu Cys Cys Tyr Tyr WO 00/44776 WO 0044776PCT/USOO/01979 cct ccc tgt tac gag gct tat cca gaa att tgt ctg taacgtgaat Pro Pro Cys Tyr Glu Ala Tyr Pro Glu Ile Cys Leu catccagacC tttgtggctg aagaccctga tgctccagga ccctctgaac cacgacgt DNA Sequence (SEQ ID NO: 14) and Protein Sequence (SEQ ID NO: 115) of Pnl. I atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc att tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Ile Ser ttc act tca gat cgt gca tct gat ggc ggg aat gcc gca gcg tct gac Phe Thr Ser Asp Arg Ala Ser Asp Gly Gly Asn Ala Ala Ala Ser Asp ctg atc .gct ctg acc atc aag gga tgc tgt tct cat cct ccc tgt gcc Leu Ile Ala Leu Thr Ile Lys Gly Cys Cys Ser His Pro Pro Cys Ala atg aat aat cca gac tat tgt ggt tgacgacgct gatgctccag gaccctctga Met Asn Asn Pro Asp Tyr Cys Gly accacgacg TABLE DNA Sequence (SEQ ID NO: 16) and Protein Sequence (SEQ ID NO: 117) of Pnl.2 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tca gat cgt gca tct gat ggc ggg aat gcc gca atg tct gac Phe Thr Ser, Asp Arg Ala Ser Asp Gly Gly Asn Ala Ala Met Ser Asp ctg atc gct ctg acc atc aag gga tgc tgt tct cat cct ccc tgt ttc Leu Ile Ala Leu Thr Ile Lys Gly Cys Cys Ser His Pro Pro Cys Phe ctg aat aat cca gac tat tgt ggt tgacgacgct gatgctccag gaccctctga Leu Asn Asn Pro Asp Tyr Cys Gly accacgacg TALE-1 DNA Sequence (SEQ ID NO: 118) and Protein Sequence (SEQ ID NO: 119) of Sml1.3 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc cct tca gat cgt gaa tct gat ggc gcg aat gac gaa gcc cgc acc Phe Pro Ser Asp Arg Glu Ser Asp Gly Ala Asn Asp Glu Ala Arg Thr gac gag cct gag gag cac gga ccg gac agg aat gga tgc tgt agg aat Asp Glu Pro Glu Glu His Gly Pro Asp Arg Asn Gly Cys Cys Arg Asn cct gcc tgt gag agc cac aga tgt ggt tgacgacgct gatgctccag Pro Ala Cys Glu Ser His Arg Cys Gly gaccctctga accacgacg WO 00/44776 PCTUSOO/01979 41 TABLE 32 DNA Sequence (SEQ ID NO:120) and Protein Sequence (SEQ ID NO:121) of Cr1.2 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc cct tca gat ogt gca tot gat ggc agg aat gcc gca gcc agc gac Phe Pro Ser Asp Arg Ala Ser Asp Gly Arg Asn Ala Ala Ala Ser Asp aga gcg tct gac gog gco cac cag gga tgc tgt tc aao cot gto tgt Arg Ala Ser Asp Ala Ala His Gln Gly Cys Cys Ser Asn Pro Val Cys cao gtg gaa cat cca gaa ott tgt ogt aga aga cgo tgatgctoca His Val Glu His Pro Glu Leu Cys Arg Arg Arg Arg ggaccctctg aaccaogacg TABLE 33 DNA Sequence (SEQ ID NO:122) and Protein Sequence (SEQ ID NO:123) of Cr1.3 atg tto acc gtg ttt otg ttg gtt gtc ttg goa aoo act gto gtt too Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc cct toa aat ogt gaa tot gat ggo gog aat goo gaa gto cgo aoo Phe Pro Ser Asn Arg Glu Ser Asp Gly Ala Asn Ala Glu Val Arg Thr gao gag cot gag gag cao gao gaa otg ggo ggg aat gga tqo tgt ggg Asp Glu Pro Glu Glu His Asp Glu Leu Gly Gly Asn Gly Cys Cys Gly aat cot gao tgt acg ago cac agt tgt gat tgacgaogct gatgotcoag Asn Pro Asp Cys Thr Ser His Ser Cys Asp gaccctctga accacgacg DNA Sequence (SEQ ID NO:124) atg tto aco gtg ttt otg ttg Met Phe Thr Val Phe Leu Leu tto act toa gat ogt gca tct Phe Thr Ser Asp Arg Ala Ser otg ato got otg aco ato aag Leu Ile Ala Leu Thr Ile Lys atg aat aat oca gao tat tgt Met Asn As Pro Asp Tyr Cys accacgacg TABLE 34 and Protein Sequence (SEQ ID NO:125) of EpI gtt gto ttg gca aco aco gto gtt too Val Val Leu Ala Thr Thr Val Val Ser gat ago agg aag gao goa gog tot ggo Asp Ser Arg Lys Asp Ala Ala Ser Gly gga tgo tgt tot gat cot cgc tgt aao Gly Cys Cys Ser Asp Pro Arg Cys Asn ggt tgaogacgct gatgotcoag gaccctctga Gly TABLE DNA Sequence (SEQ ID NO: 126) and Protein Sequence (SEQ ID NO: 127) of Sn 1.1 atg too aco gtg ttt otg ttg gtt gto ctc gca aco aoo gto gtt too Met Ser Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser WO 00/44776 PCT/USOO/01979 42 ttc act gta gat cgt gca tct gat ggc agg gat gtc gca atc gac gac Phe Thr Val Asp Arg Ala Ser Asp Gly Arg Asp Val Ala Ile Asp Asp aga ttg gtg tct ctc cct cag atc gcc cat gct gac tgt tgt tcc gat Arg Leu Val Ser Leu Pro Gin Ile Ala His Ala Asp Cys Cys Ser Asp cct gcc tgc aag cag acg ccc ggt tgt cgt taaagacgct gctgctccag Pro Ala Cys Lys Gin Thr Pro Gly Cys Arg gaccctctga accacgacg TABLE 36 DNA Sequence (SEQ ID NO: 128) and Protein Sequence (SEQ ID NO: 129) of Sni.2 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gct tcc Met Phe Thr Val Phe Leu Leu Vai Val Leu Ala Thr Thr Val Ala Ser ttc att atc gat gat cca tct gat ggc agg aat att gca gtc gac gac Phe Ile Ile Asp Asp Pro Ser Asp Giy Arg Asn Ile Ala Val Asp Asp aga ggg ctt ttc tct acg ctc ttc cat gct gat tgc tgt gaa aat cct Arg Gly Leu Phe Ser Thr Leu Phe His Ala Asp Cys Cys Glu Asn Pro gcc tgt aga cac acg cag ggt tgt tqatctttgt tcttcaaaga cactgctggc Ala Cys Arg His Thr Gin Gly Cys ccaggaccct ctgaaccacg acg TABLE37 DNA Sequence (SEQ ID NO:130) and Protein Sequence (SEQ ID NO:131) of Dal.1 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc Met Phe Thr Val Phe Leu Leu Vai Val Leu Ala Thr Thr Val Val Ser ttc act tca gat cgt gca ttt cgt ggc agg aat gcc gca gcc aaa gag Phe Thr Ser Asp Arg Ala Phe Arg Gly Arg Asn Ala Ala Ala Lys Glu tct ggc ctg gtc ggt ctg acc gac aag acg cga gga tgc tgt tct cat Ser Gly Leu Val Gly Leu Thr Asp Lys Thr Arg Giy Cys Cys Ser His cct gcc tgt aac gta gat cat cca gaa att tgt ggt tgaagacgct Pro Ala Cys Asn Val Asp His Pro Glu Ile Cys Gly gatgctccag gaccctctga accacgacgt TABLE 38 DNA Sequence (SEQ ID NO:132) and Protein Sequence (SEQ ID NO:133) of Dal.2 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Vai Ser ttc act tca gat ggt gca tct gat gac agg aaa gcc gct gcg tct gac Phe Thr Ser Asp Gly Aia Ser Asp Asp Arg Lys Ala Ala Ala Ser Asp ctg atc act ctg acc atc aag gga tgc tgt tct cgt cct ccc tgt atc Leu Ile Thr Leu Thr Ile Lys Gly Cys Cys Ser Arg Pro Pro Cys Ile ~I WO 00/44776 PCT/USOO/01979 43 gcg aat aat cca gac ttg tgt ggt cga cga cgc tgatgctcca ggaccctctg Ala Asn Asn Pro Asp Leu Cys Gly Arg Arg Arg TABLE39 DNA Sequence (SEQ ID NO: 134) and Protein Sequence (SEQ ID NO: 135) atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val tcc act tca ggt cgt cgt gca ttt cat ggc agg aat gcc gca gcc Ser Thr Ser Gly Arg Arg Ala Phe His Gly Arg Asn Ala Ala Ala gcg tct gga ctg gtc ggt ctg act gac agg aga cca caa tgc tgt Ala Ser Gly Leu Val Gly Leu Thr Asp Arg Arg Pro Gln Cys Cys gat cct cgc tgt aac gta ggt cat cca gaa ctt tgt ggt gga aga Asp Pro Arg Cys Asn Val Gly His Pro Glu Leu Cys Gly Gly Arg tgatgctcca ggaccctctg aaccacaacg t of Dal.3 tcc Ser aaa Lys agt Ser cgc Arg TABLE DNA Sequence (SEQ ID NO:136) and Protein Sequence (SEQ ID NO:137) of Dal.4 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser tcc act tca ggt cgt gca ttt cat ggc agg aat gcc gca gcc aaa gcg Ser Thr Ser Gly Arg Ala Phe His Gly Arg Asn Ala Ala Ala Lys Ala tct ggc ctg gtc ggt ctg acc gac aag agg caa gta tgc tgt agt gat Ser Gly Leu Val Gly Leu Thr Asp Lys Arg Gin Val Cys Cys Ser Asp cct cgc tgt aac gta ggt cat cca gaa att tgt ggt gga aga cgc Pro Arg Cys Asn Val Gly His Pro Glu Ile Cys Gly Gly Arg Arg tgatgctcca ggaccctctg aaccacgacg t DNA Sequence (SEQ ID atg ttc acc gtg ttt Met Phe Thr Val Phe ttc cct tca gat agt Phe Pro Ser Asp Ser gaa agg tct gac atg Glu Arg Ser Asp Met cct gcc tgt ggt ggc Pro Ala Cys Gly Gly ggaccctctc gaaccacg TABLE 41 NO:138) and Protein Sequence (SEQ ID NO:139) of Al1.2 ctg ttg gtt gtc ttg aca acc act gtc gtt tcc Leu Leu Val Val Leu Thr Thr Thr Val Val Ser gca tct ggt ggc agg gat gac gag gcc aaa gac Ala Ser Gly Gly Arg Asp Asp Glu Ala Lys Asp tac gaa ttg aaa cgg aat gga cgc tgt tgc cat Tyr Glu Leu Lys Arg Asn Gly Arg Cys Cys His aaa tac gtt aaa tgt gga cgc tgatgctcca Lys Tyr Val Lys Cys Gly Arg WO 00/44776 PCTIUSOO/01979 44 TABLE 42 DNA Sequence (SEQ ID NO:140) and Protein Sequence (SEQ ID NO:141) of Bul.l atg ttc acc gtg ttt otg ttg gtt gtc ttg gca acc act gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc tct aca gat gat gaa tct gat ggc tcg aat gaa gaa ccc agc gcc Phe Ser Thr Asp Asp Glu Ser Asp Gly Ser Asn Glu Glu Pro Ser Ala gac cag act gcc agg tcc tca atg aac agg gcg cct gga tgc tgt aac Asp Gin Thr Ala Arg Ser Ser Met Asn Arg Ala Pro Gly.Cys Cys Asn aat cot gcc tgt gtg aag cac aga tgt gga tgacgctgat gctccaggac Asn Pro Ala Cys Val Lys His Arg Cys Gly cctctgaaco acgacgt TABLE 43 DNA Sequence (SEQ ID NO:142) and Protein Sequence (SEQ ID NO:143) of Bul.2 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca aco act gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc tct aca gat gat gaa tct gat ggc tcg aat gaa gaa ccc agc gcc Phe Ser Thr Asp Asp Glu Ser Asp Gly Ser Asn Glu Glu Pro Ser Ala gac cag got gcc agg tcc gca atg aac agg ccg cct gga tgc tgt aac Asp Gin Ala Ala Arg Ser Ala Met Asn Arg Pro Pro Gly Cys Cys Asn aat oct gcc tgt gtg aag cac aga tgt ggt gga tgacgctgat gctccaggac Asn Pro Ala Cys Val Lys His Arg Cys Gly Gly cctctgaaco acgacgt TABLE 44 DNA Sequence (SEQ ID NO:144) and Protein Sequence (SEQ ID NO:145) of Bul.3 atg tto acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser tto cot toa gat cgt gac tct gat ggc gcg gat gc gaa gc agt gao Phe Pro Ser Asp Arg Asp Ser Asp Gly Ala Asp Ala Glu Ala Ser Asp gag cot gtt gag ttc gaa agg gao gag aat gga tgc tgt tgg aat coct Glu Pro Val Glu Phe Glu Arg Asp Glu Asn Gly Cys Cys Trp Asn Pro too tgt cog agg coo aga tgt aca gga oga cgo taatgotcca ggaccctctg Ser Cys Pro Arg Pro Arg Cys Thr Gly Arg Arg aaccacgacg t TABLE DNA Sequence (SEQ ID NO:146) and Protein Sequence (SEQ ID NO:170) of Bul.4 atg tto aco gtg ttt ctg ttg gtt gtc ttg aca aco act gtc gtt too Met Phe Thr Val Phe Leu Leu Val Val Leu Thr Thr Thr Val Val Ser WO 00/44776 PCTUSOO/01979 tte cet tea gat cgt gca tct gat gge agg aat gce gca gcc aac gac Phe Pro Ser Asp Arg Ala Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp aaa gcg tct gac gtg gte acg etg gte ctc aag gga tgc tgt tcc acc Lys Ala Ser Asp Val Val Thr Leu Val Leu Lys Gly Cys Cys Ser Thr cct ccc tgt gct gtg ctg tat tgt ggt aga aga cge tgatgetcca Pro Pro Cys Ala Val Leu Tyr Cys Gly Arg Arg Arg ggaccctctg aaccacgacg t TABLE 46 DNA Sequence (SEQ ID NO: 148) and Protein Sequence (SEQ ID NO:149) of Dil.1 atg ttc ace gtg ttt ctg ttg gtt gte ttc gca tee tct gtc acc tta Met Phe Thr Val Phe Leu Leu Val Val Phe Ala Ser Ser Val Thr Leu gat egt gca tct tat gge agg tat gec tca ece gte gae aga geg tct Asp Arg Ala Ser Tyr Gly Arg Tyr Ala Ser Pro Val Asp Arg Ala Ser gec ctg atc gct eag gee ate ett ega gat tge tge tee aat cct ect Ala Leu Ile Ala Gln Ala Ile Leu Arg Asp Cys Cys Ser Asn Pro Pro tgt gee eat aat aat cca gac tgt egt taaagacgct gettgctcca Cys Ala His Asn Asn Pro Asp Cys Arg ggaccctctg aaecaegaeg t TABLE 47 DNA Sequence (SEQ ID NO:150) and Protein Sequence (SEQ ID NO: 15 1) of TI gga tge tgt tet aat eet ccc tgt ate gcg aag aat cca cac atg tgt Gly Cys Cys Ser Asr Pro Pro Cys Ile Ala Lys Asn Pro His Met Cys ggt gga aga cgc tga Gly Gly Arg Arg TABLE 48 DNA Sequence (SEQ ID NO:152) and Protein Sequence (SEQ ID NO:153) of Cn 1.2 atg tte ace gtg ttt etg ttg gtt gte ttg gca ace act gte gtt tee Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc cct tea gat egt gea tet gat gge agg aat gee gea gee aae gac Phe Pro Ser Asp Arg Ala Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp aaa geg tct gae gtg ate aeg etg gce etc aag gga tge tgt tee aac Lys Ala Ser Asp Val Ile Thr Leu Ala Leu Lys Gly Cys Cys Ser Asn cct gte tgt eac ttg gag eat tea aac ctt tgt ggt aga aga cgc Pro Val Cys His Leu Glu His Ser Asn Leu Cys Gly Arg Arg Arg tgatgetcea ggaccctctg aaccacgaeg t WO 00/44776 WO 0044776PCTIUSOO/01979 46 TABLE 49 DNA Sequence (SEQ ID NO:233) and Protein Sequence (SEQ ID NO:234) of Iml.1 tct gat gga aag agt gcc gcg gcc aaa gcc aaa ccg tct cac ctg acg Ser Asp Gly Lys Ser Ala Ala Ala Lys Ala Lys Pro Ser His Leu Thr gct oca ttc ato agg gac gaa. tgc tgt tcc gat tct cgc tgt ggo aag Ala Pro Phe Ile Arg Asp Giu Cys Cys Ser Asp Ser Arg Cys Gly Lys aac tgt ctt tga Asn Cys Leu TABLE DNA Sequence (SEQ ID NO:235) and Protein Sequence (SEQ ID NO:236) of Iml.2 ttt gat qga agg aat gcc cca gcc gac gac aaa gcg tct gao ctg atc Phe Asp Gly Arg Asn Ala Pro Ala Asp Asp Lys Ala Ser Asp Leu Ile gct caa atc gtc agg aga gca. tgC tgt tcc gat ogt cgc tgt aga tgg Ala Gin Ile Val Arg Arg Ala Cys Cys Ser Asp Arg Arg Cys Arg Trp agg tgt ggt tga Arg Cys Gly TABLE51 DNA Sequence (SEQ ID NO:237) and Protein Sequence (SEQ ID NO:238) of Rgl .2 tot gat gga agg aat goc gca gcc gac gcc aga gcg tot ccc cgg atc Ser Asp Gly Arg Asn Ala Ala Ala Asp Ala Arg Ala Ser Pro Arg Ile got ctt ttc ctc agg ttc aca. tgo tgt agg aga ggt acc: tgt tcc cag Ala Leu Phe Leu Arg Phe Thr Cys Cys Arg Arg Gly Thr Cys Ser Gin cac tgt ggt tgaagacact gctgctocag gaccctctga accacgacgt His Cys Gly TABLE 52 DNA Sequence (SEQ ID NO:239) and Protein Sequence (SEQ ID NO:240) of Rgl .6 tct aat gga agg aat gcc gca gcc qac goc aaa gcg tct caa cgg ato Ser Asn Gly Arg Asn Ala Ala Ala Asp Ala Lys Ala Ser Gin Arg Ile got oca ttc ctc agg gac tat tgc tgt agg aga cat goc tgt acg ttg Ala Pro Phe Leu Arg Asp Tyr Cys Cys Arg Arg His Ala Cys Thr Leu att tgt ggt tgaagacgct gctgctccag gaccctctga acoacgaogt Ile Cys Gly TABLE 53 DNA Sequence (SEQ ID NO:24 1) and Protein Sequence (SEQ ID NO:242) of Rgl1.6A tct aat qga agg aat gcc gca gcc gac goc aaa gog tct caa. cgg ato WO 00/44776 PCT/US00101979 47 Ser Asn Gly Arg Asn Ala Ala Ala Asp Ala Lys Ala Ser Gin Arg Ile get cca tte etc agg gac tat tge tgt agg aga ect ccc tgt acg ttg Ala Pro Phe Leu Arg Asp Tyr Cys Cys Arg Arg Pro Pro Cys Thr Leu att tgt ggt tgaagacgct gctgctccag gaccctctga accaegaegt Ile Cys Gly TABLE 54 DNA Sequence (SEQ ID NO:243) and Protein Sequence (SEQ ID NO:244) of Rgl.7 tct aat aaa agg aag aat gcc gca atg ctt gac atg atc gct caa cac Ser Asn Lys Arg Lys Asn Ala Ala Met Leu Asp Met Ile Ala Gin His gcc ata agg ggt tgc tgt tcc gat cct cgc tgt aga tat aga tgt cgt Ala Ile Arg Gly Cys Cys Ser Asp Pro Arg Cys Arg Tyr Arg Cys Arg tgaagacgct gctgctccag gaecctetga aceacgacgt TABLE DNA Sequence (SEQ ID NO:245) and Protein Sequence (SEQ ID NO:246) of RgI.9 ttt aat gga agg agt gee gca gce gac caa aat geg cct ggc ctg atc Phe Asn Gly Arg Ser Ala Ala Ala Asp Gin Asn Ala Pro Gly Leu Ile get caa gtc gte aga gga ggg tgc tgt tcc gat ccc cgc tge gcc tgg Ala Gin Val Val Arg Gly Gly Cys Cys Ser Asp Pro Arg Cys Ala Trp aga tgt ggt tgaagacgtt getgctccag gaccctctga accacgacgt Arg Cys Gly TABLE 56 DNA Sequence (SEQ ID NO:247) and Protein Sequence (SEQ ID NO:248) of Rgl.l0 ttt gat gga agg aat gec gca gcc gac gec aaa gtg att aac acg gtc Phe Asp Gly Arg Asn Ala Ala Ala Asp Ala Lys Val Ile Asn Thr Val gct cga ate gce tgg gat ata tge tgt tee gaa cct gac tgt aae cat Ala Arg Ile Ala Trp Asp Ile Cys Cys Ser Glu Pro Asp Cys Asn His aaa tgt gtt tgaagacgct tctgctccag gaccctetga accacgaegt Lys Cys Val TABLE 57 DNA Sequence (SEQ ID NO:249) and Protein Sequence (SEQ ID NO:250) of Rgl. 11 tct aat aaa agg aag aat gce gca atg ctt gac atg ate get eaa cac Ser Asn Lys Arg Lys Asn Ala Ala Met Leu Asp Met Ile Ala Gin His gee ata agg ggt tge tgt tee gat ect cge tgt aaa cat cag tgt ggt Ala Ile Arg Gly Cys Cys Ser Asp Pro Arg Cys Lys His Gin Cys Gly tgaagacgct gctgctccag gaccctctga accacgacgt WO 00/44776 PCT/USOO/01979 48 TABLE 58 DNA Sequence (SEQ ID NO:251) and Protein Sequence (SEQ ID NO:252) of Ms1.7 atc aag aat aca gca gcc agc aac aaa gcg tot agc ctg gtg got ctt Ile Lys Asn Thr Ala Ala Ser Asn Lys Ala Ser Ser Leu Val Ala Leu gtt gtc agg qga tgc tgt tac aat oct gto tgo aag aaa tat tat tgt Val Val Arg Gly Cys Cys Tyr Asn Pro Val Cys Lys Lys Tyr Tyr Cys tgg aaa ggc tgatgctcca ggaccctctg aaccacgacg t Trp Lys Gly TABLE 59 DNA Sequence (SEQ ID NO:253) and Protein Sequence (SEQ ID NO:254) of P1.7 tct gaa ggc agg aat got gaa gcc atc gao aac gcc tta gao cag agg Ser Giu Gly Arg Asn Ala Giu Ala Ile Asp Asn Ala Leu Asp Gin Arg gat oca aag cga cag gag cog ggg tgc tgt agg oat oct gcc tgt ggg Asp Pro Lys Arg Gin Glu Pro Gly Cys Cys Arg His Pro Ala Cys Gly aag aao aga tgt gga aga cgc tgatgctcca ggaccotctg aaccaogacg t Lys Asn Arg Cys Giy Arg Arg TABLE DNA Sequence (SEQ ID NO:255) and Protein Sequence (SEQ ID NO:256) of Msl.2 tct gat ggo agg aat att goa gtc gao gao aga tgg tot tto tat acg Ser Asp Gly Arg Asn Ile Ala Val Asp Asp Arg Trp Ser Phe Tyr Thr otc ttc cat got act tgc tgt gc gat cot gao tgt aga tto cgg ccc Leu Phe His Ala Thr Cys Cys Ala Asp Pro Asp Cys Arg Phe Arg Pro ggt tgt tgatotttgt tottcaaaga cgctgotggc ccaggacoct otgaaccacg Gly Cys aogt TABLE 61 DNA Sequence (SEQ ID NO:257) and Protein Sequence (SEQ ID NO:258) of Msl.3 ato aag aat act goa gc ago aac aaa gog oct ago ctg gtg got att Ile Lys Asn Thr Ala Ala Ser Asn Lys Ala Pro Ser Leu Val Ala Ile gcc gto agg gga tgo tgt tao aat cot too tgt tgg cog aaa aca tat Ala Val Arg Gly Cys Cys Tyr Asn Pro Ser Cys Trp Pro Lys Thr Tyr tgt agt tggaaaggot gatgctccag gaocctotga aocacgaogt Cys Ser WO 00/44776 PCT/USOO/01979 49 TABLE 62 DNA Sequence (SEQ ID NO:259) and Protein Sequence (SEQ ID NO:260) of Msl.4 tct gat agc agg aat gto gca atc gag gac aga gtg tct gac ctg cac Ser Asp Ser Arg Asn Val Ala Ile Giu Asp Arg Val Ser Asp Leu His tct atg ttc ttc gat gtt tct tgc tgt agc aat oct acc tgt aaa gaa Ser Met Phe Phe Asp Val Ser Cys Cys Ser Asn Pro Thr Cys Lys Glu acg tat ggt tgt tgatcgttgg ttttgaagao gctgatgctc caggaccctc Thr Tyr Gly Cys TABLE 63 DNA Sequence (SEQ ID NO:261) and Protein Sequence (SEQ ID NO:262) of tct gtt ggc agg aat att gca gtc gac gac aga ggg att ttc tct acg Ser Val Gly Arg Asn Ile Ala Val Asp Asp Arg Gly Ile Phe Ser Thr ctc ttc cat gct cat tgc tgt gcc aat ccc ato tgt aaa aac acg ccc Leu Phe His Ala His Cys Cys Ala Asn Pro Ile Cys Lys Asn Thr Pro ggt tgt tgatctttgt tottoaaaga cgctgctggc ccaggaccct otgaaocacg Gly Cys acgt TABLE 64 DNA Sequence (SEQ ID NO:263) and Protein Sequence (SEQ ID NO:264) of Msl.8 tcc gat ggc agg aat gto gca atc gac gac aga gtg tct gao ctg cac Ser Asp Gly Arg Asn Val Ala Ile Asp Asp Arg Val Ser Asp Leu His tct atg ttc ttc gat att got tgc tgt aac aat cct acc tgt aaa gaa Ser Met Phe Phe Asp Ile Ala Cys Cys Asn Asn Pro Thr Cys Lys Glu acg tat ggt tgt tgatcgttgg ttttgaagac gctgatgcto caggaccctc Thr Tyr Gly Cys tgaaccacga cgt TABLE DNA Sequence (SEQ ID NO:265) and Protein Sequence (SEQ ID NO:266) of Msl .9 tct gat ggc agg aat gtc gca ato gag gac aga gtg tot gac ctg ctc Ser Asp Giy Arg Asn Val Ala Ile Giu Asp Arg Vai Ser Asp Leu Leu tct atg otc tto gat gtt got tgo tgt ago aat cot gto tgt aaa gaa Ser Met Leu Phe Asp Val Ala Cys Cys Ser Asn Pro Val Cys Lys Glu acg tat ggt tgt tgatcgttgg ttttgaagac gotgatgotc caggacocto Thr Tyr Gly Cys tgaaccacga ogt WO 00/44776 PCTJUSOO/01979 TABLE 66 DNA Sequence (SEQ ID NO:267) and Protein Sequence (SEQ ID NO:268) of Btl .7 tat gat ggc agg aat gct gcc 9CC gac gac aaa gCt ttt gac ctg ctg Tyr Asp Gly Arg Asri Ala Ala Ala Asp Asp Lys Ala Phe Asp Leu Leu gct atg acc ata agg gga gga tgc tgt tcc tat cct ccc tgt atc gcg Ala Met Thr Ile Arg Gly Gly Cys Cys Ser Tyr Pro Pro Cys Ile Ala agt aat cct aaa tgt ggt gga aga cgc tgatgctcca ggaccctctg Ser Asn Pro Lys Cys Gly Gly Arg Arg aaccacaacg t TABLE 67 DNA Sequence (SEQ ID NO:269) and Protein Sequence (SEQ ID NO:270) of LvI ttt gat ggc agg aat gct gca ggc aac gcc aaa atg tcc gcc ctg atg Phe Asp Gly Arg Asn Ala Ala Gly Asn Ala Lys Met Ser Ala Leu Met gcc ctq acc atc agg gga tgc tgt tcc cat cct gtc tgt agc gcg atg Ala Leu Thr Ile Arg Gly Cys Cys Ser His Pro Val Cys Ser Ala Met agt cca atc tgt ggc tgaagacgct gatgccccag gaccctctga accacgacgt Ser Pro Ile Cys Gly TABLE 6 DNA Sequence (SEQ ID NO:27 1) and Protein Sequence (SEQ ID NO:272) of Ms 1.10 atc aag aat gct qca. gct gac gac aaa gca tct gac ctg ctc tct cag Ile Lys Asn Ala Ala Ala Asp Asp Lys Ala Ser Asp Leu Leu Ser Gin atc gtc agg aat gct gca tcc aat gac aaa ggg tct gac ctg atg act Ile Val Arg Asn Ala Ala Ser Asn Asp Lys Gly Ser Asp Leu Met Thr ctt gcc ctc agg gga tgc tgt aaa. aat cct tac tgt ggt gcg tcg aaa Leu Ala Leu Arg Gly Cys Cys Lys Asn Pro Tyr Cys Gly Ala Ser Lys aca tat tgt ggt aga aga cgc tgatgctcca ggaccctctg aaccacgacg t Thr Tyr Cys Gly Arg Arg Arg TABLE 69 DNA Sequence (SEQ ID NO:273) and Protein Sequence (SEQ ID NO:274) of Om1.1 tctgatggca ggaatgccgc agcgtctgac ctgatggat ctg acc atc aag gga Leu Thr Ile Lys Gly tgc tgt tct tat cct, ccc tgt ttc gcg act aat cca gac tgt ggt cga Cys Cys Ser Tyr Pro Pro Cys Phe Ala Thr Asn Pro Asp Cys Gly Arg cga cgc tgatgctcca ggaccctctg aaccacgacg t Arg Arg WO 00/44776 PCTIUSOO/0I979 51 TABLE DNA Sequence (SEQ ID NO:275) and Protein Sequence (SEQ ID NO:276) of R1.6 ttt gat gqc agg aat gcc gca gcc gac tac aaa ggg tct gaa ttg ctc Phe Asp Gly Arg Asn Ala Ala Ala-Asp Tyr Lys Gly Ser Giu.Leu Leu gct atg acc gtc agg gga gga tgc tgt tcc tat cct ccc tgt atc gca Ala Met Thr Val Arg Gly Gly Cys Cys Ser Tyr Pro Pro Cys Ile Ala aat aat cct ott tgt gct gga aga cgc tga Asn Asn Pro Leu Cys Ala Gly Arg Arq TABLE 71 DNA Sequence (SEQ ID NO:277) and Protein Sequence (SEQ ID NO:278) of R1.7 ttt gat ggc agg aat gcc gca gcc gao tac aaa ggq tct gaa ttg ctc Phe Asp Gly Arg Asn Ala Ala Ala Asp Tyr Lys Giy Ser Glu Leu Leu got atg acc gto agg gga gga tgc tgt tcc tat cct ccc tgt atc gca Ala Met Thr Val Arg Gly Gly Cys Cys Ser Tyr Pro Pro Cys Ile Ala aat aat cct ttt tgt got gga aga cgc tga Asn Asn Pro Phe Cys Ala Gly Arg Arg TABLE 72 DNA Sequence (SEQ ID NO:279) and Protein Sequence (SEQ ID NO:280) of Vrl.1 tct tat gac agg tat gcc tcg ccc gtc gac aga gcg tot gc ctg ato Ser Tyr Asp Arg Tyr Ala Ser Pro Val Asp Arg Ala Ser Ala Leu Ile got cag gcc atc ctt cga gat tgc tgt tc aat oct ccc tgt tcc caa Ala Gin Ala Ile'Leu Arg Asp Cys Cys Ser Asn Pro Pro Cys Ser Gin aat aat cca gac tgt atg taaagacgct gcttgctcca ggaccctctg Asn Asn Pro Asp Cys Met aaccacgacg t TABLE 73 DNA Sequence (SEQ ID NO:281) and Protein Sequence (SEQ ID NO:282) of Vr1.2 tot tat ggc agg tat gc tca ccc gto gao aga gog tot gc ctg ato Ser Tyr Gly Arg Tyr Ala Ser Pro Val Asp Arg Ala Ser Ala Leu Ile got cag goo ato ctt oga gat tgo tgc too aat cot cot tgt gc cat Ala Gin Ala Ile Leu Arg Asp Cys Cys Ser Asn Pro Pro Cys Ala His aat aat oca gao tgt ogt taaagacgct gcttgctcca ggaocctotg Asn Asn Pro Asp Cys Arg aaccacgacg t WO 00/44776 PCT/USOO/0I979 52 TABLE 74 DNA Sequence (SEQ ID NO:283) and Protein Sequence (SEQ ID NO:284) of Al.4 tct gat ggc agg aat gcc gca gcc aac gac aaa gcg tot ggc atg agc Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala Ser Gly Met Ser gcg ctg gcc gtc aat gaa tgc tgt aco aac oct gtc tgt cac gcg gaa Ala Leu Ala Val Asn Glu Cys Cys Thr Asn Pro Val Cys His Ala Glu cat caa gaa ctt tgt got aga aga cgc tga His Gin Glu Leu Cys Ala Arg Arg Arg TABLE DNA Sequence (SEQ ID NO:285) and Protein Sequence (SEQ ID NO:286) of tct gat ggc agg aat gcc gca gcc aac gac aaa gcq tct gac gtg atc Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala Ser Asp Val Ile acg ctg gcc ctc aag gga tgc tgt tcc aac cot gtc tgt cac ttg gag Thr Leu Ala Leu Lys Gly Cys Cys Ser Asn Pro Val Cys His Leu Glu cat tca aac ott tgt ggt aga aga cgc tga His Ser Asn Leu Cys Gly Arg Arg Arg TABLE 76 DNA Sequence (SEQ ID.NO:287) and Protein Sequence (SEQ ID NO:288) ofA1.6 tct gat ggo agg aat gcc gca gcc aac gac aaa gog tot ggc atg ago Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala Ser Gly Met Ser gcg otg gc gto aat gaa tgc tgt aco aac oct gto tgt cac gtg gaa Ala Leu Ala Val Asn Glu Cys Cys Thr Asn Pro Val Cys His Val Glu oat caa gaa ott tgt got aga aga cgo tga His Gin Glu Leu Cys Ala Arg Arg Arg TABLE 77 DNA Sequence (SEQ ID NO:289) and Protein Sequence (SEQ ID NO:290) of Afl.l atg tto aco gtg ttt otg ttg gtt gto ttg gca aoo aco gto gtt too Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser tto act tca gat ogt gca ttt ogt ggo agg aat goo gca gc aaa gcg Phe Thr Ser Asp Arg Ala Phe Arg Gly Arg Asn Ala Ala Ala Lys Ala tct ggo ctg gto ggt otg aco gao aag agg caa gaa tgo tgt tot tat Ser Gly Leu Val Gly Leu Thr Asp Lys Arg Gin Glu Cys cys Ser Tyr oct gc tgt aac cta gat oat cca gaa ott tgt ggt tgaagacgct Pro Ala Cys Asn Leu Asp His Pro Glu Leu Cys Gly gatgctccag gaccctctga accacgaogt WO 00/44776 PCT/USOO/01979 53 TABLE 78 DNA Sequence (SEQ ID NO:291) and Protein Sequence (SEQ ID NO:292) of Afl.2 atg ttc acc gtg ttt ctg ttg gtt gte ttg gca acc act gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser tcc act tca ggt cgt cgt gca ttt egt ggc agg aat gcc gca gcc aaa Ser Thr Ser Gly Arg Arg Ala Phe Arg Gly Arg Asn Ala Ala Ala Lys gcg tct gga ctg gte ggt ctg act gac agg aga cca gaa tgc tgt agt Ala Ser Gly Leu Val Gly Leu Thr Asp Arg Arg Pro Glu Cys Cys Ser gat cct cgc tgt aac tcg act cat cca gaa ctt tgt ggt gga aga cgc Asp Pro Arg Cys Asn Ser Thr His Pro Glu Leu Cys Gly Gly Arg Arg tgatgctcea ggaccctctg aaccacgacg t TABLE 79 DNA Sequence (SEQ ID NO:293) and Protein Sequence (SEQ ID NO:294) of Arl.2 tct gat ggc agg aat gcc gca gee aac geg ttt gac etg atc gat ctg Ser Asp Gly Arg Asn Ala Ala Ala Asn Ala Phe Asp Leu Ile Asp Leu ace gee agg eta aat tgc tgt atg att ccc ccc tgt tgg aag aaa tat Thr Ala Arg Leu Asn Cys Cys Met Ile Pro Pro Cys Trp Lys Lys Tyr gga gac aga tgt agt gaa gta cgc tgatgctcca ggaccctctg aaecacgacg Gly Asp Arg Cys Ser Glu Val Arg t TABLE DNA Sequence (SEQ ID NO:295) and Protein Sequence (SEQ ID NO:296) of Arl.3 tct gat ggc agg aat gee gca cgc aaa geg ttt ggc tgc tgc gac tta Ser Asp Gly Arg Asn Ala Ala Arg Lys Ala Phe Gly Cys Cys Asp Leu ata ccc tgt ttg gag aga tat ggt aac aga tgt aat gaa gtg cac Ile Pro Cys Leu Glu Arg Tyr Gly Asn Arg Cys Asn Glu Val His tgatgctcea ggaccctctg aaccaegcga cgt TABLE 81 DNA Sequence (SEQ ID NO:297) and Protein Sequence (SEQ ID NO:298) of Arl.4 tet gat ggc age aat gee gea gee aae gag ttt gac etg ate get etg Ser Asp Gly Ser Asn Ala Ala Ala Asn Glu Phe Asp Leu Ile Ala Leu ace gee agg eta ggt tgc tgt aae gtt aca ccc tgt tgg gag aaa tat Thr Ala Arg Leu Gly Cys Cys Asn Val Thr Pro Cys Trp Glu Lys Tyr gga gae aaa tgt aat gaa gta cgc tgatgettea ggaccctctg aaccacgacg Gly Asp Lys Cys Asn Glu Val Arg t WO 00/44776 WO 0044776PCT/USOO/01 979 54 TABLE 82 DNA Sequence (SEQ ID NO:299) and Protein Sequence (SEQ ID NO:300) of tct gat ggc agg aat gtc gca gca aaa geg ttt cac cgg atc ggc cgg Ser Asp Gly Arg Asn Val Ala Ala Lys Ala Phe His Arg Ile Gly Arg aec ate agg gat gaa tgc tgt tcc aat cet gcc tgt agg gtg aat aat Thr Ie Arg Asp Glu Cys Cys Ser Asn Pro Ala Cys Arg Vai Asn Asn cea cac gtt tgt aqa ega cge tgatgetcea ggaecctetg aaceacgaeg t Pro His Val Cys Arg Arg Arg TABLE 83 DNA Sequence (SEQ ID NO:301) and Protein Sequence (SEQ ID NO:302) of Arl.6 tet gat ggc agg aat gee gca gcc aac gcg ttt gac ctg atg cct ctg Ser Asp Gly Arg Asn Ala Ala Ala Asn Ala Phe Asp Leu Met Pro Leu acc gcc agg eta aat tgc tgt age att eec gge tgt tgg aae gaa tat Thr Ala Arg Leu Asn Cys Cys Ser Ile Pro Gly Cys Trp Asn Giu Tyr aaa gae aga tgt agt aaa gta ege tgatgeteea ggaeeetetg aaecaegaeg Lys Asp Arg Cys Ser Lys Val Arg t TABLE84 DNA Sequence (SEQ ID NO:303) and Protein Sequence (SEQ ID NO:304) of Ayl .2 tetgatggea ggaatgccge ageegaegae aaagegtetg aeetggtegc t etg gte Leu Val gte agg gga gga tge tgt tee cac ect gtc tgt tae ttt aat aat eca Val Arg Gly Gly Cys Cys Ser His Pro Val Cys Tyr Phe Asn Asn Pro caa atg tgt egt gga aga cge tgatgeteca ggacctctg aaccacgacg t Gin Met Cys Arg Gly Arg Arg TABLE DNA Sequence (SEQ ID NO:305) and Protein Sequence (SEQ ID NO:306) of Ayl .3 tetgatggea ggaatgeege ageegaegae aaagegtetg aeetggtcge t etg gee Leu Ala gte agg gga gga tgc tgt tee eac cet gte tgt aae ttg aat aat eca.

Val Arg Gly Gly Cys Cys Ser His Pro Val Cys Asn Leu Asn Asn Pro caa atg tgt cgt gga aga ege tgatgeteea ggaceetetg aaeeaegaeg t Gin Met Cys Arg Gly Arg Arg TABLE 86 DNA Sequence (SEQ ID NO:307) and Protein Sequence (SEQ ID NO:308) of Btl.8 WO 00/44776 PCT/XJSOO/01979 ttt cgt ggc agg aat ccc gca gcc aac qac aaa agg tct gac ctg gcc Phe Arg Gly Arg Asn Pro Ala Ala Asn Asp Lys Arg Ser Asp Leu Ala gct ctg agc gtc agg gga gga tgc tgt tcc cat cct gcc tgt agc gtg Ala Leu Ser Val Arg Gly Gly Cys Cys Ser His Pro Ala Cys Ser Val act cat cca gag ctt tgt ggc tgaagacgct gatgccccag gaccctctga Thr His Pro Glu Leu Cys Gly accacgacgt TABLE 87 DNA Sequence (SEQ ID NO:309) and Protein-Sequence (SEQ ID NO:3 10) of Btl.9 tct gat ggc ggg aat gcc gca gcc aaa gcg tct gac ctg atc gct cag Ser Asp Gly Gly Asn Ala Ala Ala Lys Ala Ser Asp Leu Ile Ala Gin acc atc agg gga gga tgc tgt tcc tat cct gcc tgt agc gtg gaa cat Thr Ile Arg Gly Gly Cys Cys Ser Tyr Pro Ala Cys Ser Val Giu His caa gac ctt tgt gat gga aga cgc tgatgctcca ggaccctctg aaccacgacg Gin Asp Leu Cys Asp Gly Arg Arg t TABLE 88 DNA Sequence (SEQ ID NO:31 1) and Protein Sequence (SEQ ID NO:312) of Cal.3 tct tat ggc agg aat gcc gca gcc aaa gcg ttt gaa gtg agt tgc tgt Ser Tyr Gly Arg Asn Ala Ala Ala Lys Ala Phe Giu Val Ser Cys Cys gtc gtt cgc ccc tgt tgg att cgc tat caa gag gaa tgt ctt gaa gca Val Val Arg Pro Cys Trp Ile Arg Tyr Gin Giu Giu Cys Leu Giu Ala gat ccc agg acc ctc tga Asp Pro Arg Thr Leu TABLE 89 DNA Sequence (SEQ ID NO:313) and Protein Sequence (SEQ ID NO:314) of Cal .4 tct gat ggc agg aat gcc gca gcc aac gcc ctt gac ctg atc act ctg Ser Asp Gly Arg Asn Ala Ala Ala Asn Ala Leu Asp Leu Ile Thr Leu atc gcc agg caa aat tgc tgt agc att ccc ggc tgt tgg gag aaa tat Ile Ala Arg Gin Asn Cys Cys Ser Ile Pro Gly Cys Trp Glu Lys Tyr gga gac aaa tgt agt gaa gta cgc tga Gly Asp Lys Cys Ser Glu Val Arg DNA Sequence (SEQ ID NO:315) and Protein Sequence (SEQ ID NO:316) of C1.2 tct gat ggc agg aat gaa gca gcc aac gac gaa gcg tct gac gtg atc Ser Asp Gly Arg Asn Giu Ala Ala Asn Asp Glu Ala Ser Asp Val Ile I WO 00/44776 WO 0044776PCTIUSOO/01979 56 gag ctg gcc ctc aag gga tgo tgt tcc aac cct gtc tgt cac ttg gag Glu Leu Ala Leu Lys Gly Cys Cys Ser Asn Pro Val Cys His Leu Glu cat cca aac gct tgt ggt aga aga cgc tgatgctcca ggaccctctg His Pro Asn Ala Cys Gly Arg Arg Arg aaccaogaog t TABLE 91 DNA Sequence (SEQ ID NO:3 17) and Protein Sequence (SEQ ID NO:3 18) of C1.3 tct gat ggc agg aat gcc gca. gcc aac gao aaa gcg tct gac ctg gtc Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala Ser Asp Leu Val got ctg gcc gtc agg gga tgo tgt tcc aac cct atc tgt tac ttt aat Ala Leu Ala Val Arg Gly Cys Cys Ser Asn Pro Ile Cys Tyr Phe Asn aat cca cga att tgt cgt gga aga cgc: tgatgctoca ggaccctctg Asn Pro Arg Ile Cys Arg Gly Arg Arg aacoacgaog t TABLE 92 DNA Sequence (SEQ ID NO:3 19) and Protein Sequence (SEQ ID NO:320) of Epl.2 tct cat ggc agg aat gcc gca cgc aaa gcg tct gac otg atc got otg Ser His Gly Arg Asn Ala Ala Arg Lys Ala Ser Asp Leu Ile Ala Leu acc gtc agg gaa. tgo tgt tct cag cct ccc tgt cgc tgg aaa. cat cca.

Thr Val Arg Glu Cys Cys Ser Gln Pro Pro Cys Arg Trp Lys His Pro gaa ctt tgt agt tga Glu Leu Cys Ser TABLE 93 DNA Sequence (SEQ ID NO:32 1) and Protein Sequence (SEQ ID NO:322) of G 1. 1 tot gat ggc agg aat gac gca, gcc aaa gcg ttt gac ctg ata tct tcg Ser Asp Gly Arg Asn Asp Ala Ala Lys Ala Phe Asp Leu Ile Ser Ser acc gto aag aaa gga tgc tgt too cat oct gcc tgt gog ggg aat aat Thr Val Lys Lys Gly Cys Cys Ser His Pro Ala Cys Ala Gly Asn Asn caa. oat att tgt ggc cga aga ogo tgatgctcca. ggaccotctg aacoaogaog Gln His Ile Cys Gly Arg Arg Arg t TABLE 94 DNA Sequence (SEQ ID NO:323) and Protein Sequence (SEQ ID NO:324) of G1.3 tot gat ggc agg aat goc gca gcc aac gac caa gog tot gao ctg atg Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Gln Ala Ser Asp Leu Met WO 00/44776 PCT/USOO/01979 57 gct gcg acc gto agg gga tgc tgt gcc gtt cct tcc tgt cgc ctc cgt Ala Ala Thr Val Arg Gly Cys Cys Ala Val Pro Ser Cys Arg Leu Arg aat cca gac ctt tgt ggt gga gga cgc tgatgctcca ggaccctctg Asn Pro Asp Leu Cys Gly Gly Gly Arg aaccacgacg t TABLE DNA Sequence (SEQ ID NO:325) and Protein Sequence (SEQ ID NO:326) of Imi.3 ctt gat gaa agg aat gcc gca gcc gac gac aaa gcg tct gao ctg atc Leu Asp Glu Arg Asn Ala Ala Ala Asp Asp Lys Ala Ser Asp Leu Ile got caa atc gtc agg aga gga tgc tgt tcc cat cot gcc tgt aao gtg Ala Gin Ile Val Arg Arg Gly Cys Cys Ser His Pro Ala Cys Asn Val aat aat cca cac att tgt ggt tga Asn Asn Pro His Ile Cys Gly TABLE 96 DNA Sequence (SEQ ID NO:327) and Protein Sequence (SEQ ID NO:328) of Lvi.2 tct gat ggc agg aat act gca gcc aaa gtc aaa tat tot aag acg ocg Ser Asp Gly Arg Asn Thr Ala Ala Lys Val Lys Tyr Ser Lys Thr Pro gag gaa tgo tgt ccc aat cot ccc tgt ttc gog aca aat tog gat att Glu Glu Cys Cys Pro Asn Pro Pro Cys Phe Ala Thr Asn Ser Asp Ile tgt ggc gga aga cgc tgatgctcca ggaccctctg aaccacgacg t Cys Gly Gly Arg Arg TABLE 97 DNA Sequence (SEQ ID NO:329) and Protein Sequence (SEQ ID NO:330) of LvI.3 tct aat ggo agg aat goc gca gc aaa tto aaa gog cot gcc ctg atg Ser Asn Gly Arg Asn Ala Ala Ala Lys Phe Lys Ala Pro Ala Leu Met aag cgg aco gtc agg gat got tgo tgt toa gao cot cgo tgt too ggg Lys Arg Thr Val Arg Asp Ala Cys Cys Ser Asp Pro Arg Cys Ser Gly aaa oat caa gac ctg tgt ggc tgaagacgct gatgctccag gaccctctga Lys His Gln Asp Leu Cys Gly accacgaogt TABLE 98 DNA Sequence (SEQ ID NO:33 1) and Protein Sequence (SEQ ID NO:332) of Lvi.4 tct aat ggc agg aat gcc gca gc aaa ttc aaa gog cot gc ctg atg Ser Asn Gly Arg Asn Ala Ala Ala Lys Phe Lys Ala Pro Ala Leu Met gag otg aco gto agg gaa gat tgo tgt toa gac cot ogo tgt too gtg Glu Leu Thr Val Arg Glu Asp Cys Cys Ser Asp Pro Arg Cys Ser Val WO 00/44776 PCT/USOO/01979 58 gga cat caa gac ctg tgt ggc tgaagacgct gatgctccag gaccctctga Gly His Gin Asp Leu Cys Gly accacgacgt TABLE 99 DNA Sequence (SEQ ID NO:333) and Protein Sequence (SEQ ID NO:334) of Lv 1.6 gca ttt gat ggc agg aat gct gca gcc agc gac aaa gcg tcc gag ctg Ala Phe Asp Gly Arg Asn Ala Ala Ala Ser Asp Lys Ala Ser Glu Leu atg gct ctg gcc gtc agg gga tgc tgt tcc cat cct gcc tgt gct ggg Met Ala Leu Ala Val Arg Gly Cys Cys Ser His Pro Ala Cys Ala Gly Agt aat gca cat atc tgt ggc aga aga cgc tgatgctcca ggaccctctg Ser Asn Ala His Ile Cys Gly Arg Arg Arg aaccacgacg t TABLE 100 DNA Sequence (SEQ ID NO:335) and Protein Sequence (SEQ ID NO:336) of Lvi.7 tct aat ggc agg aat gcc gca gcc aaa ttc aaa gcg cct gcc ctg atg Ser Asn Gly Arg Asn Ala Ala Ala Lys Phe Lys Ala Pro Ala Leu Met aag ctg acc gtc agg gag gat tgc tgt tca gac cct cgc tgt tcc gtg Lys Leu Thr Val Arg Glu Asp Cys Cys Ser Asp Pro Arg Cys Ser Val gga cat caa gac atg tgt ggc tgaagacgct gatgctccag gaccctctga Gly His Gin Asp Met Cys Gly atcacgacgt TABLE 101 DNA Sequence (SEQ ID NO:337) and Protein Sequence (SEQ ID NO:338) of Lvi.8 ttt gaa tgc agg aat gct gca ggc aac gac aaa gcg act gac ctg atg Phe Glu Cys Arg Asn Ala Ala Gly Asn Asp Lys Ala Thr Asp Leu Met gct ctg act gtc agg gga tgc tgt tcc cat cct gcc tqt gct ggg aat Ala Leu Thr Val Arg Gly Cys Cys Ser His Pro Ala Cys Ala Gly Asn aat cca cat atc tgc ggc tgaagacgct gatgctccag gaccctctga Asn Pro His Ile Cys Gly accacgacgt TABLE 102 DNA Sequence (SEQ ID NO:339) and Protein Sequence (SEQ ID NO:340) of Lvi.9 ttt gat ggc agg aac gcc gca gcc aac aac aaa gcg act gat ctg atg Phe Asp Gly Arg Asn Ala Ala Ala Asn Asn Lys Ala Thr Asp Leu Met gct ctg act gtc aga gga tgc tgt ggc aat cct tca tgt agc atc cat Ala Leu Thr Val Arg Gly Cys Cys Gly Asn Pro Ser Cys Ser Ile His WO 00/44776 PCTIUSOO/01979 59 att cct tac gtt tqt aat tagagacact gatgctccag gaccctctga Ile Pro Tyr Val Cys Asn accacgacgt TABLE 103 DNA Sequence (SEQ ID NO:341) and Protein Sequence (SEQ ID NO:342) of tct aat ggc agg aat gcc gca gcc aaa ttc aaa gcg cct gcc ctg atg Ser Asn Giy Arg Asn Ala Ala Ala Lys Phe Lys Ala Pro Ala Leu Met aag cgg acc gac agc gaa gaa tgc tgt tta gac tct cgc tgt gcc ggg Lys Arg Thr Asp Ser Giu Glu Cys Cys Leu Asp Ser Arg Cys Ala Gly caa cat caa gac ctg tgt ggc gga aga cgc tgatgctcca ggaccctctg Gin His Gin Asp Leu Cys Gly Giy Arg Arg aaccacgacg t TABLE 104 DNA Sequence (SEQ ID NO:343) and Protein Sequence (SEQ ID NO:344) of Mr1.3 tct gat ggc agg aat gcc gca gcc aag gac aaa gcg tct gac ctg gtc Ser Asp Gly Arg Asn Ala Ala Ala Lys Asp Lys Ala Ser Asp Leu Val gct ctg acc gtc aag gga tgc tgt tct aat cct ccc tgt tac gcg aat Ala Leu Thr Vai Lys Gly Cys Cys Ser Asn Pro Pro Cys Tyr Ala Asn aat caa gcc tat tgt aat gga aga cgc tga Asn Gin Ala Tyr Cys Asn Gly Arg Arg TABLE 105 DNA Sequence (SEQ ID NO:345) and Protein Sequence (SEQ ID NO:346) of Mr1.4 tct gat ggc agg aat gcc gca gcc aag gac aaa gcg tct gac ctg gtc Ser Asp Gly Arg Asn Ala Ala Ala Lys Asp Lys Ala Ser Asp Leu Val gct ctg acc gtc aag gga tgc tgt tct cat cct gcc tgt agc gtg aat Ala Leu Thr Val Lys Giy Cys Cys Ser His Pro Ala Cys Ser Val Asn aat cca gac att tgt ggt tga Asn Pro Asp Ile Cys Gly TABLE 106 DNA Sequence (SEQ ID NO:347) and Protein Sequence (SEQ ID NO:348) of Msl.I tct gat ggc agg aat got gca gCC aac aac aaa gtg got ttg acc atg Ser Asp Gly Arg Asn Ala Ala Ala Asn Asn Lys Val Ala Leu Thr Met agg gga aaa tgc tgt ato aat gat gog tgt cgc tcg aaa cat coa cag Arg Gly Lys Cys Cys Ile Asn Asp Ala Cys Arg Ser Lys His Pro Gin tac tgt tct gga aga cgc tgatactcca ggaccctctg aaccacgacg t Tyr Cys Ser Gly Arg Arg WO 00/44776 WO 0044776PCT/USOO/01979 TABLE 107 DNA Sequence (SEQ ID NO:349) and Protein Sequence (SEQ ID NO:350) of Msl.6 tct gat ggc agg aat gct gca gcc aac gac aaa gtq tct gac cag atg Ser Asp Gly Arg Asri Ala Ala Ala Asn Asp Lys Val Ser Asp Gin Met qat ctg gtt gtc agg gga tgc tgt tac aat att gcc tgt aga att aat Ala Leu Val Val Arg Gly Cys Cys Tyr Asn Ile Ala Cys Arg Ile Asn aat cca cgg tac tgt cgt gga aaa cgc tgatgttcca gqaccctctg Asn Pro Arg Tyr Cys Arg Gly Lys Arg aaccacgacg t TABLE 108 DNA Sequence (SEQ ID NO:351) and Protein Sequence (SEQ ID NO:352) of 01.1 tctgaaggca ggaatgccgc agccaacgac aaagcgtctg acctgatggc t ctg aac Leu Asn gtc agg gga tgc tgt tcc cat cct gtc tgt cgc ttc aat tat cca aaa Val Arg Gly Cys Cys Ser His Pro Val Cys Arg Phe Asn Tyr Pro Lys tat tgt ggt gga aga cgc tgatggtcca ggaccctctg aaccacgacg t Tyr Cys Gly Gly Arg Arg TABLE 109 DNA Sequence (SEQ ID NO:353) and Protein Sequence (SEQ ID NO:354) of 01 .2 tctgatggcg ggaatqccgc agcaaaagcg tttgatctaa tcact ctg gcc ctc agg Leu Ala Leu Arg gat gaa tgc tgt gcc agt cct ccc tgt cgt ttg aat aat cca tac gta Asp Glu Cys Cys Ala Ser Pro Pro Cys Arg Leu Asn Asn Pro Tyr Val tgt cat tgacgacgct gatgctccag gaccctctga accacgacgt Cys His TABLE DNA Sequence (SEQ ID N0:355) and Protein Sequence (SEQ ID NO:356) of 01.4 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ccc act tca gat cgt gca tct gat agg agg aat gcc gca gcc aaa gcg Pro Thr Ser Asp Arg Ala Ser Asp Arg Arg Asn Ala Ala Ala Lys Ala ttt qac ctg aga tat tcg acc gcc aag aga gga tgc tgt tcc aat cct Phe Asp Leu Arg Tyr Ser Thr Ala Lys Arg Gly Cys Cys Ser Asn Pro gtc tgt tgg cag aat aat gca gaa tac tgt cgt gaa agt ggc Val Cys Trp Gin Asn Asn Ala Glu Tyr Cys Arg Glu Ser Gly taatgctcca ggaccctctg aaccacgacg t WO 00/44776 PCT/US00/01979 61 TABLE 111 DNA Sequence (SEQ ID NO:357) and Protein Sequence (SEQ ID NO:358) of 01.7 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tca gat cgt gca tct gat ggc ggg aat gtc gca gcg tct cac Phe Thr Ser Asp Arg Ala Ser Asp Gly Gly Asn Val Ala Ala Ser His ctg atc gct ctg acc atc aag gga tgc tgt tct cac cct ccc tgt gcc Leu Ile. Ala Leu Thr Ile Lys Gly Gys Cys Ser His Pro Pro Cys Ala cag aat aat caa gac tat tgt ggt tgacgacgct gatgctccag gaccctctga Gin Asn Asn Gin Asp Tyr Cys Gly accacgacgt TABLE 112 DNA Sequence (SEQ ID NO:359) and Protein Sequence (SEQ ID NO:360) of 01.8 atg tto acc gtg ttt ctg ttg gtt gtc tta tca acc acc gtO gtt tcc Met Phe Thr Val Phe Leu Leu Val Val Leu Ser Thr Thr Val Val Ser tcc act tca gat cgt gca tct gat agg agg aat gcc gca gcc aaa gcg Ser Thr Ser Asp Arg Ala Ser Asp Arg Arg Asn Ala Ala Ala Lys Ala tct gac ctg atg tat tcg acc gtc aag aaa gga tgt tgt tcc cat oct Ser Asp Leu Met Tyr Ser Thr Val Lys Lys Gly Cys Cys Ser His Pro gcc'tgt tog ggg aat aat oga gaa tat tgt cgt gaa agt ggc Ala Cys Ser Gly Asn Asn Arg Giu Tyr Cys Arg Glu Ser Gly taatgctoca ggaccctotg aaccacgacg t TABLE 113 DNA Sequence (SEQ ID NO:361) and Protein Sequence (SEQ ID NO:362) of Oml.2 tttgatggoa ggaatgccto agccgacago aaagtggotg cccggatcgc t cag ato Gin Ile gao agg gat oca tgo tgt too tat Oct gao tgt ggo gog aat oat cca Asp Arg Asp Pro Cys Cys Ser Tyr Pro Asp Cys Gly Ala Asn His Pro gag att tgt ggt gga aaa cgc tgatgctcca ggaccctctg aaccacgaog t Glu Ile Cys Gly Gly Lys Arg TABLE 114 DNA Sequence (SEQ ID NO:363) and Protein Sequence (SEQ ID NO:364) of Oml.3 tctcatggoa ggaatgccgc acgct otg aco gto agg gaa tgo tgt tct cag Leu Thr Val Arg Glu Cys Cys Ser Gin oct cot tgt cgc tgg aaa oat oca gaa ott tgt agt tgaagacgct Pro Pro Cys Arg Trp Lys. His Pro Glu Leu Cys Ser WO 00/44776 WO 0044776PCT/USOO/01979 62 gatgctccag gaccctctqa accacgacgt TABLE 115 DNA Sequence (SEQ ID NO:365) and Protein Sequence (SEQ ID NO:366) of Omi .4 tttgatggca ggaatgctgc agccagcgac aaagcgtctg agctgatggc t ctg gcc Leu Ala gtc agg gga tgc tgt tcc cat cct gcc tgt gct ggg aat aat cca cat Val Arg Giy Cys Cys Ser His Pro Ala Cys Ala Gly Asn Asn Pro His atc tgt ggc aga aga cgc tgatgctcca ggaccctctg aaccacgacg t Ile Cys Gly Arg Arg Arg TABLE 116 DNA Sequence (SEQ ID NO:367) and Protein Sequence (SEQ ID NO:368) of tctggtgtCa ggaaagacgc agcgcctggc ctgatcgct ctg acc atc aag gga Leu Thr Ile Lys Gly tgc tqt tct gat cct agc tgt aac gtg aat aat cca gac tat tgt ggt Cys Cys Ser Asp Pro Ser Cys Asn Val Asn Asn Pro Asp Tyr Cys Gly tgacgacgct gatgctccag gaccctctga accacgacgt TABLE 117 DNA Sequence (SEQ ID NO:369) and Protein Sequence (SEQ ID NO:370) of OmI .6 tctaatggca ggaatgccgc agccaaattc aaagcgcctg ccctgatgga g ctg acc 57 Leu Thr qtc agg gaa gaa tgc tgt tca gac cct cgc tqt tcc gtg gga cat caa 105 Val Arg Giu Glu Cys Cys Ser Asp Pro Arg Cys Ser Val Gly His Gin gat atg tgt cgg tgaagcacgt gatgctccag gaccctctga accacgacgt 157 Asp Met Cys Arg TABLE 118 DNA Sequence (SEQ ID NO:371) and Protein Sequence (SEQ ID NO:372) of P1.4 act gat ggc agg aat gct gca gcc ata gcg ctt gac ctg atc gct ccg aThr Asp Gly Arq Asn Ala Ala Ala Ile Ala Leu Asp Leu Ile Ala Pro gcc gtc agg gga gga tgc tgt tcc aat cct gcc tgt tta gtg aat cat Ala Val Arg Gly Gly Cys Cys Ser Asn Pro Ala Cys Leu Val Asn His cta gaa atg tgt ggt aaa aga cgc tgatgcccca ggaccctctg aaccacgacg Leu Giu Met Cys Giy Lys Arg Arg t WO 00/44776 PCTIUSOO/01979 63 TABLE 119 DNA Sequence (SEQ ID NO:3 73) and Protein Sequence (SEQ ID NO:374) of P tct gat ggc agg gat gcc gca gcc aac gac aaa gog tct gao ctg atc Ser Asp Gly Arg Asp Ala Ala Ala Asn Asp Lys Ala Ser Asp Leu Ile got ctg acc gcc agg aga gat oca tgo tgt ttc aat cct gcc tgt aac Ala Leu Thr Ala Arg Arg Asp Pro Cys Cys Phe Asn Pro Ala Cys Asn gtg aat aat oca oag att tgt ggt tgaagacgct gatgctccag gaccotctga Val Asn Asn Pro Gin Ile Cys Gly accaogacgt TABLE 120 DNA Sequence (SEQ ID NO:375) and Protein Sequence (SEQ ID NO:376) of P1.6 tct gat ggo agg gat got gag aaa aoa ggo ttt gao acg aoo att gtg Ser Asp Gly Arg Asp Ala Giu Lys Thr Gly Phe Asp Thr Thr Ile Val ccg gaa gao tgo tgt tog gat cct too tgt tgg agg otg oat agt tta Pro Glu Asp Cys Cys Ser Asp Pro Ser Cys Trp Arg Leu His Ser Leu got tgt aot gga att gta aac cgo tgatgctcca ggaccctctg aaccacgacg Ala Cys Thr Gly Ile Val Asn Arg t TABLE 121 DNA Sequence (SEQ ID NO:377) and Protein Sequence (SEQ ID NO:378) of P1.8 act gat ggo agg agt got gca goo ata gog ttt goo ctg ato got ccg Thr Asp Gly Arg Ser Ala Ala Ala Ile Ala Phe Ala Leu Ile Ala Pro ac gto tgo tgt aot aat oot goo tgt otc gtg aat aat ata cgc ttt Thr Val Cys Cys Thr Asn Pro Ala Cys Leu Val Asn Asn Ile Arg Phe tgt ggt gga aga cgo tgatgcccca ggaccctctg aaccacgaog t Cys Gly Gly Arg Arg TABLE 122 DNA Sequence (SEQ ID NO:379) and Protein Sequence (SEQ ID NO:3 80) of Rgl.1 tct gat gga aga aat goo goa ago gao goo aaa gog ttt ccc ogg ato Ser Asp Gly Arg Asn Ala Ala Ser Asp Ala Lys Ala Phe Pro Arg Ile got cca ato gto agg gao gaa tgo tgt ago gat cct agg tgt cac ggg Ala Pro Ile Val Arg Asp Glu Cys Cys Ser Asp Pro Arg Cys His Gly aat aat ogg gac cac tgt got tgaagacgct gotgctccag gaccctctga Asn Asn Arg Asp His Cys Ala accacgacgt WO 00/44776 PCTIUSOO/01979 64 TABLE 123 DNA Sequence (SEQ ID NO:381) and Protein Sequence (SEQ ID NO:382) of Rgl.3 tct gat ggc agg aat acc gcg gco gac gaa aaa gcq tcc gac otg atc Ser Asp Gly Arg Asn Thr Ala Ala.Asp Giu Lys Ala Ser Asp Leu Ile tct caa act gto aag aga gat tgc tgt too cat cct ctc tgt aga tta Ser Gin Thr Val Lys Arg Asp Cys Cys Ser His Pro Leu Cys Arg Leu ttt gtt cca gga ctt tgt att tgaagacgct gotgctocag gaccctotga Phe Val Pro Gly Leu Cys Ile accacgact TABLE 124 DNA Sequence (SEQ ID NO:383) and Protein Sequence (SEQ ID NO:384) of Rgl .4 tct gat ggo agg aat goo goa goo gao aao aaa gog tot gac cta atc Ser Asp Giy Arg Asn Ala Ala Ala Asp Asn Lys Ala Ser Asp Leu Ile got oaa ato gto agg aga gga tgo tgt too cat cct gto tgt aaa gtg Ala Gin Ile Val Arg Arg Gly Cys Cys Ser His Pro Val Cys Lys Val agg tat cca gac ctg tgt ogt tgaagacgct gotgctccag gaccctctga Arg Tyr Pro Asp Leu Cys Arg accacgaogt TABLE 125 DNA Sequence (SEQ ID NO:385) and Protein Sequence (SEQ ID NO:386) of tct gat ggo agg aat gc goa goo gao aao aga gog tot gac cta ato Ser Asp Gly Arg Asn Ala Ala Ala Asp Asn Arg Ala Ser Asp Leu Ile got oaa ato gto agg aga gga tgo tgt too cat cct goo tgt aat gtg Ala Gin Ile Val Arg Arg Gly Cys Cys Ser His Pro Ala Cys Asn Val aat aat oca cac att tgt ggt tgaagacgct gotgctccag gaccctctga Asn Asn Pro His Ile Cys Gly accacgaogt TABLE 126 DNA Sequence (SEQ ID NO:387) and Protein Sequence (SEQ ID NO:388) of Rgl.8 tot gat ggc agg aat gcc gca goo gao aac aaa ccg tot gac cta ato Ser Asp Gly Arg Asn Aia Ala Ala Asp Asn Lys Pro Ser Asp Leu Ile got oaa ato gto agg aga gga tgc tgt tog oat cct gto tgt aaa gtg Ala Gin Ile Val Arg Arg Gly Cys Cys Ser His Pro Val Cys Lys Val agg tat toa gao atg tgt ggt tgaagacgot gotgctccag gaccctctga Arg Tyr Ser Asp Met Cys Gly accacgacgt 1 11_ WO 00/44776 PCT/USOO/01979 5 DNA Sequence tct gat ggc Ser Asp Gly tct ggc ccc Ser Gly Pro ttt cca cac Phe Pro His accacgacgt DNA Sequence tct qat ggc Ser Asp Gly cac cag gta His Gin Val ctt tgt cgt Leu Cys Arg TABLE 127 (SEQ ID NO:389) and Protein Sequence (SEQ ID NO:390) of Sml.4 agg aat gca gag cga cga caa agc gtc tgt cct ggt cgc Arg Asn Ala Glu Arg.Arg Gin Ser Val Cys Pro Gly Arg agg gga gga tgt tgt tcc cac cct gcc tgt aag gtg cat Arg Gly Gly Cys Cys Ser His Pro Ala Cys Lys Val His agt tgt ggt tgacgacgct gatgctccag gaccctctga Ser Cys Gly TABLE 128 (SEQ ID NO:391) and Protein Sequence (SEQ ID NO:392) of agg aat gcc gca gcc agc gac aga gcg tct gac gcg gcc Arg Asn Ala Ala Ala Ser Asp Arg Ala Ser Asp Ala Ala tgc tgt tcc aac cct gtc tgt cac gtg gat cat cca gaa Cys Cys Ser Asn Pro Val Cys His Val Asp His Pro Glu aga aga cgc tgatgctcca ggaccctctg aaccacgacg t Arg Arg Arg TABLE 129 DNA Sequence (SEQ ID NO:393) and Protein Sequence (SEQ ID NO:394) of tct gat ggc agg aat gcc gcg gcc aac gac aaa gcg tct gac ctg gtc Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala Ser Asp Leo Val gct ccg gcc atc agg gga tgc tgt tcc cac cct gtc tgt aac ttg agt Ala Pro Ala Ile Arg Gly Cys Cys Ser His Pro Val Cys Asn Leu Ser aat cca caa att tgt cgt gga aga cgc tgatgctcca ggaccctctg Asn Pro Gin Ile Cys Arg Gly Arg Arg aaccacgacg t TABLE 130 DNA Sequence (SEQ ID NO:395) and Protein Sequence (SEQ ID NO:3 96) of Txl ttt cat ggc agg aat gcc gca gcc aaa gcg tct ggc ctg gtc ggt ctg Phe His Gly Arg Asn Ala Ala Ala Lys Ala Ser Gly Leo Val Gly Leo acc gac aag agg caa gaa tgc tgt tct cat cct gcc tgt aac gta gat Thr Asp Lys Arg Gin Glu Cys Cys Ser His Pro Ala Cys Asn Val Asp cat cca gaa att tgt cgt tga His Pro Glu Ile Cys Arg WO 00/44776 PCTUSOO/01979 66 TABLE 131 DNA Sequence (SEQ ID NO:397) and Protein Sequence (SEQ ID NO:398) of T1.1 act gat ggc agg agt qct gca gcc ata gcg ttt gcc ctq atc gct ccg Thr Asp Gly Arg Ser Ala Ala Ala Ile Ala Phe Ala Leu Ile Ala Pro acc gtc tgg gaa gga tgc tgt tct aat cct gcc tgt ctc gtg aat cat Thr Val Trp Glu Gly Cys Cys Ser Asn Pro Ala Cys Leu Val Asn His ata cgc ttt tgt ggt gga aga cgc tgatgcccca ggaccctctg aaccacgacg Ile Arg Phe Cys Gly Gly Arg Arg t TABLE 132 DNA Sequence (SEQ ID NO:399) and Protein Sequence (SEQ ID NO:400) of Vrl.3 tct aat ggc atg aat gcc gca gcc atc agg aaa gcg tct gcc ctg gtg Ser Asn Gly Met Asn Ala Ala Ala Ile Arg Lys Ala Ser Ala Leu Val gct cag atc gcc cat cga gac tgc tgt gac gat cct gcc tgc acc gtg Ala Gin Ile Ala His Arg Asp Cys Cys Asp Asp Pro Ala Cys Thr Val aat aat cca ggc ctt tgc act tgaagatgct gctgccccag gaccctctga Asn Asn Pro Gly Leu Cys Thr accacgacgt TABLE 133 DNA Sequence (SEQ ID NO:401) and Protein Sequence (SEQ ID NO:402) of G1.2 tct gat ggc ggg aat gcc gca gca aaa gag tct gac gtg atc gct ctg Ser Asp Gly Gly Asn Ala Ala Ala Lys Glu Ser Asp Val Ile Ala Leu acc gtc tgg aaa tgc tgt acc att cct tcc tgt tat gag aaa aaa aaa Thr Val Trp Lys Cys Cys Thr Ile Pro Ser Cys Tyr Glu Lys Lys Lys att aaa gca tgt gtc ttt tgacgacgct gatgctccag gaccctctga Ile Lys Ala Cys Val Phe accacgacgt TABLE 134 DNA Sequence (SEQ ID NO:403) and Protein Sequence (SEQ ID NO:404) of Rg 1.12 tct gat ggc gca gtc gac gac aaa gcg ttg gat cga atc gct gaa atc Ser Asp Giy Ala Val Asp Asp Lys Ala Leu Asp Arg Ile Ala Giu Ile gtc agg aga gga tgc tgt ggc aat cct gcc tgt agc ggc tcc tcg aaa Val Arg Arg Gly Cys Cys Gly Asn Pro Ala Cys Ser Gly Ser Ser Lys gat gca ccc tct tgt ggt tgaagacgct gctgctccag gaccctctga Asp Ala Pro Ser Cys Gly accacgacgt a It will be appreciated that the methods and compositions of the instant invention can be incorporated in the form of a variety of embodiments, only a few of which are disclosed herein. It will be apparent to the artisan that other embodiments exist and do not depart from the spirit of the invention. Thus, the described embodiments are illustrative and should not be construed as restrictive.

LIST OF REFERENCES Barnay, G. et al. (2000). J. Med. Chem.

Bitan, G. et al. (1997). J. Peptide Res. 49:421-426.

Blount, K. et al. (1992). Toxicon 30:835-842.

Bodansky et al. (1966). Chem. Ind. 38:1597-98.

Cartier, G.E. et al. (1996). J. Biol. Chem. 271:7522-7528.

Cruz, L.J. at al. (1976). Verliger 18:302-308.

Cruz, L.J. et al. (1987). J. Biol. Chem. 260:9280-9288.

Fainzilber, M. et al. (1994). Biochemistry 33:9523-9529.

Gray, W.R. et al. (1981). J.Biol. Chem. 256:4734-4740.

Haack, J.A. et al. (1990). J. Biol. Chem. 265:6025-6029.

Horiki, K. et al. (1978). Chemistry Letters 165-68.

Hruby, V. et al. (1994). Reactive Polymers 22:231-241.

Jacobsen, R. et al. (1997). J. Biol. Chem. 272:22531-22537.

Johnson, D.S. et al. (1995). Mol. Pharmacol. 48:194-199.

Kapoor (1970). J. Pharm. Sci. 59:1-27.

Kornreich, W.D. et al. (1986). U.S. Patent No. 4,569,967.

Luo, S. et al. (1998). J. Neurosci. 18:8571-8679.

Marshall, I.G. and Harvey, A.L. (1990). Toxicon 28:231-234.

Martinez, J.S. et al. (1995). Biochem. 34:14519-14526.

McIntosh, J.M. et al. (1982). Arch. Biochem. Biophys. 218:329-334.

Mena, E.E. et al. (1990). Neurosci. Lett. 118:241-244.

Methoden der Organischen Chemie (Houben-Weyl): Synthese von Peptiden, E. Wunsch Georg Thieme Verlag, Stuttgart, Ger. (1974).

Myers, R.A. et al. (1991). Biochemistry 30:9370-9377.

Nishiuchi, Y. et al. (1993). Int. J. Pept. Protein Res. 42:533-538.

WO 00/44776 PCT/US00/01979 68 Nowak, L. et al. (1984). Nature 307:462-465.

Olivera, B.M. et al. (1984). U.S. Patent 4,447,356.

Olivera, B.M. et al. (1985). Science 230:1338-1343.

Olivera, B.M. et al. (1996). U.S. Patent 5,514,774.

Rivier, J.R. et al. (1978). Biopolymers 17:1927-38.

Rivier, J.R. et al. (1987). Biochem. 26:8508-8512.

Sambrook, J. et al. (1989). Molecular Cloning: A Laboratory Manual, 2nd Ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.

Schroder Lubke (1965). The Peptides 1:72-75, Academic Press, NY.

Shon, et al. (1994). Biochemistry 33:11420-11425.

Stewart and Young, Solid-Phase Peptide Synthesis, Freeman Co., San Francisco, CA (1969).

Vale et al. (1978). U.S. Patent 4,105,603.

Van de Steen, P. et al. (1998). Critical Rev. in Biochem. and Mol. Biol. 33:151-208.

Zafaralla, G.C. et al. (1988). Biochemistry 27:7102-7105.

Zhou et al. (1996). J. Neurochem. 66:620-628.

U.S. Patent No. 3,972,859.

U.S. Patent No. 3,842,067.

U.S. Patent No. 3,862,925.

U.S. Patent No. 5,550,050.

PCT Published Application WO 92/19195.

PCT Published Application WO 94/25503.

PCT Published Application WO 95/01203.

PCT Published Application WO 95/05452.

PCT Published Application WO 96/02286.

PCT Published Application WO 96/02646.

PCT Published Application WO 96/11698.

PCT Published Application WO 96/40871.

PCT Published Application WO 96/40959.

PCT Published Application WO 97/12635.

EDITORIAL NOTE APPLICATION NUMBER 29735/00 The following Sequence Listing pages 1 to 132 are part of the description. The claims pages follow on pages 69 to 84.

untitled SEQUENCE LISTING <110> university of Utah Research Foundation Cognetix, Inc.

<120> Alpha-Conotoxin Peptides <130> Alphas 2 <140> <141> <150> US 60/118,381 <151> 1999-01-29 <160> 404 <170> PatentIn Ver. <210> 1 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence:Alpha-Conotoxin Peptide Generic Formula I <220> <221> SITE <222> <223> xaa at residue 1 is des-xaa, Ile, Leu or val; Xaa at residue 2 is des-xaa, Ala or Gly; Xaa at residue 3 is des-xaa, Gly, Trp (D or neo-Trp, halo-Trp or any unnatural aromatic amino acid.

<220> <221> SITE <222> <223> N-methyl-Lys, xaa at residue 4 is des-Xaa, Gly, Trp (D or neo-Trp, halo-Trp or any unnatural aromatic amino acid; xaa at residue 5 is Glu, gamma-carboxy-Glu (Gla), Asp, Ala, Thr, Ser, Gly, <220> <221> SITE <222> S <223> Ile, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, o-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; xaa at residue 8 is Ser, Thr, Arg, ornithine, <220> <221> SITE <222> <223> homoarginine, Lys, N,N-dimethyl-Lys, N,N,Ntrimethyl-Lys or any unnatural basic amino acid; xaa at residue 9 is Asp, Glu, Gla, Arg, ornithine, homoarginine, Lys, N-methyl-Lys,N,N-dimethyl- <220> <221> SITE <222> <223> Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; xaa at residue 10 is ser, Thr, Asn, SGly, Arg, Lys, ornithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, Page 1 179PCT-AU rev. APP.tXt <220> <221> SITE *<222> .(11) <223> N,N,N-trimethyl-LyS, any unnatural basic amino acid, His, halo-His, Pro or hydroxy-Pro; xaa at residue 11 is Thr, Ser, Ala, ASP, Asn, <220> <221> SITE <222> .(13) <223> Pro, hydroxy-Pro, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,Ntrimethyl-Lys or any unnatural basic amino acid; Xaa at residue 13 is Gly, Ser, Thr, Ala, Asn, <220> <221> SITE <222> (14) <223> Arg, ornithine, homoarginine,tLyS, N-methyl-LyS, N,N-dimethyl-LyS, N,N,N-trimethyl-LYS or any i unnatural basic amino acid; xaa at residue 14 i Gln, Leu, His, halo-His, Trp (D or halo-Trp, <220> <221> SITE <222> (14) <223> neo-Trp, Tyr, nor-Tyr, mono-halo-Tyr, di-halo- Tyr, o-sulpho-Tyr, 0-phospho-Tyr, nitro-Tyr, Arg, ornithine, homoarginine, Lys, N-methyl-LyS, N,Ndimethyl-Lys, N,N,N-trimethyl -Lys, any unnatural <220> <221> SITE <222> <223> basic amino acid or any unnatural aromatic amino acid; Xaa at residue 15 is Asn, His, halo-His, Ile, Leu, Val, Gln, Arg, ornithine, homoarginine, Lys, N-methyl-LyS, N,N-dimethyl-LyS, N,N,N- <220> <221> SITE <222> (17) <223> trimethyl-Lys or any unnatural basic amino acid; xaa at residue 17 is des-xaa, Val, Ile, Leu, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N- :00*00dimethyl-Lys, N,N,N-trimethyl -Lys or any <220> 0 <221>

SITE

<222> (17) <223> unnatural basic amino acid.

0 <400> 1 Xaa Xaa Xaa Xaa Xaa Cys Cys Xaa Xaa Xaa Xaa Cys Xaa Xaa Xaa Cys 1 5 10 Xaa 00%: <210> 2 <211> 21 o. <212> PRT <213> Artificial sequence 000000. <220> -oooi 0 <223> Description of Artificial Sequence:Alpha-nton Peptide Generic Formula II.

Page 2 179PCT-AUrev.APP.tXt <220> <221> SITE <222> <223> Xaa at residue 1 is des-xaa, Asp, Glu or gammacarboxy-Glu (Gla); xaa at residue 2 is des-xaa, Gin, Ala, Asp, Glu, Gla; Xaa at residue 3 is desxaa, Gly, Ala, Asp, Glu, Gla, Pro or hydroxy-Pro.

<220> <221> SITE <222> <223> xaa at residue 4 is des-Xaa, Gly, Glu, Gla, Gin, Asp, Asn, Pro or hydroxy-Pro; xaa at residue 7 is Ser, Thr, Gly, Glu, Gla, Asn, Trp (D or L), neo-Trp, halo-Trp, Arg, ornithine, homoarginine, <220> <221> SITE <222> (7) <223> Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,Ntrimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr, nitro-Tyr or any <220> <221> SITE <222> <223> unnatural hydroxy containing amino acid; xaa at residue 8 is Asp, Asn, His, halo-His, Thr, Ser, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, o-sulpho-Tyr, 0-phospho-Tyr, nitro-Tyr or any <220> <221> SITE <222> <223> unnatural hydroxy containing amino acid; Xaa at residue 9 is Pro or hydroxy-Pro; xaa at residue is Ala, Ser, Thr, Asp, Val, Ile, Pro, hydroxy- Pro, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, <220> <221> SITE <222> <223> 0-sulpho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa at residue 12 is Gly, Ile, Leu, val, Ala, Thr, Ser, Pro, hydroxy-Pro, Phe, Trp (D or neo-Trp, <220> <221> SITE <222> <223> halo-Trp, Arg, ornithine, homoarginine, Lys, Nmethyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl- Lys, any unnatural basic amino acid or any unnatural aromatic amino acid; xaa at residue 13 <220> <221> SITE <222> (13) <223> is Ala, Asn, Phe, Pro, hydroxy-Pro, Glu, Gla, Gin, His, halo-His, Val, Ser, Thr, Arg, Sornithine, homoarginine, Lys, N-methyl-Lys, N,Ndimethyl-Lys, N,N,N-trimethyl-Lys or any 220> <221> SITE <222> Page 3 179PCT-Arev.APP.txt <223> unnatural basic amino acid; xaa at residue 14 is Thr, Ser, His, halo-His, Leu, Ile, Val, Asn, Met, Pro, hydroxy-Pro, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N- <220> <221> SITE <222> <223> trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; xaa at <220> <221> SITE <222> <223> residue 15 is ASn, Pro, hydroxy-Pro, Gln, Ser, Thr, Arg, ornithine, homoarginine, Lys, N-methyl- Lys, N,N-dimethyl-Lys N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono- <220> <221> SITE <222> <223> halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho- Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; xaa at residue 16 is des-Xaa, Gly, Thr, Ser, Pro, hydroxy-Pro, Tyr, nor-Tyr, <220> <221> SITE <222> <223> mono-halo-Tyr, di-halo-Tyr, o-sulpho-Tyr 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; xaa at residue 17 is desxaa, Ile, val, Asp, Leu, Phe, Arg, ornithine, <220> <221> SITE <222> (17) <223> homoarginine, Lys, N-methyl-Lys, N,N-dimethyl- Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo- Tyr, 0-sulpho-Tyr, 0-phospho-Tyr, nitro-Tyr or <220> <221> SITE S* <222> <223> any unnatural hydroxy containing amino acid; xaa at residue 19 is des-xaa, Gly, Ala, Met, Ser, :Thr, Trp (D or neo-Trp, alo-Trp, any *unnatural aromatic amino acid, Arg, ornithine, <220> <221> SITE <222> <223> homoarginine, Lys, N-methyl-Lys, N,N-dimethyl- Lys, N,N,N-trimethyl-Lys or any unnatural basic *amino acid; xaa at residue 20 is des-Xaa, Trp (D or neo-Trp, halo-Trp, any unnatural <220> <221> SITE <222> <223> aromatic amino acid, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; xaa at residue 21 is des-xaa, Arg, Page 4 179PCT-AUrev .APP. tXt <220> <221> SITE <222> (21) <223> ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-LyS, N,N,N-trimethyl-Ly5 or any unnatural basic amino acid.

<400> 2 Xaa Xaa Xaa Xaa Cys Cys Xaa Xaa Xaa Xaa Cys Xaa Xaa Xaa Xaa Xaa 1 5 10 xaa Cys Xaa Xaa Xaa <210> 3 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> Descri pti on Of Artificial Sequence :Al pha-Conotoxi n Peptide Generic Formula III.

<220> <221> SITE <222> (3) <223> xaa at residue 1 is des-xaa, Ser or Thr; xaa at residue 2 is des-xaa, Asp, Glu, gamma-carboxy-Glu (Gla), Asn, Ser or Thr; xaa at residue 3 is des- Xaa, Ala, Gly, Asn, Ser, Thr, Pro, hydroxy-Pro, <220> .;221> SITE <222> (4) <223> Arg, ornithine, homoarginine, LyS, N-methyl-LyS, N,N-dimethyl-Lys, N,N,N-trimethyl-LYS oruany unnatural basic amino acid; Xaa at residue 4 is des-xaa, Ala, Val, Leu, Ile, Gly, Glu, Gla, Gln, <220> .,221> SITE <23 ASP A s Phe, Pro, hydroxy-Pro or any unnatural aromatic amino acid; xaa at residue 5 is des-xaa, Thr, Ser, Asp, Glu, Gla, Gln, Gly, Val, Asp, Asn, <2>Ala, Pro, hydroxy-Pro, Arg, ornithine, homo- <221> SITE <222> (8) <223> arginine, LyS, N-methyl-LyS, N,N-dimethyl-LyS, N,N,N-trimethyl-LyS or any unnatural basic amino acid; Xaa at residue 8 is Thr, Ser, ASP, Asn, met, Val, Ala, Gly, Leu, Ile, Phe, any unnatural <220> <221> SITE <222> (9) <223> aromatic amino acid, Pro, hydroxy-Pro, Tyr, nor- Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, 0-phoSpho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; xaa at residue 9 is Ile, <220> <221> SITE <222> (9) Page 179PCT-AUrev.APP.txt <223> Leu, Val, Ser, Thr, Gin, Asn, Asp, Arg, His, halo-His, Phe, any unnatural aromatic amino acid, homoarginine, ornithine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any <220> <221> SITE <222> <223> unnatural basic amino acid, Tyr, nor-Tyr, monohalo-Tyr, di-halo-Tyr, O-sulpho-Tyr, 0-phospho- Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; xaa at residue 10 is Pro, hyroxy- <220> <221> SITE <222> <223> Pro, Ser, Thr, Ile, Asp, Leu, Val, Gly, Ala, Phe, any unnatural aromatic amino acid, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino .220> <221> SITE <222> (11) <223> acid; xaa at residue 11 is val, Ala, Gly, Ile, Leu, Asp, Ser, Thr, Pro, hydroxy-Pro, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any <220> <221> SITE <222> <223> unnatural basic amino acid; xaa at residue 13 is His, halo-His, Arg, homoarginine, ornithine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl- Lys, any unnatural basic amino acid, Asn, Ala, <220> <221> SITE <222> (13) <223> Ser, Thr, Phe, Ile, Leu, Gly, Trp (D or neo- Trp, halo-Trp, any unnatural aromatic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any <220> <221> SITE <222> <223> unnatural hydroxy containing amino acid; xaa at residue 14 is Leu, Gin, Val, Ile, Gly, Met, Ala, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-tri- S methyl-Lys, Ser, Thr, Arg, homoarginine, orni- <220> <221> SITE <222> <223> thine, any unnatural basic amino acid, Asn, Glu, Gla, Gin, Phe, Trp (D or neo-Trp, halo-Trp or S any unnatural aromatic amino acid; xaa at residue is Glu, Gla, Gin, Asn, Asp, Pro, hydroxy-Pro, S <220> <221> SITE <222> <223> Ser, Gly, Thr, Lys, N-methyl-Lys, N,N-dimethyl- S Lys, N,N,N-trimethyl-Lys, Arg, homoarginine, "*ornithine, any unnatural basic amino acid, Phe, His, halo-His, any unnatural aromatic acid, Leu, Page 6 179PCT-Arev.APP.txt <220> <221> SITE <222> <223> Met, Gly, Ala, Tyr, nor-Tyr, mono-halo-Tyr, dihalo-Tyr, 0-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa at residue 16 is His, halo-His, Asn, Thr, <220> <221> SITE <222> (16) <223> Ser, Ile, val, Leu, Phe, any unnatural aromatic amino acid, Arg, homoarginine, ornithine, Lys, Nmethyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Try, <220> <221> SITE <222> <223> mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; xaa at residue 17 is Ser, Thr, Ala, Gln, Pro, hydroxy-Pro, Gly, Ile, Leu, <220> <221> SITE <222> <223> Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural asic amino acid; xaa at residue 18 is Asn, Glu, Gla, Asp, Gly, His, halo-His, Ala, Leu, <220> <221> SITE <222> (18) <223> Gin, Arg, ornithine, homoarginine, Lys, N-methyl- Lys, N,N-dimethyl-Lys, N,N,N-trimethyl -Lys, any unnatural basic amino acid, Tyr, nor-Tyr, monohalo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho- <220> <221> SITE <222> <223> Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; xaa at residue 19 is Met, Ile, Thr, Ser, Val, Leu, Pro, hydroxy-Pro, Phe, any unnatural aromatic amino acid, Tyr, nor-Tyr, mono- <220> <221> SITE S: <222> (19) <223> halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho- Tyr, nitro-Tyr, any unnatural hydroxy containing amino acid, Glu, Gl a, Ala, His, halo-His, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N- S <220> <221> SITE <222> (21) <223> dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; xaa at residue 21 is des-xaa, Gly, Asp, Asn, Ala, Ile, Leu, Ser, Thr, His, halo- His, Arg, ornithine, homoarginine, Lys, N-methyl- <220> <221> SITE <222> Page 7 l79PCT-AU rev. APP.tXt <223> LYS, N,N-dimethyl-Lys, N,N,N-triethyl-LyS or any unnatural basic amino acid; xaa at residue 22 is des-xaa, Gly, Glu, Gla, Gin, Trp (D or neo-Trp, haio-Trp, any unnatural aromatic amino acid, Arg, .<220> <221> SITE <222> (23) <223> ornithine, homoarginine, Lys, N-methyl-LYS, N,Ndimethyl-Lys, N,N,N-trimethyl-LYS or any unnatural basic amino acid; xaa at residue 23 is des-xaa, Ser, Thr, Val, Ilie, Ala, Arg, ornithine, homo- <220> <221> SITE <222> (24) <223> arginine, Lys, N-methyl-LyS, N,N-dimethyl-LYS, N,N,N-trimethyl-LyS or any unnatural basic amino acid; xaa at residue 24 is des-xaa, Val, ASP, His, halo-His, Arg, ornithine, homoarginine, Lys, N- <220> 221> SITE <222> (26) <223> methyl-Lys, N N-dimethyl-LyS, N,N,N-trimethyl-LyS or any unnatural basic amino acid; xaa at residue is des-xaa, Asn, Pro or hydroxy- Pro; Xaa at residue 26 is des-xaa, Arg orni thine, homo- <220> 221> SITE <222> (28) <223> arginine, Lys, N-methyi-LYS, N,N-dimethyi-LYS, N,N,N-trimethyl-Lys or any unnaturai basic amino acid; Xaa at residue 27 is des-xaa, Ser or Thr; xaa at residue 28 is des-xaa, Leu, Ilie or Vai.

<400> 3 Xaa Xaa Xaa Xaa Xaa Cys Cys Xaa Xaa Xaa Xaa Cys Xaa Xaa Xaa Xaa 1 5' 10 Xaa Xaa Xaa Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa <210> 4 <211> 14 <212> PRT *<213> Conus imperialis <220> <221> SITE <222> (11) <223> xaa at residue 2 is Glu or gamma-carboxy-GIU; Xaa at residue 11 is Lys, N,N-dimethyl-LyS or N,N,N-trimethyl-Lys.

<400> 4 ASP Xaa Cys Cys Ser ASP Ser Arg Cys Gly Xaa Asn Cys Leu 1 5 *ode: <210> <211> 12 *<212> PRT <213> Conus imperiaiis <220> Page 8 179PCT-AUrev.APP. tXt <221> SITE <222> <223> Xaa at residue 10 is Trp (D or L) or halo-Trp.

<400> Ala Cys Cys 1 Ser ASP Arg Arg Cys Arg Xaa Arg Cys 5 <210> 6 <211> 13 <212> PRT <213> Conus regius <400> 6 Phe Thr cys 1 Cys Arg Arg Gly Thr Cys Ser Gin His Cys 5 <210> <211> <5212> <213> <220> .5221> <222> <223> 13

PRT

Conus regius

SITE

(2) Xaa at residue 2 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-Suipho-Tyr, 0-phospho-Tyr or ni tro-Tyr.

<400> 7 ASP Xaa Cys Cys Arg 1 5 Arg His Ala Cys Thr Leu Ilie Cys <210> <211> <212> <213> <220> <221> <222> <223> 8 13

PRT

Conus regius

SITE

xaa at residue 2 is Tyr, nor-Ty r, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-ph ospho-Tyr or nitro-Tyr; xaa at residues 7 and 8 is Pro or hydroxy-Pro.

00 0 0 *0 0 S. 0 *O 0 0 0 9 0 0009 <400> 8 ASP Xaa Cys Cys Arg Arg Xaa Xaa Cys Thr Leu Ilie Cys 1 5 2 10> <211> <212> <213> <220> <221> <222> <223> 9 13

PRT

Conus regius

SITE

xaa at residue 6 is Pro or hdroxy-Pro; Xaa at residue 10 is Tyr, nor-Tyr mono-haio-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr or ni tro-Tyr.

<400> 9 Page 9 179PCT-AUrev .APP. txt Gly Cys Cys ser ASP Xaa Arg Cys Arg Xaa Arg Cys Arg 1 5 <210> <211> 13 <212> PRT <213> Conus regius <220> <221> SITE <222> .(11) <223> Xaa at residue 7 is Pro or hydroxy-Pro; Xaa at residue 11 is Trp (D or L) or haio-Trp.

<400> Giy Giy Cys CyS Ser ASP Xaa Arg Cys Ala Xaa Arg Cys 1 5 <210> 11 <211> 17 <212> PRT <213> Conus regius <220> <221> SITE .5222> <223> xaa at residue 3 is Trp (D or L) or haio-Trp; Xaa at residue 9 is GiU or gamma-carboxy-Glu; Xaa at residue 10 is Pro or hydroxy-Pro.

<220> <221> SITE <222> <223> Xaa at residue 15 is LYS, N-methyi-LyS, N,N-dimethyi-LyS or N,N,N-trimethyl LyS.

<400> 11 lie Ala Xaa ASP Ilie Cys Cys Ser Xaa Xaa ASP Cys Asn His Xaa Cys 1 5 10 Val <210> 12 <211> 12 21>PRT <213> Conus regius <220> <221> SITE <222> (9) .5223> Xaa at residue 6 is Pro or hydroxy-Pro; Xaa at residue 9 is LyS, N-methyl-LyS, N,N-dimethyl-LyS or N,N,N-trimethyl-Lys.

<400> 12 Gly Cys Cys Ser ASP Xaa Arg Cys Xaa His Gin Cys 1 5 <210> 13 211> 14 <212> PRT <213> Conus sponsalis Page 179PCT-AU rev. APP. tXt <220> <221> SITE <222> .(11) <223> xaa at residues 5 and 11 is Pro or hydroxy-Pro; xaa at residue 8 is Lys, N-methyl-LyS, N.N-dimethyl-LyS or N.N.n-trimethyl-LyS.

<400> 13 Cys Cys Ser ASP Xaa Ala Cys Xaa Gin Thr Xaa Gly CyS Arg 1 5 <210> 14 <211> 13 <212> PRT <213> Conus sponsalis <220> <221> SITE <222> <223> xaa at residue 3 is Glu or gamma-carboxy-GlU; Xaa at residue 5 is Pro or hydroxy-Pro.

<400> 14 Cys Cys Xaa Asn Xaa Ala Cys Arg His Thr Gin Gly Cys 1 5 <210> <211> 13 <212> PRT <213> Conus sulcatus <220> <221> SITE <222> (12) <223> xaa at residue 4 is Trp or halo-rrp; Xaa at residue 6 is Pro or hydroxy-Pro; xaa at residue 12 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr or nitro-Tyr.

<400> *Gly CyS Cys Xaa His Xaa Ala Cys Gly Arg His Xaa Cys 1 5 <210> 16 <211> 1 <213> Conus achatinus <220> <221> SITE <222> (11) <223> Xaa at residues 2 and 7 is Pro or hydroxy-I'ro; xaa at residue 11 is Lys, N-methyl-LyS, N,N-dimethyl-Lys or N,N,N-trimethYl-LYS.

<400> 16 Ala Xaa Cys Cys Asn Asfl Xaa Ala Cys Val Xaa HiS Arg Cys 1 5 <210> 17 <211> <212> PRT <213> Conus bullatus Page 11 179PCT-AUrev .APP .txt <220> <221> SITE <222> (12) <223> Xaa at residues 2 and 8 is Pro or hydroxy-Pro; xaa at residue 12 is Lys, N-methyl-LyS, N,N-dimethyl-LyS or N,N,N-trimethyl-Lys.

<400> 17 Ala Xaa Gly Cys Cys Asn Asn Xaa Ala cys \/al Xaa His Arg Cys 1 5 10 <210> 18 <211> 14 <212> PRT <213> Conus bullatus <220> <221> SITE <223> Xaa at residues 1, 2 and 7 is Pro or hydroxy-Pro; xaa at residue 11 is Lys, N-methyl-LyS, N,N-dimethyl-LyS or N,N,N-trimethyl-Lys.

<400> 18 Xaa Xaa Cys Cys Asn Asn Xaa Ala Cys Val Xaa His Arg Cys 1 5 <210> 19 <211> 16 <212> PRT <213> Conus bullatus <220> <221> SITE 222> (13) <223> xaa at residue 2 is Glu or gamma-carboxy-Glu; Xaa at residue 6 is Trp or halo-Trp; Xaa at residues 8 11 and 13 is Pro or hydroxy-Pro.

<400> 19 Asp Xaa Asn cys cys xaa Asn Xaa Ser Cys Xaa Arg Xaa Arg Cys Thr 1@ 5 10 <210> <211> 13 <212> PRT <213> Conus bullatus <220> <221> SITE <222> (12) <223> Xaa at residues 6 and 7 is Pro or hydroxy-pro; Xaa at residue 12 is Tyr, nor-Tyr, mono-halo-Tyr, di -halo-Tyr, 0-sul pho-Tyr, 0-phospho-Tyr or 000 400> Gly Cys Cys Ser Arg Xaa Xaa Cys Ala Val Leu Xaa Cys 1 5 <210> 21 <211> 13 '.600 <212> PRT <213> Conus circumcisus Page 12 179PCT-AUrev .APP .txt <220> <221> SITE <222> (6) <223> xaa at residue 6 is Pro or hydroxy-Pro.

<400> 21 Gly Cys Cys Gly Asn Xaa Asp Cys Thr Ser His Ser Cys 1 5 <210> 22 <211> 16 <212> PRT <213> Conus stercusmuscarum <220> <221> SITE <222> .(11) <223> xaa at residue 6 is Pro or hydroxy-Pro; Xaa at residue 11 is Glu or gamma-carboxy-Glu.

<400> 22 Gly Cys Cys Ser Asn Xaa Val Cys His Leu Xaa His Ser Asn met Cys 1 5 10 <210> 23 <211> 17 <212> PRT <213> Conus obscurus <220> <221> SITE <222> <223> Xaa at residue 6 is Pro or hydroxy-Pro; Xaa at residue 14 is GlU or gamma-carboxy-Glu; Xaa at residue 15 is Tyr, nor-Tyr, mono- alo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr or <220> <221> SITE <222> <223> nitro-Tyr.

<400> 23 Gly Cys CyS Ser Asn Xaa \(al Cys Arg Gin Asn Asn Ala Xaa Xaa Cys 1 5 10 Arg 0 0- <210> 24 <211> 18 <212> PRT <213> Conus textile 0. *0000* <220> <221> SITE o* <222> 5223> xaa at residues 1, 7 and 14 is Pro or hydroxy-pro; Xaa at residue 15 is GlU or gamma-carbOXY-GlU.

:oO. <400> 24 0090 Xaa Gln Cys Cys Ser His Xaa Ala Cys Asn Val Asp His xaa Xaa Ile 0000 1 5 10 Page 13 179PCT-AUrev.APP.tXt Cys Arg <210> <211> 18 <212> PRT <213> Conus radiatus <220> <221> <222> <223>

SITE

xaa at residues 1, 7 and 14 is Pro or xaa at residues 2 and 15 is Glu or gamma-carboxy-Gi u.

hydroxy-Pro; <400> Xaa Xaa Cys Cys Ser His Xaa Ala Cys Asn 1 5 10 Val ASP His Xaa Xaa Ile Cys Arg <210> <211> <212> <213> <220> <221> <222> <223> 26 18

PRT

Conus radiatus

SITE

xaa at residues 1, 7 and 14 is Pro or hydroxy-Pro; xaa at residue 15 is Giu or gamma-carboXy-GlU.

<400> 26 Xaa Gin Cys Cys Ser His Xaa Ala Cys 1 5 Asn V'al ASP His Xaa Xaa Ile 10 CyS ASP a* 0, 0 <210> 27 <211> 18 <212> PRT <213> Conus omaria <220> <221> <222> <223>

SITE

Xaa at residues 1, 7 and 14 is Pro or hydroxy-Pro; Xaa at residue 15 is Glu or gamma-carboxy-Glu.

<400> 27 Xaa Arg Cys Cys Ser His Xaa Ala Cys Asn Val ASP His Xaa xaa le 1 5 10 Cys Arg <210> 28 <211> 18 <212> PRT <213> Conus omaria <220> Page 14 179 PCT-AU rev. APP .txt <221> SITE <222> (14) <223> Xaa at residues 1, 7 and 14 is Pro or <400> 28 Xaa Gin Cys Cys Ser His Xaa Ala Cys Asn Val 1 5 10 hyd roxy- Pro.

ASP His Xaa Gly lie CYS Arg <210> <211> <212> <213> <220> <221> <222> <223> 29 18

PRT

Conus omaria

SITE

Xaa at residues 1, 7 and 14 is Pro or hydroxy-Pro; Xaa at residue 15 is Giu or gamma-carboxy-GlU.

<400> 29 Xaa Gin Cys cys Ser His Xaa 1 5 Ala Cys Asn \Ial ASP His Xaa Xaa Thr 10 CyS Arg <210> <211> <212> <213> <220> <221> <222> <223> 18

PRT

Conus omaria

SITE

Xaa at residues 1, 7 and 14 is Pro or hydroxy-Pro; Xaa at residue 15 is Giu or gamma-carboxy-GIU.

0e <400> Xaa Gin Cys Cys Ser His Xaa Ala Cys 1 5 Asn Val ASP His SXaa Xaa Val 10 Cys Arg <210> <211> <212> <213> <220> <221> <222> <223> 31 18

PRT

conus omaria

SITE

Xaa at residues 1, 7 and 14 is Pro or hydroxy-Pro; xaa at residue 15 is Giu or gamma-carboXy-GlU.

<400> 31 Xaa Gin cys cys Ser His Xaa Ala Cys Asn lie ASP His Xaa Xaa Ilie 1 5 10 CyS Arg Page 179PCT-AUrev.APP.txt <210> <211> <212> <213> <220> <221> <222> <223> 32 21

PRT

onus omaria

SITE

(15) 1, xaa at residues 1, 7 and 14 is Pro or hydroxy-ro; Glu or gamma-carboxy-Glu.

Ala CyS Asn Val ASP His xaa xaa Ile 10 <400> 32 xaa ln cys cys Ser His xaa 1 5 CyS Arg Arg Arg Arg <210> <211> <212> <213> <220> <221> <222> <223> 33 17

PRT

onus betulinus

SITE

(7)..(15)des Xaa at residues 7 and 14 is Pro or hydroxy-Pro; is GlU or gamma-carboxy-Glu.

<400> 33 Gly Gly Cys Cys Ser His 1 5 xaa Ala ys Ala Val Asn Hi S xaa Xaa Leu 10 Cys <210> <211> <212> <213> <220> <221> <222> <223> 34 16

PRT

onus betulinus

SITE

(6)..(14)des xaa at residues 6 and 13 is Pro or hydroxy-Pro; is GlU or gamma-carboxy-Glu.

Ala ys Ser Val Asn His xaa xaa Leu ys 10 <400> 34 Gly CyS CyS Ser His xaa 1 5 <210> <211> 16 <212> PRT <213> Conus dalli <220> .5221> <222> <223>

SITE

(6)..(14)des xaa at residues 6 <400> 3 Gly CyS CyS Ser His xaa and 13 is Pro or hydroxy-Pro; is lu or gamma-carboxy-GIu.

Ala CyS Asn Val ASP His xaa xaa Ile Cys Page 16 179PCT-AU rev. APP.txt <210> <211> <212> <213> <220> <221> <222> <223> 36 19

PRT

Conus obscurus

SITE

xaa at residues 6 and 15 is Pro or hydroxy-Pro; xaa at reside 11 is LYS, N,-rnethyl-LyS, N,N-dimethyl-LyS or N,N,N-trimethyl-Lys; xaa at residues 14 and 18 is Glu or gamma-carboxy-GlU.

<400> 36 Gly CyS Cys Ser His Xaa Ala cys Ser 1 5 Gly Xaa Thr Gin Xaa Xaa Cys 10 Arg Xaa Ser <210> 37 <211> 18 <212> PRT <213> Conus tulipa <220> <221> <222> <223>

SITE

Xaa at residues 1, 6 and 13 is Pro or hydroxy-Pro; xaa at residue 14 is Glu or gamma-carboXy-GIU.

<400> 37 Xaa Cys Cys Ser His Xaa Ala Cys Ser Gly Asn Asn Xaa xaa Phe Cys 1 5 10 Arg Gin a S S S SOS U 0* S S 0 a

S.

S

555 5.55 S G a 55 55 5* 5

S.

S.

S

<210> <211> <212> <213> <220> <221> <222> <223> 38 18

PRT

Conus tulipa

SITE

Xaa at residues 6 xaa at residue 14 and 13 is Pro or hydroxy-Pro; is Glu or gamma-carboXy-GlU.

<400> 38 Gly Cys Cys Ser His Xaa V,1 5 Arg Gin <210> 39 <211> 16 <212> PRT *<213> Conus pennaceus <220> Ala Cys Ser Gly Asn Asn Xaa Xaa Phe cys 10 Page 17 179PCT-AU rev. APP.tXt <221> SITE <222> <223> xaa at residues 6, 7 and 13 is Pro or hydroxy-Pro; Xaa at residue 15 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr or nit ro-Tyr.

<400> 39 Gly Cys CySsSer His Xaa Xaa Cys Ala met Asn Asn Xaa ASP Xaa Cys 1 5 10 <210> <211> 16 <212> PRT <213> Conus pennaceus <220> <221> SITE <222> <223> Xaa at residuew 6, 7 and 13 is Pro or hydroxy-Pro; xaa at residue 15 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr or ni tro-Tyr.

<400> Gly CyS Cys Ser His Xaa Xaa Cys Phe Leu Asn Asn Xaa ASP Xaa Cys 1 5 10 <210> 41 <211> 17 <212> PRT <213> Conus textile <220> <221> SITE <222> (13) <223> Xaa at residues 6, 7 and 13 is Pro or hydroxy-Pro; xaa at residue 11 is LyS, N-methyl-LyS, N,N-dimethyl-LyS or N.N.N-trimethyl-LYS.

<400> 41 Gly Cys Cys Ser Asn Xaa Xaa Cys Ilie Ala Xaa Asn Xaa His met Cys 1 5 10 Gly <210> 42 <211> 16 <212> PRT <213> Conus distans <220> <221> SITE 222> .(13) <223> Xaa at residues 6, 7 and 13 is Pro or hydroxy-Pro.

<400> 42 Gly Cys Cys Ser Asn Xaa Xaa CyS Ala His Asn Asn Xaa ASP Cys Arg 1 5 10 210> 43 <211> 17 212> PRT Page 18 179PCT-Aurev .APP. txt <213> Conus tulipa <220> <221> SITE <222> (13) <223> xaa at residues 6 <400> 43 Gly Cys Cys Ser Asn Xaa 1 5 and 13 is Pro or hydroxy-Pro.

Ala Cys Ala Gly Asn Asn Xaa His Val Cys 10 A rg <210> <211> <212> <213> <220> <221> <222> <223> 44 16

PRT

Conus dalli

SITE

xaa at residues 6 <400> 44 Qly Cys Cys Ser Arg Xaa ~1 5 and 13 is Pro or hydroxy-Pro.

Ala Cys lie Ala Asn Asn Xaa Asp Leu Cys 10 <210> <211> <212> <213> <220> <221> <222> <223>

PRT

Conus circumcisus

SITE

Xaa at residues 6 and 13 is Pro or hydroxy-Pro; Xaa at residues 11 and 14 is Glu or gamma-carboxy-Gi u.

<400> Gly Cys CyS Ser Asn Xaa Val Cys His 1 5 Val Xaa Hi s 10 Xaa Xaa Leu Cys Arg Arg Arg Arg <210> <211> <212> <213> <220> <221> <222> <223> <220> <221> <222> <223> 46 18

PRT

Conus sulcatus

SITE

Xaa at residues 7, 12 and 14 is Pro or hydroxy-Pro; Xaa at residue 11 is Lys, N-methyl-LyS, N,N-dimethyl-LYS or N,N,N-trimethyl-LyS; Xaa at residue 15 is GlU or

SITE

gamma-ca rboxy-Gl u.

Page 19 179 PCT-AU rev. APP.txt <400> 46 Gly Gly Cys Cys Ser Phe Xaa Ala Cys Arg Xaa Xaa Arg Xaa Xaa Met 1 5 10 Cys Gly <210> <211> <212> <213> <220> <221> <222> <223> 47 18

PRT

conus textile

SITE

.(15) xaa at residues 1, 7 and xaa at residues 2 and 15 gamma-carboxy-Gi U.

14 is Pro is Glu or or hydroxy-Pro; <400> 47 Xaa Xaa Cys Cys Ser ASP Xaa Arg CyS Asn Ser 1 5 10 Ser His xaa Xaa Leu CyS Arg <210> <211> <212> <213> <220> <221> <222> <223> 48 18

PRT

conus dalli

SITE

Xaa at residues 1, 7 and 14 is Pro or hydroxy-pro; Xaa at residue 15 is Glu or gamma-carboXy-GlU.

<400> 48 Xaa Gin Cys Cys Ser ASP Xaa Arg Cys 1 5 Asn Val Gly His Xaa Xaa Leu 10 CyS Gly <210> <211> <212> <213> <220> <221> <222> <223> 49 18

PRT

Conus dalli

SITE

xaa at residue 1 is Gin or pyro-Glu; Xaa at residues 7 and 14 is Pro or hydroxy-Pro; Xaa at residue 15 is Glu or gamma-carboxy-GIU.

<400> 49 xaa Val cys Cys ser ASP Xaa Arg Cys Asn \/al Gly His xaa xaa Ile 1 5 10 Cys Gly <210> Page 179PCT-Aurev .APP .txt <400> 46 Gly Gly Cys Cys Ser Phe Xaa Ala Cys Arg Xaa Xaa Arg Xaa Xaa met 1 5 10 Cys Gly <210> 47 <211> 18 <212> PRT <213> Conus textile <220> <221> <222> <223>

SITE

xaa at residues 1, 7 and Xaa at residues 2 and 15 gamma-carboxy-Gl u.

14 i s Pro is Glu or or hydroxy-Pro; <400> 47 Xaa Xaa Cys Cys Ser ASP Xaa 1 5 Arg Cys Asn Ser Ser His Xaa Xaa Leu 10 CyS Arg <210> 48 <211> 18 <212> PRT <213> Conus dalli <220> <221> <222> <223>

SITE

Xaa at residues 1, 7 and 14 is Pro or hydroxy-pro; xaa at residue 15 is Glu or gamma-carboxy-GlU.

<400> 48 Xaa Gln Cys Cys Ser ASP Xaa Arg Cys Asn Val Gly His Xaa Xaa Leu 1 5 10 CyS Gly <210> <211> <212> <213> <220> <221> <222> 223> 49 18

PRT

Conus dalli

SITE

xaa at residue 1 is Gln or pyro-Glu; Xaa at residues 7 and 14 is Pro or hydroxy-Pro; xaa at residue 15 is Glu or gamma-carboXy-GlU.

<400> 49 xaa Val Cys Cys Ser ASP Xaa Arg Cys Asn Val Gly His xaa xaa Ile 1 5 10 CyS Gly <210> Page 179 PCT-AU rev. APP.tXt <211> <212> <213> <220> <221> <222> <223> 16

PRT

conus textile

SITE

Xaa at residues 6, 7 and 13 is Pro or hydroxy-Pro.

<400> Gly Cys Cys Ser Arg Xaa 1 5 Xaa cys le Ala Asn Asn Xaa ASP Leu Cys 10 <210> <211> <212> <213> <220> <221> <222> <223> 51 18

PRT

Conus omaria

SITE

xaa at residues 1 xaa at residue 15 and 14 is Pro or hydroxy-Pro; is Glu or gamma-carboxy-Glu.

Leu Ala Cys Asn \/al ASP His Xaa xaa Ile 10 <400> 51 Xaa Gln Cys Cys Ser His 1 5 CyS Arg <210> <211> <212> <213> <220> <221> <222> <223> 52 19

PRT

Conus sulcatus

SITE

xaa at residue 5 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phoSpho-Tyr or nitro-Tyr; xaa at residue 13 is Pro or hydroxy-Pro; xaa at residue 14 is Glu or <220> <221> <222> <223>

SITE

.(18) Samma-carboxy-GIU; Xaa at alo-Trp.

residue 18 is Trp or Arg Met Met Phe xaa xaa met Cys 10 <400> 52 Gly Cys CySs er Xaa Phe ASP Cys 1 5 y Xaa Arg <210> 53 <211> 18 <212> PRI <213> Conus sulcatus *Ga <220> <221> SITE Page 21 179PCT-AUrev.APP.txt <222> <223> Xaa at residue 11 is Lys, N-methyl-Lys, N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa at residue 12 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr or <220> <221> SITE <222> <223> nitro-Tyr; Xaa at residue 14 is Pro or hydroxy- Pro; Xaa at residue 15 is Glu or gamma-carboxy- Glu.

<400> 53 Gly Gly Cys Cys Ser Phe Ala Ala Cys Arg Xaa Xaa Arg Xaa Xaa Met 1 5 10 Cys Gly <210> 54 <211> <212> PRT <213> Conus sulcatus <220> <221> SITE <222> <223> Xaa at residue 7 is Pro or hydroxy-Pro; xaa at residue 10 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr or nitro-Tyr; Xaa at residue 15 is Glu or <220> <221> SITE <222> <223> gamma-carboxy-Glu.

<400> 54 Gly ly Cys Cys Phe His Xaa Val Cys Xaa Ile Asn Leu Leu Xaa Met 1 5 10 Cys Arg Gin Arg <210> <211> 19 <212> PRT <213> Conus betulinus <220> <221> SITE <222> <223> Xaa at residues 7, 11 and 14 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr; xaa at residues 8, 9 and 15 is Pro or hydroxy-Pro.

<220> <221> SITE <222> <223> Xaa at residues 12 and 16 is Glu or S gamma-carboxy-Glu.

<400> Ser Ala Thr Cys Cys Asn Xaa Xaa Xaa Cys Xaa Xaa Thr Xaa Xaa Xaa Page 22 179PCT-AUrev .APP.txt Ser Cys Leu <210> <211> <212> <213> <220> <221> <222> <223> 56 17

PRT

Conus betulinus

SITE

Xaa at residues 5 and 12 is Tyr, no-Tyr, mono-hal 0-Tyr, di -hal o-Tyr, 0-sul pho-Tyr, 0-phospho-Tyr or nitro-Tyr; Xaa at residues 6, 7 and 13 is Pro or hydroxy-Pro.

<220> <221> <222> <223>

SITE

.(14) xaa at residues 10 and 14 gamma-carboxy-Gl U.

is Glu or Phe Xaa Ala Xaa Xaa Xaa Arg cys 10 <400> 56 Ala Cys Cys Ala xaa xaa Xaa Cys 1 5 <210> <211> <212> <213> <220> <221> <222> <223> <220> <221> <222> <223> 57 19

PRT

conus betulinus

SITE

xaa at residues 3, 12 and 16 is GlU or gamma-carboxy-GlU; xaa at residues 6, 7, 11 and 14 is Ty, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sul pho-Tyr, 0-phospho-Tyr or nitro-Tyr.

C.

C 0 C C OS* 00 eg e

C

S

C.

.e.

C

09 Se 0* C

CS

be

C

C.

C 6 5505 g.e.

ge C

S

ee egg...

0 eg *C 0 0 g e.g.

0 See.

SITE

xaa at residues 8, 9 and 15 is Pro or <400> 57 Asn Ala xaa cys cys xaa Xaa xaa xaa cys Xaa 1 5 10 hydroxy-Pro.

Xaa Ala xaa Xaa Xaa Ile CyS Leu <210> <211> <212> <213> <220> <221> <222> 58 227

DNA

Conus magus

CDS

Page 23 179PCT-AUrev .APP. txt <400> 58 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt met Phe Thr val Phe LeU Leu Val Val Leu Ala Thr Thr Val Val 1 5 10 ttc cct tca gat cgt gca tct gat ggc agg aat gcc gca gcc aac Phe Pro Ser ASP Arg Ala Ser ASP G~y Arg Asn Ala Ala Ala Asn 25 aaa gcg tct gac gtg atc acg ctg gcc ctc aag gga tgc tgt tcc LYS Ala Ser ASP Val Ile Thr Leu Ala Leu Lys Gly Cys cys Ser 40 cct gtc tgt cac ttg gag cat tca aac ctt tgt ggt aga aga cgc Pro Val Cys His Leu Glu HiSsSer Asn Leu Cys Gly Arg Arg Arg 55 tgatgctcca ggaccctctg aaccacgacg ttcgagca <210> 59 <211> 63 <212> PRT <213> Conus magus <400> 59 met Phe Thr Val Phe LeU Leu Val Val Leu Ala Thr Thr Val Val 1 5 10 Phe Pro Ser ASP Arg Ala Ser ASP Gly Arg Asn Ala Ala Ala Asn 25 Lys Ala Ser ASP Val Ile Thr LeU Ala LeU LYS Gly CyS Cys Sen 40 Pro Val Cys His LeU GlU HiSsSer Asn Leu Cys Gly Arg Arg Arg 55 <210> <211> 208 <212> DNA <213> Conus aulicus <220> <221> CDS <222> (1)..C(168) <400> 60 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt met Phe Thr va] Phe Leu Leu Val Val LeU Ala Thr Thr Val Val 1 5 10 ttc act tca gat cgt gca tct gat ggc agg aag gac gca gcg tct Phe Thr Ser ASP Arg Ala Ser ASP G~y Arg Lys ASP Ala Ala ser 20 25 ttg atc gct ctg acc atc aag gga tgc tgt tct tat cct ccc tgt Leu Ile Ala LeU Thr Ile Lys G ly Cys Cys Sen Tyr Pro Pro Cys 35 40 gcg act aat tca gac tat tgt ggt tgacgacgct gatgctccag gaccc Ala Thr Asn Sen ASP Tyr Cys G~y 50 accacgacgt tcc Sen gac

ASP

aac Asn 48 96 144 Sen

ASP

Asfl tcc Sen ttc Ph e :tctga 48 96 144 198 Page 24 179PCT-AUrev .APP. txt <210> 61 <211> 56 <212> PRT <213> Conus aulicus <400> 61 Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Thr Ser ASP Arg Ala Ser ASP Gly Arg LYS ASP Ala Ala Ser Gly 25 Leu Ile Ala Leu Thr Ile Lys Gly Cys Cys Ser Tyr Pro Pro Cys Phe 40 Ala Thr Asn Ser ASP Tyr CyS Gly <210> 62 <211> 205 <212> DNA <213> Conus aulicus <220> <221> CDS <222> .(174) <400> 62 atg ttc acc gtg ttt ctg ttg gtc gtc ttg gca acc acc gtc gtt tcc met Phe Thr Va 1 Phe Leu Leu V/al Val Leu Ala Thr Thr Val Val ser 1 5 10 ttc act tca gat cgt gca tct gat ggc agg aag gac gca gcg tct ggc Mhe Thr Ser ASP Arg Ala Ser ASP G] y Arg LYS ASP Ala Ala Ser Gy 25 ctg att gct ctg acc atg aag gga tgc tgt tct tat cct ccc tgt ttc Leu Ile Ala Leu Thr met Lys G] y Cys Cys Ser Tyr Pro Pro Cys Phe 40 gcg act aat cca gac tgt g gt cga cga cgc tgatgctcca ggaccctctg Ala Thr Asn Pro ASP Cys GBY Arg Arg Arg 50 aaccacgacg t <210> 63 <211> 58 <212> PRT <213> Conus aulicus <400> 63 met Phe Thr val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser .15 10 Phe Thr Ser ASP Arg Ala Ser ASP Gly Arg Lys ASP Ala Ala Ser Gly 20 25 Leu Ile Ala Leu Thr met LYS Gly Cys CyS Ser Tyr Pro Pro cys Phe 35 40 Ala Thr Asn Pro ASP CyS Gly Arg Arg Arg 50 <210> 64 Page 48 96 144 194 205 179PCT-Aurev .APP.txt <211> 223 <212> DNA <213> Conus textile <2 <221> CDS <222> (192) <400> 64 ,atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc 48 met Phe Thr va] Phe Le U Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 ttc tct tca ggt cgt agt aca ttt cgt ggc agg aat gcc gca gcc: aaa 96 Phe Ser Ser Gly Arg Ser Thr Phe Arg G] y Arg Asn Ala Ala Ala Lys 25 gcg tct ggc ctg gtc agt ctg act gac agg aga cca gaa tgc tgt agt 144 Ala Se r Gly Leu Val Ser Leu Thr ASP Arg Arg Pro GlU Cys Cys Ser 40 gat cct cgc tgt aac tcg agt cat cca gaa ctt tgt ggt gga aga cgc 192 ASP Pro Arg Cys Asn Ser Ser His Pro Glu Leu Cys Gly G IY Arg Arg 55 tgatgctcca ggaccctctg aaccacgacg t 223 <210> <211> 64 <212> PRT <213> Conus textile <400> met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Ser Ser Gly Arg Ser Thr Phe Arg Gly Arg Asn Ala Ala Ala LyS 25 Ala ser Gly Leu Val Ser Leu Thr ASP Arg Arg Pro Glu CyS CySsSen 40 ASP Pro Arg Cys Asn Ser Ser His Pro Glu Leu CyS Gly Gly Arg Ang 5 55 <210> 66 <211> 244 213> Conus textile <220> <221> CDS <222> .(168) S <400> 66 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc gcc gtc gtt tcc 48 met Phe Thr Va 1 Phe Leu Leu Val Val Leu Ala Thr Ala Val Val Sen 1 5 10 ttc act tca gat cgt gca tct gat gac g g aaa gcc gct gcg tct gac 96 Phe Thr Sen ASP Arg Ala Sen ASP ASP G] y Lys Ala Ala Ala Ser ASP 25 ctg atc act ctg acc atc aag g~ a tgc tgt tct cgt cct ccc tgt atc 144 Leu Ile Thr LeU Thr Ilie LyS GI y Cys CySsSen Ang Pro Pro Cys Ile 40 Page 26 179PCT-AUrev .APP.txt gcg aat aat cca gac ttg tgt ggt tgacgacgct gatgctccag aacggtctga 198 Ala Asn Asn Pro ASP Leu Cys G]y accacgacgt tcgagcaatg ttcaccgtgt ttctgttggt tgtctt 244 <210> 67 <211> 56 <212> PRT <213> Conus textile <400> 67 met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Ala Val Val ser 1 5 10 Phe Thr Ser ASP Arg Ala Ser ASP ASP Gly LYS Ala Ala Ala Ser ASP 25 Leu Ile Thr Leu Thr Ile Lys Gly Cys Cys Ser Arg Pro Pro Cys Ile 40 Ala Asn Asn Pro ASP Leu Cys Gly <210> 68 <211> 223 <212> DNA 213> Conus textile <220> <221> CDS <222> (183) <400> 68 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc 48 met Phe Thr Va 1 Phe Le U Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 ttc act tca ggt cgt agt aca ttt cgt ggc agg aat gcc gca gcc aaa 96 Phe Thr Ser Gly Arg Ser Thr Phe Arg G~y Arg Asn Ala Ala Ala Lys 25 gcg tct g~c ctg gtc agt ctg act gac agg aga cca caa tgc tgt tct 144 Ala Ser GyLeu V/al Ser Leu Thr ASP Arg Arg Pro Gln Cys Cys Ser 40 4 cat cct gcc tgt aac gta gat cat cca gaa att tgt cgt tgaagacgct 193 His Pro Ala Cys Asn Val ASP His Pro GlU Ile cyS Arg 55 6 gatgctccag gaccctctga accacgacgt 223 <210> 69 <211> 61 <212> PRT <213> Conus textile <400> 69 met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Thr ser Gly Arg Ser Thr Phe Arg Gly Arg Asn Ala Ala Ala Lys 25 Page 27 179PCT-AU rev. APP .txt Ala Ser Gly Leu \'al Ser Leu Thr ASP Arg Arg Pro Gin Cys cys Ser 40 His Pro Ala Cys Asn Val ASP His Pro Glu le Cys Arg 55 <210> <211> 223 <212> DNA <213> Conus radiatus <220> <221> CDS <222> (183) <400> atg ttc acc gt gttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc 48 met Phe Thr va] Phe Leu Leu Val Val Leu Ala Thr rhr Val val Ser 1 5 10 ttc act tca ggt cgt cgt aca ttt cat g gc agg aat gcc gca gcc aaa 96 Phe Thr Ser G~y Arg Arg Thr Phe His G~y Arg Asn Al a Ala Ala Lys 25 gcg tct g gc ctg gtc agt ctg act gac agg aga cca gaa. tgc tgt tct 144 Ala Ser Gly Leu Val Ser LeU Thr ASP Arg Arg Pro Glu Cys Cys Ser 40 cat cct gcc tgt aac gta gat cat cca gaa att tgt cgt tgaagacgct 193 His Pro Ala Cys Asn Val ASP His Pro Glu Ile Cys Arg 55 gatgctccag gaccctctga accacgacgt 223 <210> 71 <211> 61 <212> PRT <213> Conus radiatus <400> 71 met Phe Thr Val Phe Leu Leu Val VIal LeU Ala Thr Thr Val Val Ser 1 5 10 Phe Thr Ser Gly Arg Arg Thr Phe His Gly Arg Asn Ala Ala Ala LYS *20 25 Ala Ser Gly Leu \/al Ser Leu Thr ASP Arg Arg Pro GlU Cys Cys Ser His Pro Ala Cys Asn Val ASP His Pro Glu Ile Cys Arg 55 <210> 72 <211> 223 <212>DN <213> Conus radiatus <220> <221> CDS <222> .(183) <400> 72 atg ttc acc gt9 ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc 48 met Phe Thr va I Phe Leu Leu Val Val LeU Ala Thr Thr va] Val Ser 1 5 10 Page 28 179PCT-AUrev.APP. txt ttc act tca ggt cgt agt aca ttt cgt ggc agg aat gcc gca gcc aaa 96 Phe Thr ser G] y Arg Ser Thr Phe Arg Gly Arg Asn Ala Ala Ala LyS 25 gcg tct ggc ctg gtc agt ctg act gac agg aga cca caa tgc tgt tct 144 Ala Ser Gly Leu Val Ser Leu Thr ASP Arg Arg Pro Gln Cys cys Ser 40 cat cct gcc tgt aac gta gat cat cca gaa att tgc gat tgaagacgct 193 His Pro Ala Cys Asn Val ASP His Pro GlU Ile Cys ASP 55 gatgctccag gaccctctga accacgacgt 223 <210> 73 <211> 61 <212> PRT <213> Conus radiatus <400> 73 met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val val Ser 1 5 10 Phe Thr Ser Gly Arg Ser Thr Phe Arg Gly Arg Asn Ala Ala Ala LyS 25 Ala Ser Gly Leu Val Ser Leu Thr ASP Arg Arg Pro Gln cys cys Ser 40 His Pro Ala Cys Asn Val ASP His Pro GlU Ile Cys ASP 55 <210> 74 <211> 218 <212> DNA <213> Conus striatus <220> <221> CDS <222> (171) <400> 74 atg ttc act gtj ttt ctg ttg gtt gtc ttg gca atc act gtc gtt tcc 48 met Phe Thr vay Phe Leu Leu Val Val Leu Ala Ile Thr val Val Ser 1 5 10 ttc cct tta gat cgt gaa tct gat gygc gcg aat gcc gaa gcc cgc acc 96 Phe Pro Leu ASP Arg Glu Ser ASP Gly Al a ASn Ala GlU Ala Arg Thr 25 cac gat cat gag aag cac gca ctg gac cgg aat gga tgc tgt agg aat 144 His ASP His GlU Lys His Ala Leu ASP Arg Asn Gly Cys Cys Arg Asn 40 cct gcc tgt gag agc cac aga tgt ggt tgacgacgct gatgctccag 191 Pro Ala Cys Glu Ser His Arg Cys Gly gaccctctga accacgacgt tcgagca 218 <211> 57 <212> PRT <213> Conus striatus Page 29 179 PCT-AU rev. APP.tXt ttc act tca g gt cgt agt aca ttt cgt g gc agg aat gcc gca gcc aaa 96 Phe Thr Ser GTy Arg Ser Thr Phe Arg G] y Arg Asn Ala Ala Ala Lys 25 gcg tct g gc ctg gtc agt ctg act gac agg aga cca caa tgc tgt tct 144 Ala Ser G]Y Leu Val Ser Leu Thr ASP Arg Arg Pro Gin Cys Cys Ser 40 cat cct gcc tgt aac gta gat cat cca gaa att tgc gat tgaagacgct 193 His Pro Ala Cys Asn Val ASP His Pro GIU Ile Cys ASP 55 gatgctccag gaccctctga accacgacgt 223 <210> 73 <211> 61 <212> PRT <213> Conus radiatus <400> 73 met Phe Thr Val Phe Leu Leu val Val Leu Ala Thr Thr val Val Ser 1 5 10 Phe Thr Ser Gly Arg Ser Thr Phe Arg Gly Arg Asn Ala Ala Ala Lys 25 Ala Ser Gly Leu Val Ser LeU Thr ASP Arg Arg Pro Gin Cys Cys Ser 40 His Pro Ala cys Asn Val ASP His Pro Giu le Cys ASP 55 <210> 74 <211> 218 <212> DNA <213> Conus striatus <220> <221> cos <222> (171) <400> 74 atg ttc act gt ttt ctg ttg gtt gtc ttg gca atc act gtc gtt tcc 48 met Phe Thr va? Phe Leu Leu Val Val Leu Ala Ile Thr Val Val Ser 1 5 10 ttc cct tta gat cgt gaa tct gat gpgc gcg aat gcc gaa gcc cgc acc 96 Phe Pro Leu ASP Arg Giu Ser ASP G] y Ala Asn Ala Giu Ala Arg Thr 25 cac gat cat gag aag cac gca ctg gac cgg aat gga tgc tgt agg aat 144 His ASP His Giu LYS His Ala Leu ASP Arg Asn G] y Cys Cys Arg Asn 40 cct gcc tgt gag agc cac aga tgt ggt tg acgacgct gatgctccag 191 Pro Ala Cys Giu Ser His Arg cys Gly gaccctctga accacgacgt tcgagca 218 <210> <211> 57 <212> PRT <213> Conus striatus Page 29 179 PCT-Au rev. APP .txt <400> met Phe Thr Val Phe Leu Leu Val Val Leu Ala Ile Thr Val Val Ser 1 5 10 Phe Pro Leu ASP Arg Glu Ser ASP Gly Ala Asn Ala Glu Ala Arg Thr 25 His ASP His Glu Lys His Ala Leu ASP Arg Asn Gly Cys Cys Arg Asfl 40 Pro Ala Cys Glu Ser His Arg Cys Gly <210> 76 <211> 227 <212> DNA <213> Conus bandanus <220> <221> CDS <222> .(180) <400> 76 atg ttc acc atg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc met Phe Thr met Phe Leu Leu Val Val LeU Ala Thr Thr Val Val Ser 1 5 10 ttc gct tca gat cgt gca tct gat ggc agg aat gcc gca gcc aag gac Phe Ala Ser ASP Arg Ala Ser ASP Gi y Arg Asn Ala Ala Ala LyS ASP 25 aaa gcg tct gac ctg gtc gct ctg acc gtc aag gga tgc tgt tct cat LyS Ala Ser ASP Leu Vfal Ala Leu Thr Val Lys Gly CyS Cys Ser His 40 cct gcc tgt agc gtg aat aat cca gac att tgt ggt tgaagacgct Pro Ala Cys Ser va] As n Asn Pro ASP Ile Cys Gy 55 gatgctccag gaccctctga accacgacgt tcgagca <210> 77 <211> <212> PRT <213> Conus bandanus <400> 77 met Phe Thr met Phe Leu Leu Val Val LeU Ala Thr Thr Val Val Ser 1 5 10 Phe Ala Ser ASP Arg Ala Ser ASP Gly Arg Asn Ala Ala Ala Lys ASP 25 LyS Ala Ser ASP Leu V/al Ala Leu Thr Val LyS Gly CyS Cys Ser His 35 40 Pro Ala Cys ser Val Asn Asn Pro ASP Ile Cys Gly 50 55 <210> 78 <211> 104 <212> DNA <213> Conus bandanus 48 96 144 190 227 9* 0 0 0000 0 0000 0* 00 00 00 0 0 0 0 0000 0 0 0000 Page 179PCT-Aurev .APP. txt <220> <221> CDS <222> (54) <400> 78 aaa gaa tgc tgt act cat cct gcc tgt cac gtg agt cat cca gaa ctc Lys Glu Cys Cys Thr His Pro Ala Cys His Val Ser His Pro GlU Leu 1 5 10 tgt g gt tgaaaagcga cgtgacgctc caggaccctc tgaaccacga cgttcgagca Cys G~y <210> 79 <211> 18 <212> PRT <213> Conus bandanus <400> 79 Lys Glu cys Cys Thr His Pro Ala Cys His Val Ser His Pro Glu Leu 1 5 10 Cys Gly 6 066* <210> <211> 206 <212> DNA <213> Conus bandanus <220> <221> CDS <222> (171) <400> atg ttc acc gt gttt met Phe Thr va] Phe 1 5 gtc act tta gat cgt \/al Thr Leu ASP Arg aaa acg cct cgc ctg Lys Thr Pro Ang Leu aga gg t ccc tgt atg Arg Gly Pro Cys met gaccctctga accac <210> 81 <211> 57 <212> PRT <213> Conus bandanus <400> 81 met Phe Thr Val Phe 1 5 \/al Thr Leu ASP Arg LYS Thr Pro Arg Leu ctg Leu gca Al a atc Ilie gta Val ttg gtt gtc ttg gca act gct gtt ctt cca Leu Val Val Leu Ala Thr Ala Val Leu Pro 10 tct gat g ga agg aat gca gca gcc aac gcc Ser ASP Gly Arg Asn Ala Ala Ala Asn Ala 25 gcg cca ttc atc agg gat tat tgc tgt cat Ala Pro Phe Ile Arg ASP Tyr CyS Cys His 40 tgg tgt g t tgaagccgct gctgctccag Trp CyS Gly 48 96 144 191 Leu Leu Val Val Leu Ala Thr Ala Val Leu Pro 10 Ala Ser ASP Gly Arg Asn Ala Ala Ala Asn Ala 25 Ile Ala Pro Phe lie Arg ASP Tyr Cys Cys His Page 31 179PCT-AU rev .APP.tXt 40 Arg Gly Pro Cys Met VIal Trp Cys Gly <210> 82 <211> 174 <212> DNA <213> Conus caracteristicus <220> <221> CDS <222> .(171) <400> 82 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtg gtt tcc 48 met Phe Thr Va 1 Ph e Leu Leu Val Val Leu Ala Thr Thr Val Val se r 1 5 10 ttc act tca gat cgt gct tct gat ggc agg aat gcc gca gcc aac: gcg 96 Phe Thr Ser ASP Arg Ala Ser ASP Gly Arg Asn Ala Ala Ala Asn Ala 25 ttt gac ctg atc gct ctg atc gcc agg caa aat tgc tgt agc att ccc 144 Phe ASP Leu Ile Ala Leu Ile Ala Arg Gln Asn Cys Cys Ser Ile Pro 40 agc tgt tgg gag aaa tat aaa tgt agt taa 174 Ser CyS Trp GlU LyS Tyr Lys CySsSer <210> 83 <211> 57 <212> PRT <213> Conus caracteristicus <400> 83 met Phe Thr Val Phe Leu Leu Vial Val LeU Ala Thr Thr Val Val Ser 1 5 10 Phe Thr Ser ASP Arg Ala Ser ASP Gly Arg Asn Ala Ala Ala Asn Ala :.20 25 Phe ASP Leu Ile Ala Leu Ile Ala Arg Gln Asn Cys cys Ser Ile Pro 35 40 45 Ser CyS Trp GlU Lys Tyr LyS CySsSer <210> 84 <211> 219 <212> DNA <213> Conus caracteristicus <220> <221> CDS <222> .(189) <400> 84 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtg gtt tcc 48 met Phe Thr val rhe Leu Leu Val Val Leu Ala Thr Thr val Val ser 1 5 10 ttc act tca gat cgt gcg tct gaa g gc agg aat gct gca gcc aag gac 96 Phe Thr Ser ASP Arg Ala Ser Gl u Gly Arg Asn Ala Ala Ala LyS ASP Page 32 179 PCT-AU rev. APP .txt 40 Arg Gly Pro Cys met Val Trp Cys Gly <210> 82 <211> 174 <212> DNA <213> Conus caracteristicus <220> <221> CDS <222> (171) <400> 82 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtg gtt tcc 48 met Phe Thr va] Phe Le U Leu Val \/al Leu Ala Thr Thr Va] Val Ser 1 5 10 ttc act tca gat cgt gct tct gat ggc agg aat gcc gca gcc aac gcg 96 Phe Thr Ser ASP Arg Ala Ser ASP Gly Arg Asn Ala Ala Ala Asn Ala 25 ttt gac ctg atc gct ctg atc gcc agg caa aat tgc tgt agc att ccc 144 Phe ASP Leu Ile Ala Leu Ile Ala Arg Gln Asn Cys Cys Ser Ile Pro 40 agc tgt tgg gag aaa tat aaa tgt agt taa 174 Ser Cys Trp Glu Lys Tyr Lys Cys Ser <210> 83 <211> 57 <212> PRT <213> Conus caracteristicus <400> 83 met Phe Thr Val Phe LeU Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Thr Ser ASP Arg Ala Ser ASP Gly Arg Asn Ala Ala Ala Asn Ala 20 25 Phe ASP Leu Ile Ala Leu Ile Ala Arg Gln Asn Cys Cys Ser Ile Pro 40 em. Ser Cys Trp GlU Lys Tyr Lys Cys Ser 50050 <210> 84 <211> 219 <212> DNA <213> Conus caracteristicus <220> <221> CDS <222> (189) <400> 84 S atg ttc acc gt gttt ctg ttg gtt gtc ttg gca acc act gt ggtt tcc 48 met Phe Thr va I Phe LeU Leu Val Val Leu Ala Thr Thr va? Val Ser 1 5 10 ttc act tca gat cgt gcg tct gaa ggc agg aat gct gca gcc aag gac 96 Phe Thr Ser ASP Arg Ala Ser Glu GMy Arg Asn Ala Ala Ala Lys ASP Page 32 179 PCT-AU rev. APP.tXt 25 aaa gcg tct gac ctg gtg gct ctg aca gtc agg gga tgc tgt gcc att 144 Lys Ala Ser ASP Leu va] Ala Leu Thr Val Arg Gly Cys Cys Ala Ilie 40 cgt gaa tgt cgc ttg cag aat gca gcg tat tgt ggt gga ata tac 189 Arg Giu Cys Arg Leu Gin Asn Ala Ala Tyr Cys G y G ly Ilie Tyr 55 tgatgctcca ggaccctctg aaccacgacg 219 <210> <211> 63 <212> PRT <213> Conus caracteristicus <400> met Phe Thr Val Phe Leu Leu Val Vl Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Thr Ser ASP Arg Ala Ser GiU Gly Ang Asn Ala Ala Ala Lys ASP 25 Lys Ala Ser ASP Leu V/al Ala LeU Thr Val Arg Gly Cys Cys Ala le 40 Arg Giu CyS Arg LeU Gin Asn Ala Ala Tyr Cys Gly Gly le Tyr 55 <210> 86 <211> 217 <212> DNA <213> Conus tulipa <220> <221> CDS <222> .(186) <400> 86 atg ttc acc gtj ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc 48 met Phe Thr vPhe Leu Leu Val V/al Leu Ala Thr Thr \'al Val Ser 1 5 10 ttc cct tca gat att gca act gag g gc agg aat gcc gca gcc aaa gcg 96 Phe Pro Ser ASP le Ala Thr Giu Gy Arg Asn Ala Ala Ala Lys Ala 25 ttt gac ctg ata tct tcg atc gtc aag aaa g a tgc tgt tcc cat cct 144 40 gcc tgt tcg ggg aat aat cca gaa ttt tgt cgt caa ggt cgc 186 Ala Cys Ser Gly Asn Asn Pro Glu Phe Cys Arg Gin Gly Arg 55 tgatgctcca ggaccctctg aaccacgacg t 217 <210> 87 <211> 62 <212> PRT <213> Conus tulipa <400> 87 met Phe Thr Val Phe Leu Leu Val \'al LeU Ala Thr Thr Val Val Ser Page 33 179 PCT-AU rev. APP. tXt 25 aaa gcg tct gac ctg gtg gct ctg aca gtc agg gga tgc tgt gcc att 144 LyS Ala Ser ASP Leu va] Ala Leu Thr Val Arg G] y Cys Cys Ala Ile 40 cgt gaa tgt cgc ttg cag aat* gca gcg tat tgt gt ggaata tac 189 Arg Glu Cys Arg Leu Gin Asn Ala Ala Ty Cys G ly Gly Ilie Tyr 55 tgatgctcca ggaccctctg aaccacgacg 219 <210> <211> 63 <212> PRT <213> Conus caractenisticus <400> met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Thr Ser ASP Arg Ala Sen Glu Gly Arg Asn Ala Ala Ala Lys ASP 25 Lys Ala Ser ASP Leu Val Ala Leu Thr Val Arg Gly Cys Cys Ala Ile 40 Arg Glu Cys Arg Leu Gin Asn Ala Ala Tyr Cys Gly Gly le Tyr 55 <210> 86 <211> 217 <212> DNA <213> Conus tulipa <220> <221> CDS <222> .(186) <400> 86 atg ttc acc gt ttt ctg ttg gtt gtc ttg gca. acc act gtc gtt tcc 48 met Phe Thr va? Phe Leu Leu V/al Val Leu Ala Thr Thr Val Val Sen 1 5 10 ttc cct tca gat att gca act gag ggc agg aat gcc gca gcc aaa gcg 96 Phe Pro Sen Asp Ile Ala Thr Giu Gly Arg Asn Ala Ala Ala Lys Ala 25 ttt gac ctg ata tct tcg atc gtc aag aaa g a tgc tgt tcc cat cct 144 Phe ASP Leu Ile Sen Sen le Val Lys Lys GyCys Cys Sen His Pro 40 gcc tgt tcg ggg aat aat cca gaa ttt tgt cgt caa ggt cgc 186 Ala Cys Sen Gyy Asn Asn Pro GlU Phe Cys Ang Gin GiYY Ang 55 tgatgctcca ggaccctctg aaccacgacg t 217 <210> 87 <211> 62 *<213> Conus tulipa <400> 87 met Phe Thr Val Phe Leu Leu Val VIal Leu Ala Thr Thr Val Val Sen Page 33 179 PCT-AU rev. APP. txt 1 5 10 Phe Pro Ser ASP le Ala Thr Glu Gly Arg Asn Ala Ala Ala Lys Ala 25 Phe ASP Leu Ile Ser Ser Ile Val Lys Lys Gly Cys Cys Ser His Pro 40 Ala cys Ser Gly Asn Asn Pro GlU Phe Cys Arg Gin Giy Arg 55 <210> 88 <211> 217 <212> DNA <213> Conus tulipa <220> <221> CDS <222> .(186) <400> 88 atg ttc acc gt gttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc met Phe Thr Va 1 Phe Leu Leu 'al Vial Leu Ala Thr Thr Val val Ser 115 10 ttc cct tca gat ata gca act gag ggc agg aat gcc gca gcc aaa gcg Phe Pro Ser ASP Ilie Ala Thr Gi U Gyy Arg Asn Ala Ala Ala Lys Ala 25 ttt gac ctg ata tct tcg atc gtc agg aaa gga tgc tgt tcc aat ccc Phe ASP Leu lie Ser Ser Ilie VIal Arg Lys GMy Cys CySsSer Asfl Pro 40 gcc tgt gcg ggg aat aat cca cat gtt tgt cgt caa ggt cgc Ala Cys Ala Gly Asn Asn Pro His Val Cys Arg Gin Gyy Arg 55 tgatgctcca ggaccctctg aaccacgacg t <210> 89 <211> 62 <212> PRT <213> conus tulipa <400> 89 met Phe Thr Val Phe LeU Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Pro Ser ASP Ile Ala Thr Giu Gly Arg Asn Ala Ala Ala Lys Ala 25 Phe ASP Leu Ilie Ser ser Ilie V/al Arg LYS Gly Cys Cys Ser Asn Pro 40 Ala Cys Ala Gly Asn Asn Pro His Val Cys Arg Gin Gly Arg 55 <210> <211> 226 <212> DNA <213> Conus sulcatus <220> <221> CDS <222> .(195) Page 34 48 96 144 186 217 *0 .0 0 179 PCT-AU rev. APP.tXt 1 5 10 Phe Pro Ser ASP Ilie Ala Thr Glu Gly Arg Asn Ala Ala Ala LyS Ala 25 Phe ASP Leu Ile ser Ser Ile Val LyS Lys Gly Cys CySsSer His Pro 40 Ala Cys ser Gly Asn Asn Pro GlU Phe Cys Arg Gln Gly Arg 55 <210> 88 <211> 217 <212> DNA <213> Conus tulipa <220> <221> CDS <222> (186) <400> 88 atg ttc acc gt gttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc 48 met Phe Thr Va 1 Phe L eu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 ttc cct tca gat ata gca act gag ggc agg aat gcc gca gcc aaa gcg 96 Phe Pro Ser ASP le Ala Thr Glu Gly Arg Asn Ala Ala Ala Lys Ala 25 ttt gac ctg ata tct tcg atc gtc agg aaa gga tgc tgt tcc aat ccc 144 Phe ASP Leu Ile Ser Ser Ile Val Arg Lys G~y CyS CySsSer ASfl Pro 40 gcc tgt gcg g g gaat aat cca cat gtt tgt cgt caa ggt cgc 186 Ala Cys Ala G~y Asn Asn Pro His val CyS Arg Gin G ly Arg 55 tgatgctcca ggaccctctg aaccacgacg t 217 <210> 89 <211> 62 <212> PRT <213> Conus tulipa <400> 89 met Phe Thr vai Phe LeU Leu Vtal V.al Leu Ala Thr Thr Val Val Ser 1 5 10 Pile Pro Ser ASP Ile Ala Thr Giu Gly Arg Asn Ala Ala Ala Lys Ala 25 Phe ASP Leu Ile Ser Ser le Val Arg Lys Gly Cys CySsSer Asn Pro 40 Ala CyS Ala Gly Asn Asn Pro His Val Cys Arg Gin Gly Arg 00050 55 <210> <211> 226 <212> DNA 0* <213> Conus sulcatus 0 <220> <221> CDS <222> (195) Page 34 179 PCT-AU rev. APP .txt <400> atg ttc acc gtq ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc 48 met Phe Thr Va 1 Phe Leu Leu V/al Val Leu Ala Thr Thr Val Val Ser 1 5 10 ttc aat tca gat cgt gat cca gca tta ggt ggc agg aat gct gca gcc 96 Phe Asn Ser ASP Arg ASP Pro Ala Leu G y G ly Arg Asn Ala Ala Ala 25 aaa gcg tct gac aag atc gct tcg acc ctc aag aga aga gga tgc tgt 144 Lys Ala Ser ASP Lys Ile Ala Ser Thr LeU Lys Arg Arg G] y Cys Cys 40 tcg tat ttt gac tgt aga atg atg ttt cca gaa atg tgt ggt tgg cga 192 Ser Tyr Phe ASP Cys Arg met met Phe Pro Glu Met Cys Gly Trp Arg 55 gyc tgatgctcca ggaccctctg aaccacgacg t 226 <210> 91 <211> <212> PRT <213> Conus sulcatus <400> 91 met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Asn Ser ASP Arg ASP Pro Ala Leu Gly Gly Arg Asn Ala Ala Ala 25 Lys Ala Ser ASP LYS Ile Ala Ser Thr Leu Lys Arg Arg Gly CyS CyS 40 Ser Tyr Phe ASP Cys Arg met met Phe Pro Glu met Cys Gly Trp Arg 55 Gl y <210> 92 <211> 226 <212> DNA <213> Conus sulcatus <221> CDS <222> .(195) <400> 92 atg ttc acc gt gttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc 48 met Phe Thr va I Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 ttc aat tca gat cgt gat cca gca tta ggt ggc agg aat gct gca gcc 96 Phe Asn Ser ASP Arg ASP Pro Ala Leu G ly Gly Arg Asn Ala Ala Ala 25 ata gcg tct gac aag atc gct tcg acc ctc agg aga g ga gg a tgc tgt 144 Ile Ala Ser ASP LYS Ile Ala Ser Thr LeU Arg Arg Gly Gi y Cys Cys 40 tct ttt cct gcc tgt aga aag tat cgt cca gaa atg tgt ggt gga. cga 192 Page 179PCT-Au rev. APP. txt Ser Phe Pro Ala Cys Arg Lys Tyr Arg Pro Glu Met Cys Gly Gly Arg 55 cgc tgatgctcca ggaccctctg aaccacgacg t 226 Arg <210> 93 <211> <212> PRT <213> Conus suicatus <400> 93 met Phe Thr Val Phe Leu Leu Val \Ial Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Asn Ser ASP Arg ASP Pro Ala Leu Gly Gly Arg Asn Ala Ala Ala 25 Ile Ala Ser ASP LYS le Ala Ser Thr Leu Arg Arg Gly Gly Cys Cys 40 Ser Phe Pro Ala Cys Arg LYS Tyr Arg Pro Glu met Cys Gly Giy Arg 55 Arg <210> 94 <211> 211 <212> DNA <213> Conus sulcatus <220> <221> CDS <222> (180) <400> 94 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc 48 met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val val Ser 1 5 10 ttc act tca gat cat gaa tct gat cgc ggt gat gcc caa acc atc caa 96 Phe Thr Ser ASP His Glu Ser ASP Arg Gly ASP Ala Gin Thr Ilie Gin 25 gaa gtg ttt gag atg ttc gct ctg gac agc gat g ga tgc tgt tgg cat 144 Glu Va] Phe Glu met Phe Ala LeU ASP ser ASP Gly Cys Cys Trp His 0*e*35 40 cct gct tgt ggc aga cac tat tgt ggt cga aga cgc tgatgctcca 190 Pro Al a CyS GI y Arg His Tyr Cys G ly Arg Arg Arg 55 ggaccctctg aaccacgacg t 211 <210> <211> <212> PRT <213> Conus sulcatus met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val val Ser 1 5 10 Page 36 179PCT-Au rev .APP. txt Phe Thr Ser ASP His Glu ser ASP Arg Gly ASP Ala Gin Thr Ile Gin 25 Giu Val Phe GiU met Phe Ala Leu ASP Ser Asp Gly Cys Cys Trp His 40 Pro Ala Cys Gly Arg His Tyr Cys Gly Arg Arg Arg 55 <210> 96 <211> 202 <212> DNA <213> Conus suicatus <220> <221> CDS <222> (195) <400> 96 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc 48 met Phe Thr Val Phe L eu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 ttc aat tca gat cgt gat cca gca tta ggt ggc agg aat gct gca gcc 96 Phe Asn Ser ASP Arg ASP Pro Ala Leu GMy Gly Arg Asn Ala Ala Ala 25 ata gcg tct gac aag atc gct tcg acc ctc agg aga gga gga tgc tgt 144 Ilie Ala Ser ASP Lys Ilie Ala Ser Thr Leu Arg Arg Gly Gi y CyS Cys 40 tct ttt gct gcc tgt aga aag tat cgt cca gaa atg tgt g gt gg a cga 192 Ser Phe Ala Ala Cys Arg Lys Tyr Arg Pro Giu met CyS GMy Gly Arg 55 cgc tgatgct 202 Arg <210> 97 <211> 65 siau <212> PRT *<213> Conus slau <400> 97 met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Asn Ser ASP Arg ASP Pro Ala Leu Gly Gly Arg Asn Ala Ala Ala *20 25 Ile Ala Ser ASP Lys le Ala Ser Thr Leu Arg Arg Gly Gly Cys Cys 40 Ser Phe Ala Ala Cys Arg Lys Tyr Arg Pro Giu met Cys Gly Gly Arg 55 Arg <210> 98 <211> 220 <212>DN <213> Conus suicatus Page 37 179PCT-AUrev .APP.tXt <220> <221> CDS <222> <400> 98 atg ttc acc gt gttt ctg ttg gtt ctc ttg gca met Phe Thr va] Phe Leu Leu Vial Leu Leu Ala 1 5 10 ttc aat tca gat cgt gca tta g gt gygc agg aat Phe Asn Ser ASP Arg Ala Leu Gly Gly Arg Asn 25 tct gac aag atc ctt tcg aac ctc agg aga g ga Ser ASP Lys Ilie Leu Ser Asn Leu Arg Arg G~y 40 cct gtc tgt tac atc aat ctt cta gaa atg tgt Pro Val Cys Tyr Ile Asn Leu Leu Glu met Cys 55 tgatcgtcca ggaccctctg aaccacgacg t <210> 99 <211> 63 <212> PRT <213> Conus suicatus <400> 99 met Phe Thr Val Phe Leu Leu Val Leu Leu Ala 1 5 10 Phe Asn Ser ASP Arg Ala Leu Gly Gly Arg Asn 25 Ser ASP Lys Ile Leu Ser Asn LeU Arg Arg Gly 40 Pro V'al Cys Tyr lie Asn Leu Leu Glu met Cys 55 <210> 100 <211> 208 <212> DNA <213> Conus consors <220> <221> CDS <222> .(177) <400> 100 atg ttc acc gt gttt ctg ttg gtt gtc ttg aca met Phe Thr va 1 Phe Le U Leu V/al Val Leu Thr 1 5 10 ttc cct tca gat agt gca tct gat gtc agg gat Phe Pro Ser ASP Ser Ala Ser ASP Val Arg ASP 20 25 gaa agg tct gac atg tac aaa tcg aaa cgg aat Glu Arg Ser ASP met Tyr Lys Ser LYS Arg Asn 35 40 cct gcc tgt g gc aaa cac ttt agt tgt g ga cgc Pro Ala Cys Gly Lys His Phe Ser Cys Gly Arg acc Th r gct Al a cgt Arg acc gtc gtt Thr Val Val gca gcc aaa Ala Ala LYS tgc tgt ttt Cys Cys Phe caa cga ggc Gin Arg Gi y 48 96 144 Thr Thr Val Val Ser Ala Ala Ala Lys Ala Gly Cys Cys Phe His Arg Gin Ang Gly a. a.

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a *S SO a a a a acc act gtc gtt tcc 48 Thr Thr val Val ser gac gaa gcc aaa gac 96 ASP Giu Ala Lys ASP gga. cgc tgt tgc cat 144 Gi y Arg Cys Cys His tgatgctcca ggaccctctg 197 Page 38 179PCT-AUrev .APP.tXt aaccacgacg t 208 <210> 101 <211> 59 <212> PRT <213> Conus consors <400> 101 met Phe Thr Val Phe Leu Leu Val Val Leu Thr Thr Thr Val Val Ser 1 5 10 Phe Pro Ser ASP Ser Ala Ser ASP 'ial Arg ASP ASP GlU Ala Lys ASP 25 GlU Arg Ser ASP met Tyr Lys Ser Lys Arg Asn Gly Arg Cys Cys His 40 Pro Ala Cys Gly Lys His Phe Ser CyS Gly Arg <210> 102 <211> 219 <212> DNA <213> Conus stercusmuscarum <220> <221> CDS <222> (189) <400> 102 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc 48 met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 tcc cct tca gat cgt gca tct gat ggc agg aat gcc gca gcc aac gag 96 Ser Pro Ser ASP Arg Ala Ser ASP G~y Arg Asn Ala Ala Ala Asn Glu 25 aaa gcg tct gac gtg atc gcg ctg gcc ctc aag gga tgc tgt tcc aac 144 L YS Ala Ser ASP va? Ile Ala Leu Ala Leu Lys Gly Cys Cys Ser Asn 40 cct gtc tgt cac ctg gag cat tca aac atg tgt ggt aga. aga cgc 189 Pro Val Cys His Leu Glu His Ser Asn met Cys GiyY Arg Arg Arg 55 tgatgctcca ggaccctctg aaccacgacg 219 <210> 103 <211> 63 <212> PRT <213> Conus stercusmuscarum <400> 103 met Ph e Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 Ser Pro Ser ASP Arg Ala Ser ASP Gly Arg Asn Ala Ala Ala Asn GlU 25 Lys Ala Ser ASP Val Ile Ala Leu Ala Leu LYS Gly cys Cys Ser Asn 40 Pro Val Cys His Leu Glu His Ser Asn met cys Gly Arg Arg Arg Page 39 179PCT-AU rev. APP.txt 55 <210> 104 <211> 248 <212> DNA <213> Conus betulinus <220> <221> CDS <222> (180) <400> 104 atg ttc tcc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc met Phe ser val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 tcc act tca ggt ggt gca tct ggt ggc agg aag gct gca gcc aaa gcg Ser Thr Ser Gly G y Al a Ser G y G y Arg Lys Ala Ala Ala Lys Ala 25 tct aac cgg atc gct ctg acc gtc agg agt gca aca tgc tgt aat tat Ser Asn Arg Ilie Ala LeU Thr Val Arg Ser Ala Thr Cys Cys Asn Tyr 40 cct ccc tgt tac gag act tat cca gaa agt tgt ctg taacgtgaat Pro Pro Cys Tyr Glu Thr Tyr Pro Glu Ser Cys Leu 55 catccagagc tttgtggctg aagacactga tgctccagga ccctctgaac cacgacgt <210> 105 <211> <212> PRT <213> Conus betulinus <400> 105 met Phe Ser Val Phe Leu Leu Val Val Leu Ala Thr Thr Val val Ser 1 5 10 Ser Thr Ser Gly Gly Ala Ser Gly Gly Arg Lys Ala Ala Ala Lys Ala 20 25 Ser Asn Arg Ile Ala Leu Thr Val Arg Ser Ala Thr Cys Cys Asn Tyr 35 40 Pro Pro Cys Tyr GlU Thr Tyr Pro Glu Ser cys Leu 50 55 <210> 106 <211> 223 <212> DNA <213> Conus betulinus <220> <221> CDS <222> (183) <400> 106 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtg gtt tcc met Phe Thr val Phe Leu Leu V/al Val Leu Ala Thr Thr val Val ser 1 5 10 ttc act tca ggt cgt gca ttt cgt ggc agg aat cgc gca gcc gac gac Phe Thr Ser G] y Arg Ala Phe Arg GBy Arg Asn Arg Ala Ala ASP ASP 25 Page 48 96 144 190 248

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APP. txt Phe Thr Ser Gly Arg Ala Ser Gly Gly Arg Asn Ala Ala Ala LyS Ala 25 Ser Asn Arg Ile Ala met Ala Ile ser Ser Gly Ala Cys Cys Ala Tyr 40 Pro Pro Cys Phe Glu Ala Tyr Pro Glu Arg Cys Leu 55 <210> 110 <211> 223 <212> DNA <213> Conus betulinus <220> <221> CDS <222> (192) <400> 110 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc met Phe Thr val Phe LeU Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 ttc act tca gat cgt gca ttt cgt ggc agg aat tcc gca gcc aac gac Phe Thr Ser ASP Arg Ala Phe Arg G] y Arg Asn Ser Ala Ala Asn ASP 25 aaa agg tct gac ctg gcc gct ctg agc gtc agg aga gga tgc tgc tcc Lys Arg Ser ASP Leu Ala Ala Leu Ser Val Arg Arg Gly Cys Cys Ser 40 cat ccc gcc tgt agc gtg aat cat cca gag ctt tgt ggt aga aga cgc His Pro Ala Cys Ser val Asn His Pro Glu Leu Cys Gly Arg Arg Arg 55 tgatgcccca ggaccctctg aaccacgacg t <210> 111 <211> 64 <212> PRT <213> Conus betulinus <400> 111 met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Thr Ser ASP Arg Ala Phe Arg Gly Arg Asn Ser Ala Ala Asn ASP 20 25 Lys Arg Ser ASP Leu Ala Ala Leu Ser Val Arg Arg Gly cys cys Ser 40 His Pro Ala Cys Ser Val Asn His Pro Glu Leu CyS Gly Arg Arg Arg 55 <210> 112 <211> 248 <212> DNA <213> Conus betulinus <220> <221> CDS <222> (180) 48 96 144 192 223 Page 42 179PCT-AUrev.APP. tXt <400> 112 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc Met Phe Thr Va] Phe Le U Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 ttc act tca ggt cgt gca tct ggt ggc agg aat gct gca. gcc aaa gcg Phe Thr Ser Gly Arg Ala Ser Gyy G~y Arg Asn Ala Ala Ala LYS Ala 25 tct aac cgg atc gct ctg atc gtc agg aat gca gaa tgc tgt tat tat Ser Asn Arg le Ala Leu Ile Val Arg Asn Ala Giu Cys Cys Tyr Tyr 40 cct ccc tgt tac gag gct tat cca gaa att tgt ctg taacgtgaat Pro Pro Cys Tyr Glu Ala Tyr Pro Glu Ile Cys Leu 55 catccagacc tttgtggctg aagaccctga tgctccagga ccctctgaac cacgacgt <210> 113 <211> <212> PRT <213> Conus betulinus <400> 113 met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Thr Ser Gly Arg Ala Ser Gly Gly Arg Asn Ala Ala Ala Lys Ala 25 Ser Asn Arg Ile Ala Leu Ile Val Arg Asn Ala GlU Cys Cys Tyr Tyr 40 Pro Pro Cys Tyr Glu Ala Tyr Pro Giu Ile Cys Leu 55 <210> 114 <211> 207 <212> DNA <213> Conus pennaceus <220> <221> CDS <222> .(168) <400> 114 atg ttc acc gt gttt ctg met Phe Thr va I Phe Leu 1 5 ttc act tca gat cgt gca Phe Thr Ser ASP Arg Ala 20 ctg atc gct ctg acc atc Leu le Ala Leu Thr Ile 35 atg aat aat cca gac tat met Asn Asn Pro Asp Tyr 50 accacgacg ttg gtt gtc ttg gca acc acc gtc att tcc Leu Val Val Leu Ala Thr Thr Val le Ser 10 tct gat gg c g gg aat gcc gca gcg tct gac Ser ASP Gly GI y Asn Ala Ala Ala Ser ASP 25 aag g ga tgc tgt tct cat cct ccc tgt gcc Lys Gly Cys Cys Ser His Pro Pro Cys Ala 40 tgt g gt tgacgacgct gatgctccag gaccctctga Cys Gy 207 Page 43 179PCT-AUrev .APP. tXt <210> 115 <211> 56 <212> PRT <213> Conus pennaceus <400> 115 met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val le Ser 1 5 10 Phe Thr Ser ASP Arg Ala Ser ASP Gly Gly Asn Ala Ala Ala Ser ASP 25 Leu Ile Ala LeU Thr Ile Lys Gly Cys Cys Ser His Pro Pro Cys Ala 40 met Asn Asn Pro ASP Tyr Cys Gly <210> 116 <211> 207 <212> DNA <213> Conus pennaceus <220> <221> CDS <222> (168) <400> 116 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca, acc: acc gtc gtt tcc met Phe Thr va] Phe LeU Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 ttc act tca gat cgt gca tct gat g gc g gg aat gcc: gca atg tct gac Phe Thr Ser ASP Arg Ala Ser ASP G~y G] y Asn Ala Ala met Ser ASP 25 ctg atc gct ctg acc atc aag gga tgc tgt tct cat cct ccc tgt ttc Leu Ile Ala LeU Thr Ie Lys Gi y Cys Cys Ser His Pro Pro Cys Phe 40 ctg aat aat cca gac tat tgt g gt tgacgacgct gatgctccag gaccctctg Leu Asn Asn Pro ASP Tyr CyS G~y 50 accacgacg <210> 117 <211> 56 <212> PRT <213> Conus pennaceus <400> 117 met Phe Thr Val Phe Leu Leu Val Val LeU Ala Thr Thr Val Val Ser 1 5 10 Phe Thr Ser ASP Arg Ala Ser Asp Gly Gly Asn Ala Ala met Ser ASP 25 Leu Ile Ala LeU Thr Ile Lys Gly Cys Cys Ser His Pro Pro Cys Phe 40 LeU Asn Asn Pro ASp Tyr Cys Gly 50 <210> 118 Page 44 a 179 PCT-Au rev. APP.tXt <211> 210 <212> DNA <213> Conus stercusmuscarum <220> <221> CDS <222> .(171) <400> 118 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc 48 met Phe Thr Vat Phe Leu Leu Val Val LeU Ala Thr Thr Val Val Ser 1 5 10 ttc cct tca gat cgt gaa tct gat ggc gcg aat gac gaa gcc cgc acc 96 Phe Pro Ser ASP Arg Glu Ser Asp Gi y Ala Asn ASP Glu Ala Arg Thr 25 gac gag cct gag gag cac gga ccg gac agg aat gga tgc tgt agg aat 144 ASP Glu Pro Glu Glu His GBy Pro ASP Arg Asn Gly Cys Cys Arg Asn 40 cct gcc tgt gag agc cac aga tgt ggt tgacgacgct gatgctccag 191 Pro Ala Cys Glu Ser His Arg Cys Gly gaccctctga accacgacg 210 <210> 119 <211> 57 <212> PRT <213> Conus stercusmuscarum <400> 119 met Phe Thr Val Phe LeU Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Pro Ser ASP Arg Glu Ser Asp Gly Ala Asn ASP Glu Ala Arg Thr 25 ASP Glu Pro Glu Glu His Gly Pro ASP Arg Asn Gly Cys Cys Arg Asn 40 Pro Ala Cys Glu Ser His Arg Cys Gly <210> 120 <211> 210 <213> Conus circumcisus <220> <221> CDS <222> .(180) <400> 120 atg ttc acc gt gttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc 48 Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 ttc cct tca gat cgt gca tct gat g gc agg aat gcc gca gcc agc gac 96 Phe Pro Ser ASP Arg Ala Ser ASP G ly Arg Asn Ala Ala Ala Ser ASP 25 aagcg tct gac gcg gcc cac cag gg a tgc tgt tcc aac cct gtc tgt 144 Arg Ala Ser ASP Ala Ala His Gln G~y Cys Cys Ser Asn Pro Va] Cys 40 Page 179PCT-AUrev .APP.tXt cac gtg gaa cat cca gaa ctt tgt cgt aga aga cgc tgatgctcca 190 HiS va] Glu His Pro GlU Leu Cys Arg Arg Arg Arg 55 ggaccctctg aaccacgacg 210 <210> 121 <211> <212> PRT <213> Conus circumcisus <400> 121 met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Pro Ser ASP Arg Ala Ser ASP Gly Arg Asn Ala Ala Ala Ser ASP 25 Arg Ala Ser ASP Ala Ala His Gln Gly Cys CySsSer Asn Pro Val Cys 40 His Val Glu His Pro GlU Leu Cys Arg Arg Arg Arg 55 <210> 122 <211> 213 <212> DNA <213> Conus circumcisus <220> <221> CDS <222> .(174) <400> 122 atg ttc acc gt gttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc 48 met Phe Thr va] Phe Le U Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 ttc cct tca aat cgt gaa tct gat ggc gcg aat gcc gaa gtc cgc acc 96 Phe Pro Ser Asn Arg Glu Ser ASP Gly Ala Asn Ala Glu Val Arg Thr 25 gac gag cct gag gag cac gac gaa ctg ggcg g g aat gga tgc tgt gg g 144 ASP Glu Pro GlU GlU His ASP Glu Leu G Iy G y Asn G ly Cys Cys G Iy 40 aat cct gac tgt acg agc cac agt tgt gat tgacgacgct gatgctccag 194 Asn Pro ASP Cys Thr Ser HiSsSer Cys ASP gaccctctga accacgacg 213 <210> 123 <211> 58 <212> PRT <213> Conus circumcisus met Phe Thr Val Phe LeU Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Pro Ser Asn Arg Glu Ser ASP Gly Ala Asfl Ala GlU Val Arg Thr 25 Page 46 179 PCT-AU rev. APP.txt ASP Glu Pro GlU Glu His ASp Glu Leu Gly Gly Asn Gly CyS CyS Gly 40 Asn Pro ASP Cys Thr Ser His Ser Cys ASP <210> 124 <211> 207 <212> DNA <213> Conus episcopatus <220> <221> CDS <222> (168) <400> 124 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc 48 met Phe Thr va] Phe Le U Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 ttc act tca gat cgt gca tct gat agc agg aag gac gca gcg tct ggc 96 Phe Thr Ser ASP Arg Ala Ser ASP Ser Arg LYS ASP Ala Ala Ser Gly 25 ctg atc gct ctg acc atc aag gga tgc tgt tct gat cct cgc tgt aac 144 Leu ile Ala LeU Thr Ilie Lys Gi y Cys CySsSer ASP Pro Arg Cys Asn 40 atg aat aat cca gac tat tgt ggt tgacgacgct gatgctccag gaccctctga 198 met Asn Asn Pro ASp Tyr Cys G ly accacgacg 207 <210> 125 <211> 56 <212> PRT <213> Conus episcopatus <400> 125 met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Thr Ser ASP Arg Ala Ser ASP ser Arg Lys ASP Ala Ala Ser Gly 25 Leu lie Ala Leu Thr Ile Lys Gly Cys Cys Ser ASP Pro Arg Cys Asn 35 40 45 met Asn Asn Pro ASP Tyr Cys Gly <210> 126 *<211> 213 *<212> DNA <213> Conus sponsalis <220> <221> CDS <222> .(174) 00 so <400> 126 atg tcc acc gt gttt ctg ttg gtt gtc ctc gca acc acc gtc gtt tcc 48 met ser Thr va I Phe LeU Leu Val \Ial Leu Ala Thr Thr Val Val Ser 1 5 10 Page 47 179PCT-Au rev. APP. tXt ttc act gta gat cgt gca tct gat ggc agg gat gtc gca atc gac gac 96 Phe Thr Val ASP Arg Ala Ser ASP Gly Arg ASP Val Ala Ile ASP ASP 25 aga ttg gtg tct ctc cct cag atc gcc cat gct gac tgt tgt tcc gat 144 Arg Leu va] Ser Leu Pro Gin lie Ala His Ala ASP CYS Cys Ser ASP 40 cct gcc tgc aag cag acg ccc ggt tgt cgt taaagacgct gctgctccag 194 Pro Ala Cys Lys Gin Thr Pro G] y Cys Arg gaccctctga accacgacg 213 <210> 127 <211> 58 <212> PRT <213> Conus sponsalis <400> 127 met Ser Thr V'al Phe LeU Leu \/al Val Leu Ala Thr Thr Val Val ser 1 5 10 Phe Thr Val ASP Arg Ala Ser ASP Gly Arg ASP Val Ala Ilie ASP ASP 25 Arg Leu V/ai Ser Leu Pro Gin Ile Ala His Ala ASP Cys Cys Ser ASP 40 Pro Ala Cys Lys Gin Thr Pro Gly CyS Arg <210> 128 <211> 221 <212> DNA <213> Conus sponsalis <220> <221> CDS <222> (168) 400 128 at ac gt ttt ctg ttg gtt gtc ttg gca acc acc gtc gct tcc 48 met Phe Thr va? ire Leu Leu VIal Val Leu Ala Thr Thr Val Ala Ser *1 5 10 ttc att atc gat gat cca tct gat g c agg aat att gca gtc gac gac 96 Phe Ilie Ilie ASP ASP Pro Ser ASP GMy Arg Asn Ilie Ala Val ASP ASP 25 aga ggg ctt ttc tct acg ctc ttc cat gct gat tgc tgt gaa aat cct 144 Arg Gly Leu Phe Ser Thr Leu Phe His Ala ASP Cys Cys Giu Asn Pro 40 gcc tgt aga cac acg cag ggt tgt tgatctttgt tcttcaaaga cactgctggc 198 Ala Cys Arg His Thr Gin Miy Cys 950 ccaggaccct ctgaaccacg acg 221 <210> 129 <211> 56 <212> PRT <213> Conus sponsalis Page 48 179PCT-Aurev .APP.txt <400> 129 met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Ala Ser 1 5 10 Phe Ile le ASP ASP Pro Ser ASP Gly Arg Asn le Ala Val ASP ASP 25 Arg Gly Leu Phe Ser Thr Leu Phe His Ala ASP Cys CyS GIU Asn Pro 40 Ala Cys Arg His Thr Gin Giy Cys <210> 130 <211> 220 <212> DNA <213> Conus dalli <220> <221> CDS <222> (180) <400> 130 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc 48 met Phe Thr va] Phe LeU Leu VIal Val LeU Ala Thr Thr Val Val Ser 1 5 10 ttc act tca gat cgt gca ttt cgt ggc agg aat gcc gca. gcc aaa gag 96 Phe Thr ser ASP Arg Ala Phe Arg Gyy Arg Asn Ala Ala Ala LyS Giu 25 tct ggc ctg gtc ggt ctg acc gac aag acg cga gga tgc tgt tct cat 144 Ser Gly Leu Val GlY Leu Thr ASP Lys Thr Arg Gyy Cys Cys Ser His 40 cct gcc tgt aac gta gat cat cca gaa att tgt ggt tgaagacgct 190 Pro Ala Cys Asn Val ASP His Pro Gu Ilie Cys Gy 55 gatgctccag gaccctctga accacgacgt 220 <210> 131 .21>6 <212> PRT *<213> Conus daili <400> 131 *~met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Thr Ser ASP Arg Ala Phe Arg Gly Arg Asn Ala Ala Ala LYS Giu 25 Ser Gly Leu \'al Gly Leu Thr ASP Lys Thr Arg Gly Cys Cys Ser His 40 Pro Ala Cys Asn Val ASP His Pro Giu le Cys Gly 50 55 <210> 132 <211> 208 <212> DNA <213> Conus dalli Page 49 179PCT-Au rev. APP. tXt <220> <221> CDS <222> (177) <400> 132 atg ttc acc gt gt met Phe Thr va Pi 1 ttc act tca gat gi Phe Thr ser ASP G ctg atc act ctg a Leu lie Thr Leu T gcg aat aat cca g~ Ala Asn Asn Pro A aaccacgacg t <210> 133 <211> 59 <212> PRT <213> Conus daili <400> 133 met Phe Thr Val P 1 Phe Thr Ser Asp G Leu lie Thr Leu T Ala Asn Asn Pro A <210> 134 <211> 223 <212> DNA <213> Conus dalli <220> <221> CDS <222> (192) <400> 134 atg ttc acc gt gt met Phe Thr vai P 1 tcc act tca g gt c Ser Thr Ser GMY A 20 ,gcg tct g 9a ctg g Ala Ser Gly Leu V 35 gat cct cgc tgt a Asp Pro Arg Cys A tt ctg he Leu 5 cc atc h r Ilie ac ttg Sp Leu ttg gtt gtc ttg gca acc acc gtc gtt tcc 48 Leu Val Val LeU Ala Thr Thr Val Val Ser 10 tct gat gac agg aaa gcc gct gcg tct gac 96 Ser ASP ASP Arg Lys Ala Ala Ala Ser ASP 25 aag g ga tgc tgt tct cgt cct ccc tgt atc 144 Lys Gly Cys Cys Ser Arg Pro Pro Cys Ilie 40 tgt gg t cga cga cgc tgatgctcca ggaccctctg 197 CSG Y Arg Arg Arg he LeU Leu Vial Val LeU Ala Thr Thr Val Val Ser 5 10 ly Ala Ser ASP ASP Arg Lys Ala Ala Ala Ser ASP 25 hr lie Lys Gly CyS Cys Ser Arg Pro Pro Cys Ilie 40 sp Leu Cys Gly Arg Arg Arg

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eeC.

tt ctg he Leu 5 gt cgt rg Arg tc g gt al GMy ac gta sn Val ttg gtt gtc Leu \'al Val gca ttt cat Ala Phe His 25 ctg act gac Leu Thr ASP 40 gyt cat cca GyHis Pro 55 ttg gca acc act gtc gtt tcc Leu Ala Thr Thr Val Val Ser 10 ggc agg aat gcc gca gcc aaa Gi y Arg Asn Ala Ala Ala Lys agg aga cca caa tgc tgt agt Arg Arg Pro Gin Cys Cys Ser gaa ctt tgt g gt g ga aga cgc Giu Leu Cys Gly Gly Arg Arg Page 48 96 144 192 179PCT-AUrev.APP. txt tgatgctcca ggaccctctg aaccacaacg t 223 <210> 135 <211> 64 <212> PRT <213> Conus dalli <400> 135 met Phe Thr Val Phe Leu Leu VIal Val Leu Ala Thr Thr Val Val Ser 1 5 10 ser Thr Ser Gly Arg Arg Ala Phe His Gly Arg Asn Ala Ala Ala Lys 25 Ala Ser Gly Leu \/al Gly Leu Thr ASP Arg Arg Pro Gln cys cys Ser 40 ASP Pro Arg Cys Asn Vial Gly His Pro GlU Leu Cys Gly Gly Arg Arg 55 <210> 136 <211> 220 <212> DNA <213> Conus dalli <220> <221> CDS <222> .(189) <400> 136 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc 48 met Phe Thr va] Phe Le U Leu Val Val LeU Ala Thr Thr Val Val Ser 1 5 10 tcc act tca ggt cgt gca ttt cat ggc agg aat gcc gca. gcc aaa gcg 96 Ser Thr Ser Gly Arg Ala Phe His G] y Arg Asn Ala Ala Ala Lys Ala 25 tct ggc ctg gtc ggt ctg acc gac aag agg caa gta tgc tgt agt gat 144 Ser Gyy Leu Val Gyy Leu Thr ASP Lys Arg Gln Val Cys Cys Ser ASP 40 4 cct cgc tgt aac gta g gt cat cca gaa att tgt ggt g ga aga cgc 189 Pro Arg Cys Asn \'al Gly His Pro Glu Ile Cys Gy1y Gly Arg Arg 55 tgatgctcca ggaccctctg aaccacgacg t 220 <210> 137 <211> 63 <212> PRT <213> Conus dalli <400> 137 met Phe Thr Val Phe LeU Leu \/al Val LeU Ala Thr Thr Val Val Ser 1 5 10 Ser Thr Ser Gly Arg Ala Phe His Gly Arg Asn Ala Ala Ala LYS Ala 25 Ser Gly Leu Val Gly Leu Thr ASP LYS Arg Gln Val cys Cys Ser Asp 40 Pro Arg Cys Asn Val Gly His Pro Glu Ile Cys Gly Gly Arg Arg Page 51 179 PCT-AU rev APP. tXt 55 <210> 138 <211> 208 <212> DNA <213> Conus achatinus <220> <221> CDS <222> .(180) <400> 138 atg ttc acc gtg ttt ctg ttg gtt gtc ttg aca. acc act gtc gtt tcc 48 met Phe Thr val Phe LeU Leu Val Val Leu Thr Thr Thr Val Val Ser 1 5 10 ttc cct tca gat agt gca tct pgt ggc agg gat gac: gag gcc aaa gac 96 Phe Pro Ser ASP Ser Ala Ser Gly Gly Arg ASP ASP Glu Ala LYS ASP 25 gaa agg tct gac atg tac gaa ttg aaa cgg aat gga cgc tgt tgc cat 144 Glu Arg Ser ASP met Tyr GlU Leu LYS Arg Asn G] y Arg Cys Cys His 40 cct gcc tgt ggt ggc aaa tac gtt aaa tgt gga cgc: tgatgctcca 190 Pro Ala CyS Gly G y Lys Tyr V/al LYS Cys G~y Arg 55 ggaccctctc gaaccacg 208 <210> 139 <211> <212> PRT <213> Conus achatinus <400> 139 met Phe Thr Val Phe Leu Leu Val Val Leu Thr Thr Thr val Val Ser .1 5 10 Phe Pro Ser ASP Ser Ala Ser Gly Gly Arg Asp Asp Glu Ala Lys Asp 25 Glu Arg Ser ASP met Tyr GlU Leu Lys Arg Asn Gly Arg CyS CyS His 0, 35 40 Pro Ala Cys Gly Gly LYS Tyr Val Lys Cys Gly Arg 0 .0 50 55 <210> 140 <211> 211 <212> DNA <213> Conus bullatus <220> <221> CDS <222> .(174) <400> 140 atg ttc acc gt gttt ctg ttg gtt gtc ttg gca. acc: act gtc gtt tcc 48 met Phe Thr Vat Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 ttc tct aca gat gat gaa tct gat ggc tcg aat gaa, gaa ccc agc: gcc 96 Phe Ser Thr ASP ASp Glu Ser ASP Gly Ser Asn Glu Glu Pro Ser Ala 25 Page 52 gac cag act gcc agg1 ASP Gin Thr Ala Arg aat cct gcc tgt gtg Asn Pro Ala Cys va] cctctgaacc acgacgt <210> 141 <211> 58 <212> PRT <213> Conus bullatus <400> 141 met Phe Thr Val Phe 1 5 Phe Ser Thr ASP ASP ASP Gin Thr Ala Arg Asn Pro Ala Cys \talI <210> 142 <211> 214 <212> DNA <213> Conus bullatus <220> <221> CDS <222> (177) <400> 142 atg ttc acc gtg ttt met Phe Thr va] Phe I 1 5 ttc tct aca gat gat Phe Ser Thr ASP ASP gac cag gct gcc agg1 ASP Gin Ala Ala Arg 35 ;aat cct gcc tgt gt g Asn Pro Ala Cys Vat 1 cctctgaacc acgacgt <210> 143 <211> 59 <212> PRT <213> Conus bullatus <400> 143 met Phe Thr Val PheI 1 5 179 PCT-AU rev. APP.tXt tcc tca atg aac agg gcg cct g ga tgc tgt aac Ser Ser met Asn Arg Ala Pro Gyy Cys CyS Asn 40 iag cac aga tgt gga tgacgctgat gctccaggac Lys His Arg Cys Gyy 144 194 Leu Leu Vial V.al Leu Ala Thr Thr Val Val Ser 10 3lu Ser ASP Gly Ser Asn Glu Glu Pro Ser Ala 25 Ser Ser Met Asn Arg Ala Pro Gly CyS Cys Asn 40 Lys His Arg CyS Gly 9 9* ttg gtt gtc ttg gca acc act gtc gtt tcc 48 Leu V/al Vial Leu Ala Thr Thr Val Val Ser 10 tct gat g gc tcg aat gaa gaa ccc agc gcc 96 Ser Asp Gly Ser Asn Glu Glu Pro Ser Ala 25 gca atg aac agg ccg cct g ga tgc tgt aac 144 Ala met Asn Arg Pro Pro GyCyS Cys Asn 40 cac aga tgt ggt g ga tgacgctgat gctccaggac 197 His Arg Cys Gi y G y 214 LeU Leu Val Val Leu Ala Thr Thr Val Val Ser 10 Page 53 179PCT-AUrev.APP. tXt Phe Ser Thr ASP ASP GlU Ser ASP Gly Ser Asn GlU GlU Pro Ser Ala 25 ASP Gin Ala Ala Arg Ser Ala met Asn Arg Pro Pro Gly Cys CyS Asn 40 Asn Pro Ala Cys V/al Lys His Arg Cys Gly Gly <210> 144 <211> 208 <212> DNA <213> Conus bullatus <220> <221> cos <222> (177) <400> 144 atg ttc acc gt gttt ctg ttg gtt gtc ttg gca acc: act gtc gtt tcc Met Phe Thr Ma Phe Le U Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 ttc cct tca gat cgt gac tct gat gygc: gcg gat gcc: gaa gcc agt gac Phe Pro Ser ASP Arg ASP ser ASP Gly Ala Asp Ala Gl U Ala Ser ASP 25 gag cct gtt gag ttc gaa agg gac gag aat g ga tgc tgt tgg aat cct Glu Pro Val Glu Phe Glu Arg ASP GlU Asn GlIy CyS Cys Trp Asn Pro 40 tcc tgt ccg agg ccc aga tgt aca g ga cga cgc taatgctcca ggaccctctg Ser Cys Pro Arg Pro Arg Cys Thr G ly Arg Arg aaccacgacg t <210> 145 <211> 59 <212> PRT <213> Conus bullatus <400> 145 met Phe Thr Val Phe Leu Leu Val val Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Pro Ser ASP Arg ASP ser ASP Gly Ala Asp Ala Glu Ala Ser ASP 20 25 Glu Pro Val Glu Phe Glu Arg ASP GlU Asn Gly Cys Cys Trp Asn Pro 35 40 Ser Cys Pro Arg Pro Arg Cys Thr Gly Arg Arg 50 <210> 146 <211> 211 <212> DNA <213> Conus bullatus <220> <221> cDS <222> .(180) Page 54 <400> 146 atg ttc acc gt gttt ctg met Phe Thr Val Phe Leu 1 5 ttc cct tca gat cgt gca Phe Pro Ser ASP Arg Ala aaa gcg tct gac gtg gtc Lys Ala Ser ASP Va] Val cct ccc tgt gct gtg ctg Pro Pro Cys Ala ValI Leu ggaccctctg aaccacgacg t <210> 147 <211> <212> PRT <213> Conus bullatus <400> 147 met Phe Thr Val Phe Leu 1 5 Phe Pro ser ASP Arg Ala Lys Ala ser ASP Val Val Pro Pro CyS Ala Val Leu .<210> 148 <211> 212 <212> DNA <213> Conus distans <220> <221> CDS <222> (171) <400> 148 atg ttc acc gtg ttt ctg met Phe Thr Va] Phe Leu 1 5 gat cgt gca tct tat ggc ASP Arg Ala Ser Tyr G] y gcc ctg atc gct cag gcc Ala Leu ile Ala Gln Ala 35 tgt gcc cat aat aat cca Cys Ala His Asn Asn Pro 50 ggaccctctg aaccacgacg t 179PCT-Aurev .APP. txt ttg gtt gtc ttg aca acc act gtc gtt tcc Leu Val Val Leu Thr Thr Thr Val Va] Ser 10 tct gat g gc agg aat gcc gca gcc aac gac Ser ASP Gly Arg Asn Ala Ala Ala Asn ASP 25 acg ctg gtc ctc aag g ga tgc tgt tcc acc Thr Leu Va] Leu LyS GMy CyS CySsSer Thr 40 tat tgt g gt aga. aga. cgc tgatgctcca Tyr Cys Gly Arg Arg Arg 55 48 96 144 190 211 Leu Va] Val Leu Thr Thr Thr Val Va] Ser 10 Ser ASP Gly Arg Asn Ala Ala Ala Asn ASP 25 Thr Leu Val Leu LyS Gly Cys CySsSer Thr 40 Tyr Cys Gly Arg Arg Arg 55 ttg gtt gtc ttc gca tcc tct gtc acc tta Leu Va] Val Phe Ala Ser Ser Val Thr Leu 10 agg tat gcc tca ccc gtc gac aga gcg tct Arg Tyr Ala Ser Pro val ASP Arg Ala Ser 25 atc ctt cga gat tgc tgc tcc aat cct cct ile Leu Arg ASP CyS Cys Ser Asn Pro Pro 40 gac tgt cgt taaagacgct gcttgctcca ASP Cys Arg 48 96 144 191 Page 179PCT-AUrev .APP.txt <210> 149 <211> 57 <212> PRT <213> Conus distans <400> 149 met Phe Thr Val Phe LeU Leu \/al Val Phe Ala Ser Ser Val Thr Leu 1 5 10 ASP Arg Ala Ser Tyr Gly Arg Tyr Ala Ser Pro Val ASP Arg Ala Ser 25 Ala Leu Ile Ala Gln Ala Ile Leu Arg ASP Cys CySsSer Asn Pro Pro 40 Cys Ala His Asn Asn Pro ASP Cys Arg <210> 150 <211> 63 <212> DNA <213> Conus textile <220> <221> CDS <222> <400> 150 gga tgc tgt tct aat cct ccc tgt atc gcg aag aat cca. cac atg tgt 48 Gly Cys Cys Ser Asn Pro Pro Cys Ile Ala Lys Asn Pro His met Cys 1 5 10 ggt gg a aga cgc tga 63 Gly Gly Arg Arg <210> 151 <211> <212> PRT <213> Conus <400> 151 Gly CYS Cys 1 Gly Gly Arg

S

textil1e Ser Asn Pro Pro Cys Ile Ala LYS Asn Pro His Met Cys 5 10 Arg <210> 152 <211> 220 <212> DNA <213> Conus consors <220> <221> CDS <222> (189) <400> 152 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc met Phe Thr va] Phe Leu Leu Val Val LeU Ala Thr Thr Val Val ser 1 5 10 ttc cct tca gat cgt gca tct gat ggc agg aat gcc gca gcc aac gac Phe Pro Ser ASP Arg Ala Ser ASP GHy Arg Asn Ala Ala Ala Asn ASP 25 Page 56 179 PCT-AU rev. APP.txt aaa gcg tct gac gt g atc acg ctg gcc Lys Ala Ser ASP Val Ilie Thr Leu Ala 40 ctc aag g a Leu LYS M y tgc cys tgt tcc aac Cys Ser Asfl 144 cct gtc tgt cac ttg gag cat tca aac ctt tgt t Pro Val Cys His Leu Glu His Ser Asn Leu Cys Gly 55 tgatgctcca ggaccctctg aaccacgacg t <210> 153 <211> 63 <212> PRT <213> Conus consors aga aga cgc Arg Arg Arg <400> 153 met Phe Thr 1 Phe Pro Ser Lys Ala Ser Pro \'al Cys \Ial Phe Leu Leu Val VIal 5 Ala Thr Thr Val \Ial Ser ASP Arg Ala Ser ASP Gi y 25 Arg Asn Ala Ala Ala Asn ASP Cys Ser Asfl ASP val Ile Thr Ala Leu LYS Gly Cys Hi S Leu Gl U His Ser Asn Leu cys Arg Arg Arg <210> <211> <212> <213> <220> <221> <222> <223> <220> <221> <222> <223> 154

PRT

Conus musicus

SITE

xaa at residues 4, 11 and 12 is Tyr, nor-Tyr, mono-hal 0-Tyr, di -hal o-Tyr, o-sul pho-Tyr, 0-phospho-Tyr or nitro-Tyr. Xaa at residue 6 is Pro or hydroxy-Pro.

SITE

Xaa at residues 9, 10 and 15 is Lys, N-methyl-LyS, N,N-dimethyl-LyS or N,N,N-trimethyl-LyS; Xaa at residue 14 IS Trp (D or L) or halo-Trp.

S

<400> 154 Gly Cys Cys xaa Asn Xaa Val Cys Xaa Xaa Xaa Xaa Cys Xaa Xaa 1 5 10 <210> <211> <212> <213> <220> <221> <222> <223> 155 16

PRT

Conus purpurascens

SITE

xaa at residue 1 is Gin or pyro-GIU; Xaa at residue 2 is Glu or gamma-carboxy-GiU; Xaa at residues 3 and 9 is Pro or hydroxy-Pro.

Page 57 l79PCT-Au rev .APP.txt <220> <221> SITE <222> (13) <223> xaa at residue 13 is LYS, N-methyl-LyS, N,N-dimethyl-LyS or N,N,N-trimethyl-LyS.

<400> 155 Xaa Xaa Xaa Gly Cys Cys Arg His Xaa Ala Cys Gly Xaa Asn Arg Cys 1 5 10 <210> <2 11> <212> <213> <220> <221> <222> <223> 156 13

PRT

Conus musicus

SITE

(11) xaa at residues 5 <400> 156 Cys Cys Ala ASP Xaa ASP 1 5 and 11 is Pro or hydroxy-Pro.

Cys Arg Phe Arg Xaa Gly Cys <210> <211> <212> <213> <220> <221> <222> <223> 157 17

PRT

Conus musicus

SITE

Xaa at residues 4 and 13 is mono-hal 0-Tyr, di -hal 0-Tyr, 0-phospho-Tyr or nitro-Tyr; is Pro or hydroxy-Pro.

Tyr, nor-Tyr, o-sul pho-Tyr, xaa at residues 6 and <220> <221> <222> <223>

SITE

xaa at residues 9 and 16 is Trp (D or L) or halo-Trp; Xaa at residues 11 and 17 is Lys, N -me thy] Lys, N,N-dimethyl-LyS or N,N,N-trimethyl-LyS.

4* <400> 157 Gly Cys Cys Xaa Asn 1 5 Xaa Ser Cys Xaa Xaa Xaa 10 Thr Xaa cys Ser Xaa xaa <210> <211> <212> <213> <220> <221> <222> <223> <220> 158 13

PRT

Conus musicus

SITE

xaa at residue 5 is Pro or hydroxy-Pro; xaa at residue 8 is LYS, N-methyl-LyS, N,N-dimethyl-Lys or N,N,N-trimethyl-LyS.

Page 58 179 PCT-AU rev .APP. tXt <221> SITE <222> (11) <223> xaa at residue 9 is Glu or gamma-carboxy-G1U; Xaa at residue 11 is Tyr, nor-Tyr, mono-halo-Tyr, di -hal 0-Tyr, 0-sul pho-Tyr, 0-phospho-Tyr or ni tro-Tyr.

<400> 158 Cys Cys Ser Asn Xaa Thr Cys Xaa Xaa Thr Xaa Gly Cys 1 5 <210> 159 <211> 13 <212> PRT <213> Conus musicus <220> <221> SITE <222> (11) <223> Xaa at residues 5 and 11 is Pro or hydroxy-Pro; Xaa at residue 8 is Lys, N-methyl-Lys, N,N-dimethyl-LyS or N,N,N-trimethyl-LyS.

<400> 159 Cys Cys Ala Asn Xaa Ilie Cys Xaa Asn Thr Xaa Gly CyS 1 5 <210> 160 <211> 13 <212> PRT <213> Conus musicus <220> <221> SITE <222> (8) <223> xaa at residue 5 is Pro or hydroxy-Pro; Xaa at residue 8 is Lys, N-methyl-LyS, N,N-dimethyl-LyS or N,N,N-trimethyl-LYS.

<220> <221> SITE <223> Xaa at residue 9 is Glu or gamma-car-boxy-Glu; Xaa at residue 11 is Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr or nitro-Tyr.

<400> 160 Cys Cys Asn Asn Xaa Thr Cys Xaa Xaa Thr Xaa Gly Cys 008 1 5 <210> 161 <211> 13 <212> PRT <213> Conus musicus <220> <221> SITE <222> (8) <223> Xaa at residue 5 is Pro or hydroxy-Pro; Xaa at residue 8 is Lys, N-methyl-LyS, N,N-dimethyl-LyS or N,N,N-trimethyl-LYS.

<220> <221> SITE <222> .(11) Page 59 179 PCT-Au rev. APP.tXt <223> xaa at residue 9 is Glu or gamma-carboxy-Glu; Xaa at residue 11 is Tyr, nor-Tyr, mono-halo-Tyr, di -hal 0-Tyr, 0-sul pho-Tyr, 0-phospho-Tyr or ni tro-Tyr.

<400> 161 Cys Cys Ser Asn Xaa Val Cys Xaa Xaa 1 5 Thr Xaa Gly Cys <210> <211> <212> <213> <220> <221> <222> <223> <220> <221> <222> <223> 162 17

PRT

conus betulinus

SITE

xaa at residue 6 is Tyr, nor-Ty r, mono-halo-Tyr, di-halo-Tyr, 0-Suipho-Tyr, 0-ph ospho-Tyr or nitro-Tyr; Xaa at residues 7, 8 and 14 is Pro or hydroxy-Pro.

SITE

Xaa at residue 15 is Lys, N-methyl-LyS, N,N-dimethyl-LYS or N,N,N-trimethyl-LyS.

<400> 162 Gly Gly Cys Cys Ser Xaa Xaa Xaa 1 5 cys lie Ala Ser Asn Xaa Xaa Cys 10 <210> <211> <212> <213> <220> <221> <222> <223> 163

PRT

Conus lividus 000* so 0 0.

.00.4*

S

:0.0 *9040* **so

SITE

xaa at residues 6 <400> 163 Gly Cys Cys Ser His Xaa 1 5 and 13 is Pro or hydroxy-Pro.

Val Cys Ser Ala met Ser xaa Ile Cys 10 <210> <211> <212> <213> <220> <221> <222> <223> <220> <221> <222> <223> 164

PRT

Conus musicus

SITE

xaa at residues 4 and 12 is Lys, N-methyl-LYS, N,N-dimethyl-LyS or N,N,N-trimethyl-LyS; Xaa at residue 6 is Pro or hydroxy-pro.

SITE

xaa at residues 7 and 14 is Tyr, mono-halo-Tyr, Page 179 PCT-AU rev. APP.txt di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr or ni tro-Tyr.

<400> 164 Gly Cys cys Xaa Asn Xaa Xaa 1 5 Cys Gly Ala 10 Ser Xaa Thr xaa cys <2 10> <2 11> <212> <2 13> <220> <221> <222> <223> 165

PRT

Conus omaria

SITE

xaa at residue 5 is Tyr, nor-Ty r, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, o-ph ospho-Tyr or nitro-Tyr; Xaa at residues 6, 7 and 13 is Pro or hydroxy-pro.

<400> 165 Gly Cys Cys Ser Xaa Xaa Xaa Cys Phe 1 5 Ala Thr Asn Xaa ASP Cys 10 <2 10> <211> <212> <213> <220> <221> <222> <223> 166 17

PRT

Conus radiatus

SITE

Xaa at residue 6 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Ty r, 0-pho spho-Tyr or nitro-Tyr; xaa at residues 7, 8 and 14 is Pro or hydroxy-Pro..

<400> 166 Gly Gly CyS 1 cys Ser Xaa Xaa Xaa 5 cys lie Ala Asn Asn Xaa Leu Cys 10 Al a 0S @0 0 0 S

U

0* Od S 6

S

S.

U

S..

S

0S*S

S.

C

0* *5 0

OS

@0

S

0* 00 0 0 0 *05* S. 0 0S *5 0 ego...

0 OS @5 S S 0 <210> <211> <212> <213> <220> <221> <222> <223> 167 17

PRT

Conus radiatus

SITE

xaa at residue 6 is Tyr, nor-Ty r, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-ph ospho-Tyr or nitro-Tyr; Xaa at residues 7, 8 and 14 is Pro or hydroxy-Pro.

<400> 167 Gl y Gl y cys 1 Cys Ser Xaa Xaa Xaa Cys Ile Ala Asn Asn Xaa Phe Cys 5 10 Al a Page 61 179 PCT-AU rev. APP .txt <210> <211> <212> <213> <220> <221> <222> <223> 168 16

PRT

Conus virgo

SITE

xaa at residues 6, 7 and 13 is Pro or hydroxy-Pro.

<400> 168 ASP Cys Cys Ser Asn Xaa Xaa cys Ser Gin Asn 1 5 10 Asn Xaa. ASP Cys met <210> 11> <212> <213> <220> <221> <222> <223> 169 16

PRT

Conus virgo

SITE

xaa at residues 6, 7 and 13 is Pro or hyd roxy- Pro.

<400> 169 ASP Cys Cys Ser Asn Xaa Xaa Cys Ala His Asfl 1 5 10 Asn Xaa ASP CyS Arg <210> <211> <212> <213> <220> <221> <222> <223> 170

PRT

conus achatinus

SITE

xaa at residues 1, 11 and Samma-carboxy-GIU; Xaa at yd roxy -Pro.

14 is Glu or residue 6 is Pro or Hi S Al a Xaa Hi S Gi n Xaa Leu Cys 10 <400> 170 Xaa Cys Cys Thr Asn Xaa \Ial Cys 1 5 Ala.Arg Arg Arg <210> <211> <212> <213> <220> <221> <222> <223> 171 16

PRT

Conus achatinus

SITE

xaa at residue 6 is Pro or hydroxy-Pro; Xaa at residue 10 is Glu or gamma-carboxy-GlU.

<400> 171 Gly Cys Cys Ser Asn Xaa val Cys His Leu Xaa His Ser Asn Leu Cys 1 5 10 <210> 172 <211> Page 62 179PCT-AUrev.APP. txt <212> PRT <213> Conus achatinus <220> <221> <222> <223>

SITE

Xaa at residues 1, Samma-carboxy-GI U; yd roxy -Pro.

11 and 14 is Glu or xaa at residue 6 is Pro or <400> 172 Xaa cys Cys Thr Asn Xaa 1 5 val Cys Hi S val 10 Xaa His Gin Xaa Leu Cys Ala Arg Arg Arg <210> <211> <212> <213> <220> <221> <222> <223> 173 17

PRT

Conus ammiralis

SITE

xaa at residue 1 is Gin or pyro-Glu; Xaa at residues 2 and 15 is Glu or gamma-carboxy-Glu; Xaa at residue 6 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr,' o-sul pho-Tyr, 0-phospho-Tyr or <220> <221> <222> <223>

SITE

nitro-Tyr; Xaa at hydroxy-Pro.

residues 7 and 14 is Pro or <400> 173 Xaa Xaa Cys Cys Ser Xaa 1 5 Xaa Ala Cys Asn Leu ASP His Xaa Xaa Leu 10 <210> <211> <212> <213> <220> <221> <222> <223> 174 18

PRT

Conus ammiralis

SITE

xaa at residues 1, 7 and Xaa at residues 2 and 15 gamma-ca rboxy-Gl u.

<400> 174 Xaa Xaa Cys Cys Ser ASP Xaa 1 5 Ar4 14 is Pro or is Glu or g Cys Asn Ser 10 hydroxy-Pro; Thr His xaa Xaa Leu CyS Gly <210> 175 <211> 21 Page 63 l79PCT-AUrev APP. tXt <212> PRT <213> Conus arenatus <220> <221> SITE <222> (12) <223> xaa at residues 7 and 8 is Pro or hydroxy-Pro; Xaa at residue 10 is Trp (D or L) or halO-Trp; Xaa at residues 11 and 12 is Lys, N-methyl-LyS, N,N-dimethyl -LyS or N, N,N-trimethyl-LYS.

<220> <221> SITE <222> .(19) <223> xaa at residue 13 is Tyr, nor-Tyr, mono-halo-Tyr, di -hal 0-Tyr, 0-sul pho-Tyr, 0-phospho-Tyr or nitro-Tyr xaa at residue 19 is Glu or gamma-ca rboxy-Gl u.

<400> 175 Leu Asn Cys Cys met Ile xaa Xaa Cys Xaa Xaa Xaa Xaa Gly ASP Arg 1 5 10 Cys Ser Xaa Val Arg <210> 176 <211> 22 <212> PRT <213> Conus arenatus <220> <221> SITE <222> <223> xaa at residue 9 is Pro or hydroxy-Pro; xaa at residues 12 and 20 is Glu or gamma-carboxy-Glu; Xaa at residue 14 is Tyr, nor-Tyr, mono-halo-Tyr, di -hal 0-Tyr, 0-sul pho-Tyr, 0-phospho-Tyr or <220> <221> SITE <222> <223> nitro-Tyr.

:0 0. <400> 176 Ala Phe Gly Cys Cys ASP Leu Ile Xaa Cys Leu Xaa Arg Xaa Gly Asn 1 5 10 Arg Cys Asn xaa Val His <210> 177 <211> 21 <212> PRT <213> Conus arenatus <220> <221> SITE <222> .(16) <223> Xaa at residue 8 i-s Pro or hydroxy-Pro; Xaa at 0: residue 10 is Trp (D or L) or halo-Trp; Xaa at residues 12 and 16 is Lys, N-methyl-LYS, N, N-dimethyl -LyS or N, N,N-trimethyl <220> <221> SITE Page 64 179PCT-AU rev. APP.txt <222> (19) <223> xaa at residues 11 and 19 is Glu or gamma-carboxy-Glu; xaa at residue 13 is Tyr, mono-hal 0-Tyr, di -hal 0-Tyr, 0-sul pho-ryr, 0-phospho-Tyr or nitro-Tyr.

<400> 177 Leu Gly Cys Cys Asn Val Thr xaa Cys xaa 1 5 10 Xaa Xaa Xaa Gly ASP Xaa Cys Asn xaa Val Arg <210> <2 11> <212> <213> <220> <221> <222> <223> 178

PRT

Conus arenatus

SITE

Xaa at residue 2 is Glu or gamma-carboxy-Glu; Xaa at residues 7 and 14 is Pro or hydroxy-Pro.

<400> 178 Asp Xaa Cys Cys Ser Asn Xaa Ala cys Arg Val Asn Asn 1 5 10 Xaa His Val Cys Arg Arg Arg <210> <211> <212> <213> <220> <221> <222> <223> <220> <221> <222> <223> 179 21

PRT

Conus arenatus

SITE

xaa at residue 7 is Pro or hydroxy-pro; xaa residue 10 is Trp (D or L) or halo-Trp; Xaa residue 12 is Glu or gamma-carboxy-Glu; Xaa residue 13 is Tyr, nor-Tyr, mono- halo-Tyr,

SITE

(19) di-halo-Tyr, o-sulpho-Tyr, 0-phospho-ryr or nitro-Tyr; xaa at residues 14 and 19 is LyS, N-methyl -Lys, N,N-dimethyl-LyS or N,N,N-tri methyl -Lys.

<400> 179 Leu Asn cys cys Ser Ile Xaa Gly cys Xaa 1 5 10 cys Ser xaa Val Arg <210> 180 <211> 18 <212> PRT <213> Conus aurisiacus <220> Asn Xaa Xaa Xaa ASP Arg Page <221> <222> <223> 179PCT-AUrev.APP.txt

SITE

xaa at residues 7 and 14 is Pro or hydroxy-Pro; xaa at residue 10 is Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr or nitro-Tyr.

<400> 180 Gly Gly Cys Cys Ser His Xaa 1 5 Val Cys Xaa Phe Asn Asn Xaa Gin met 10 CyS Arg <210> <211> <212> <213> <220> <221> <222> <223> 181 18

PRT

Conus aurisiacus

SITE

xaa at residues 7 <400> 181 Gly Gly Cys CySsSer His 1 5 and 14 is Pro or hydroxy-Pro.

Xaa Val Cys Asn LeU Asn Asn Xaa Gin met 10 CyS Arg <210> <211> <212> <213> <220> <221> <222> <223> 182 17

PRT

conus bandanus

SITE

xaa at residues 6 and 7 is Pro or hydroxy-Pro; Xaa at residues 9 and 15 is Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr or ni tro-Tyr.

<400> 182 Gly Cys Cys Ser His Xaa 1 5 Xaa Cys Xaa Ala Asn Asn Gin Ala Xaa Cys 10 <210> <211> <212> <213> <220> <221> <222> <223> 183 17

PRT

Conus betulinus

SITE

xaa at residues 7 xaa at residue 15 and 14 is Pro and h ydroxy-Pro; is GIU or gamma-carboXy-GlU.

<400> 183 Gly Gly Cys Cys Ser His 1 5 Xaa Ala Cys Ser Val Thr His Xaa Xaa Leu 10 Page 66 179PCT-AUrev.APP.txt Cys <210> 184 <211> 18 <212> PRT <213> Conus betulinus <220> <221> SITE <222> <223> xaa at residue 6 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr or nitro-Tyr; xaa at residue 7 is Pro and hydroxy-Pro; Xaa at residue 12 is Glu or <220> <221> SITE <222> <223> gamma-carboxy-Glu.

<400> 184 Gly Gly Cys Cys Ser Xaa Xaa Ala Cys Ser val Xaa His Gln Asp Leu 1 5 10 Cys Asp <210> 185 <211> <212> PRT <213> Conus caracteristicus <220> <221> SITE <222> <223> xaa at residues 8 and 22 is Pro or hydroxy-Pro; xaa at residue 10 is Trp (D or L) or halo-Trp; Xaa at residue 13 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr or S <220> <221> SITE <222> <223> nitro-Tyr; Xaa at residues 15, 16 and 19 is Glu or gamma-carboxy-Glu.

o <400> 185 Val Ser Cys Cys Val Val Arg Xaa Cys Xaa Ile Arg Xaa Gin Xaa Xaa S 1 5 10 Cys Leu Xaa Ala Asp Xaa Arg Thr Leu 0 0 <210> 186 <211> 21 <212> PRT S <213> Conus caracteristicus <220> <221> SITE <222> <223> Xaa at residue 1 is Gln or pyro-Glu; Xaa at Page 67 <220> <221> <222> <223> 179PCT-AU rev. APP.txt residue 7 is Pro or hydroxy-Pro; xaa at residue is Trp (D or L) or hal o-Trp; Xaa at residues 11 and 19 is Glu or gamma-carboXy-Glu.

SITE

xaa at residues 12 and 16 is Lys, N-methyl-Lys, N,N-dimethyl-LyS or N,N,N-trimethyl-Lys; Xaa at residue 13 is Tyr, mono-halo-Tyr, di- halo-Tyr, 0-sul pho-Tyr, 0-phospho-Tyr or ni tro-Tyr.

<400> 186 Xaa Asn Cys Cys Ser 1 5 Cys Ser Xaa Val Arg lie Xaa Gly Cys Xaa Xaa Xaa 10 Xaa Gly ASP Xaa <210> <211> <212> <213> <220> <221> <222> <223> 187 16

PRT

Conus catus

SITE

xaa at residues 6 Xaa at residue 11 and 13 is Pro or hydroxy-Pro; is Glu or gamma-carboxy-Glu.

Val Cys His Leu Xaa His Xaa Asn Ala Cys 10 <400> 187 Gly Cys CyS Ser Asn Xaa 1 5 <210> <211> <212> <213> <220> <221> <222> <223> 188 17

PRT

Conus catus

SITE

xaa at residues 6 and 13 is Pro or hydroxy-Pro; Xaa at residue 9 is Tyr, nor-Ty r, mono-ha o-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-ph ospho-Tyr or nitro-Tyr.

S S S S

S.

S

S. 55

S

S

.5 5 S S 55

S

55

S

S

*5*S

S

<400> 188 Gly Cys Cys Ser Asn Xaa lie Cys Xaa 1 5 Phe Asn Asn Xaa Arg Ilie Cys 10 Arg <210> <211> <212> <213> <220> <221> <222> <223> 189 17

PRT

Conus episcopatus

SITE

xaa at residues 1 and 14 is Glu or gamma-carboxy-Glu; Xaa at residues 6, 7 and 13 is Pro or hydroxy-Pro; Xaa at residue 10 is Trp (D or Page 68 179PCT-AUrev.APP.txt L) or haio-Trp.

<220> <221> SITE <222> (11) <223> xaa at residue 11 is Lys, N-methyi-LYS, N,N-dimethyi-LyS or N,N,N-trimethyl-Lys.

<400> 189 xaa cys Cys Ser Gin Xaa Xaa Cys Arg Xaa Xaa His Xaa Xaa Leu Cys 1 5 10 Se r <210> <211> <212> <213> <220> <221> <222> <223> 190 16

PRT

Conus geographus

SITE

(6) xaa at residue 6 is Pro or hydroxy-pro.

<400> 190 Gly Cys Cys Ser His Xaa 1 5 Ala Cys Ala Gly Asn Asn Gin His lie Cys 10 <210> <211> <212> <213> <220> <221> <222> <223> 191 18

PRT

Conus geographus

SITE

xaa at residues 6 and 13 is Pro or hydroxy-Pro.

<400> 191 Gly Cys Cys Ala Val Xaa 1 5 Ser CyS Arg Leu Arg Asn Xaa Asp Leu Cys 10 0 00 0* 00 0 00 00 0 00 00 0 0 0 Gly Giy <210> <211> <212> <213> <220> <221> <222> <223> 192 16

PRT

Conus imperialis

NP-BIND

xaa at residues 6 and 13 is Pro or hydroxy-Pro.

000 0 00 00 0 0 0 0 0000 <400> 192 Gly'Cys Cys Ser His Xaa 1 5 <210> 193 <211> <212> PRT <213> Conus lividus Ala Cys Asn Val Asfl Asn Xaa His Ile Cys 10 Page 69 179PCT-Au rev .APP.txt <220> <221> SITE <222> <223> Xaa at residues 2, 7, 9 and 10 is Pro or hydroxy-Pro; Xaa at residues 3 and 4 is Giu or gamma-ca rboxy-Gi U.

<400> 193 Thr Xaa Xaa Xaa Cys cys Xaa Asn Xaa Xaa Cys Phe Ala Thr Asn Ser 1 5 10 ASP Ilie Cys Gly <210> 194 <211> 17 <212> PRT <213> Conus lividus <220> <221> SITE <222> (12) <223> Xaa at residue 7 is Pro or hydroxy-Pro; Xaa at residue 12 is LyS, N-methyl-LyS, N,N-dimethyl-LYS or N,N,N-trimethyi-LyS.

<400> 194 ASP Ala Cys Cys Ser ASP Xaa Arg Cys Ser Gly Xaa His Gin ASP Leu 1 5 10 Cys <210> 195 <211> 17 <212> PRT <213> Conus lividus <220> <221> SITE <222> (7) <223> Xaa at residue 1 is Giu or gamma-carboxy-Glu; Xaa at residue 7 is Pro or hydroxy-Pro.

V <400> 195 0. Xaa Asp Cys Cys Ser Asp Xaa Arg Cys Ser Vai Gly His Gin ASP Leu 1 5 10 S.9 Cys <210> 196 <211> 16 *212 PR <212> conus lividus <220> <221> SITE <222> (6) <223> xaa at residue 6 is Pro or hydroxy-Pro.

<400> 196 **.Gly CyS Cys Ser His Xaa Ala Cys Ala Giy Ser Asn Aia His Ile cys 1 5 10 Page 179 PCT-AU rev. APP. tXt <210> 197 <211> 17 <212> PRT <213> Conus lividus <220> <221> SITE <222> (7) <223> xaa at residue 1 is Glu or gamma-carboxy-Giu; Xaa at residue 7 is Pro or hydroxy-Pro.

<400> 197 Xaa Asp Cys Cys Ser Asp Xaa Arg Cys Ser Val 1 5 10 Gly His Gin Asp Met cys <210> 198 <211> 16 <212> PRT <213> Conus lividus <220> <221> <222> <223>

SITE

Xaa at residues 6 <400> 198 Gly Cys Cys Ser His Xaa 1 5 <210> 199 <211> 17 <212> PRT <213> Conus lividus and 13 is Pro or hydroxy-Pro.

Ala Cys Ala Gly Asn Asn Xaa His Ilie cys 10 <220> <221> <222> <223> $se see* we**

SITE

xaa at residues 6 and 13 is Pro or hydroxy-Pro; xaa at residue 14 is Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr or ni tro-Tyr.

<400> 199 Gly Cys Cys Gly Asn Xaa Ser Cys Ser Ilie 1 5 10 His Ilie Xaa Xaa Val Cys <210> <211> <212> <213> <220> <221> <222> <223> 200 21

PRT

Conus lividus

SITE

xaa at residues 4 and 5 is Giu or gamma-carboxy-GI u.

Page 71 179PCT-AUrev .APP.tXt <400> 200 Thr ASP Ser Xaa Xaa Cys Cys Leu Asp Ser Arg Cys Ala Gly Gin His 1 5 10 Gin ASP Leu Cys Gly <210> <211> <212> <213> <220> <221> <222> <223> 201 17

PRT

Conus marmoreus

SITE

Xaa at residues 6 at residues 9 and di-halo-Tyr, O-sul ni tro-Tyr.

and 7 is Pro or hydroxy-Pro; Xaa 15 is Tyr, mono-halo-Tyr, pho-Tyr, 0-phospho-Tyr or <400> 201 Gly Cys Cys Ser Asn Xaa 1 5 Xaa Cys Xaa Ala Asn Asn Gin Ala Xaa Cys 10 As n <210> <211> <212> <213> <220> <221> <222> <223> 202 16

PRT

Conus marmoreus

SITE

xaa at residues 6 <400> 202 Gly Cys CyS Ser His Xaa 1 5 and 13 is Pro or hydroxy-Pro.

Ala Cys Ser Val Asn Asn Xaa ASP lie Cys 10 <210> <211> <212> <213> <220> <221> <222> <223> <220> <221> <222> <223> 203 18

PRT

Conus musicus

SITE

Xaa at residues 2 and 12 is Lys, N-methyl-LYS, N,N-dimethyi-LyS or N,N,N-trimethyi-LyS; Xaa at residue 14 is Pro or hydroxy-Pro.

SITE

(16) xaa at residue 16 is Tyr, mono-halo-Tyr, di -hal o-Tyr, 0-sul pho-Tyr, 0-phospho-Tyr or nitro-Tyr.

<400> 203 Gly Xaa Cys Cys Ilie Asn Asp Ala Cys Arg Ser Xaa His Xaa Gin Xaa 1 5 10 Cys Ser Page 72 179PCT-AUrev .APP. txt <210> <211> <212> <213> <220> <221> <222> <223> 204 17

PRT

conus musicus

SITE

Xaa at residues 4 and 15 is mono-halo-Tyr, di-halo-Tyr, 0-phospho-Tyr or nitro-Tyr; Pro or hydroxy-Pro.

Tyr, nor-Tyr, 0-sul pho-ryr, xaa at residue 13 is <400> 204 Gly Cys Cys Xaa Asn le Ala Cys 1 5 Arg lie Asn Asn Xaa 10 Arg Xaa Cys <210> <211> <212> <213> <220> <221> <222> <223> 205 17

PRT

Conus obscurus

SITE

xaa at residues 6 and 13 is Pro or hydroxy-Pro; xaa at residues 12 and 15 is Tyr, nor-Tyr, mono-hal 0-Tyr, di -hal 0-Tyr, 0-sul pho-Tyr, 0-phospho-Tyr or nitro-Tyr.

SITE

(14) Xaa at residue 14 is LYS, N-methyl-LyS, N,N-dimethyl-LyS or N,N,N-trimethyl-LyS.

<220> <221> <222> <223> 4* <400> 205 Gly CyS Cys Ser His Xaa Val Cys Arg 1 5 Phe Asn Xaa Xaa Xaa Xaa Cys 10 <210> <211> <212> <213> <220> <221> <222> <223> <220> <221> <222> <223> 206 18

PRT

Conus obscurus

SITE

xaa at residue 2 is GlU or gamma-carboxy-Glu; Xaa at residues 7, 8 and 14 is Pro or hydroxy-Pro; xaa at residue 15 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr or

SITE

ni tro-Tyr Page 73 179PCT-AUrev.APP.txt <400> 206 Asp Xaa Cys Cys Ala Ser xaa Xaa Cys Arg Leu Asn Asn Xaa Xaa Val 1 5 10 Cys His <210> 207 <211> 19 <212> PRT <213> Conus obscurus <220> <221> SITE <222> <223> Xaa at residue 6 is Pro or hydroxy-Pro; Xaa at residue 9 is Trp (D or L) or halo-Trp; xaa at residues 14 and 18 is Glu or gamma-carboxy-Glu.

<220> <221> SITE <222> <223> xaa at residue 15 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr or nitro-Tyr.

<400> 207 Gly Cys Cys Ser Asn Xaa Val Cys Xaa Gln Asn Asn Ala Xaa Xaa Cys 1 5 10 Arg Xaa Ser <210> 208 <211> 16 <212> PRT <213> Conus obscurus <220> <221> SITE <222> <223> xaa at residues 6 and 7 is Pro or hydroxy-Pro; Xaa at residue 15 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, o-sulpho-Tyr, 0-phospho-Tyr or nitro-Tyr.

<400> 208 Gly Cys Cys Ser His Xaa Xaa Cys Ala Gln Asn Asn Gin Asp Xaa Cys 1 5 10 <210> 209 <211> 19 S<212> PRT <213> Conus obscurus S <220> S <221> SITE <222> <223> xaa at residue 6 is Pro or hydroxy-Pro; xaa at residues 14 and 18 is Glu or gamma-carboxy-Glu; S* xaa at residue 15 is Tyr, nor-Tyr, mono-halo-Tyr, *mo *di-halo-Tyr, O-sulpho-Tyr, 0-phospho-Tyr or <220> Page 74 179 PCT-AU rev. APP .txt <221> SITE <222> <223> nitro-Tyr.

<400> 209 Gly Cys Cys Ser His Xaa Ala Cys Ser 1 5 Gly Asn Asn Arg Xaa Xaa Cys 10 Arg Xaa Ser <210> <211> <212> <213> <220> <221> <222> <223> <220> <221> <222> <223> 210 18

PRT

Conus omaria

SITE

xaa at residues 2, 7 and 14 is Pro or hydroxy-Pro; xaa at residue 6 is Tyr, nor-Ty r, mono- halo-Tyr, di-halo-Tyr, 0-suipho-Ty r, O-phosyho-Tyr o nitro-Tyr; xaa at residue 15 is or o

SITE

gamma-carboxy-GI U <400> 210 ASP Xaa Cys Cys Ser Xaa 1 5 Xaa ASP Cys Gly Ala Asn His Xaa Xaa Ilie 10 CyS Gly S S

S.

S

<210> <211> <212> 213> <220> <221> <222> <223> <220> <221> <222> <223> 211 17

PRT

conus omaria

SITE

xaa at residues 1 and 14 is Glu or gamma-carboxy-Glu; Xaa at residues 6, Pro or hydroxy-Pro; xaa at residue 10 L) or halo-Trp.

7 and 13 i s is Trp (D or

SITE

(11) Xaa at residue 11 is Lys, N-methyl-LyS, N,N-dimethyl-LYS or N,N,N-trimethyl-LyS.

S. 55 S S

S

<400> 211 Xaa Cys Cys Ser Ser <210> 212 <211> 16 <212> PRT Gin Xaa Xaa Cys Arg Xaa Xaa His Xaa Xaa Leu Cys 10 Page l79PCT-AU rev .APP .txt <213> Conus omaria <220> <221> SITE <222> (13) <223> xaa at residues 6 <400> 212 Gly Cys Cys Ser His Xaa 1 5 and 13 is Pro or hydroxy-Pro.

Ala Cys Ala Gly Asn Asn Xaa His Ilie Cys 10 <210> 213 <211> 16 <212> PRT <213> Conus omaria <220> <221> <222> <223>

SITE

xaa at residues 6 and 13 is Pro or hydroxy-Pro; xaa at residue 15 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr or ni tro-Tyr.

<400> 213 Gly Cys Cys Ser ASP Xaa Ser Cys Asn Val Asn Asn Xaa ASP Xaa Cys 1 5 10 <210> <211> <212> <213> <220> <221> <222> <223> 214 18

PRT

Conus omaria

SITE

xaa at residues 1 and 2 is Giu or gamma-carboxy-Glu; xaa at residue hyd roxy -Pro.

7 is Pro or Val Gly His <400> 214 Xaa Xaa Cys Cys Ser ASP Xaa Arg Cys Ser 1 5 10 Gin ASP Met CyS Arg <210> 215 <211> 17 <212> PRT <213> Conus purpurascens <220> <221> SITE <222> <223> xaa at residue 7 is Pro or hydroxy-Pro; xaa at residue 15 is Giu or gamma-carboxy-GIU.

<400> 215 Gly Gly Cys Cys Ser 1 5 Asn Xaa Ala Cys Leu Val Asn His Leu Xaa Met 10 Cys Page 76 179 PCT-AU rev. APP .txt <210> 216 <211> 18 <212> PRT <213> Conus purpurascens <220> <221> <222> <223>

SITE

xaa at residues 3, 8 and 15 is Pro or <400> 216 Arg ASP Xaa Cys Cys Phe Asn Xaa Ala Cys Asn 1 5 10 hydroxy-Pro.

Val Asn Asn Xaa Gin Ile Cys <210> <211> <212> <213> <220> <221> <222> <223> 217 21

PRT

Conus purpurascens

SITE

Xaa at residue 5 is Pro or hydroxy-Pro; Xaa at ridue 8 is Trp (D or L) or halo-Trp.

<400> 217 Cys Cys Ser ASP Xaa Ser Cys Xaa Arg Leu His Ser 1 5 10 Leu Aia CyS Thr Gly Ilie Val Asfl Arg <210> 218 <211> 16 <212> PRT <213> Conus purpurascens 0e <220> <221> <222> <223>

SITE

Xaa at residue 5 is Pro or hydroxy-Pro.

<400> 218 Cys cys Thr Asn Xaa Aia Cys Leu Vai Asn Asn Ilie Arg Phe Cys Giy 1 5 10 <210> 219 <211> 18 <212> PRT <213> Conus regius <220> <221> <222> <223>

SITE

xaa at residue 2 is Giu or gamma-carboXY-Giu; Xaa at residue 7 is Pro or hydroxy-Pro.

<400> 219 ASP Xaa Cys Cys Ser ASP Xaa Arg Cys His Giy Asn Asn 1 5 10 Arg ASP His Page 77 179PCT-AU rev .APP. txt CyS Al a <210> 220 <211> 17 <212> PRT <213> Conus regius <220> <221> <222> <223>

SITE

Xaa at residues 6 <400> 220 ASP Cys Cys Ser His Xaa 1 5 and 13 is Pro or hydroxy-Pro.

Leu Cys Arg Leu Phe Val Xaa Gly Leu Cys 10 le <210> <211> <212> <213> <220> <221> <222> <223> <220> <221> <222> <223> 221 17

PRT

Conus regius

SITE

xaa at residues 6 and 13 is Pro or hydroxy-Pro; xaa at residue 9 is Lys, N-methyl-LYS, N,N-dimethyl-LyS or N,N,N-trimethyl-LyS.

SITE

(12) xaa at residue 12 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-suipho-Tyr O-phospho-Tyr or ni tro-Tyr.

0O 0 0 00* 00 0* 0 <400> 221 Gly Cys Cys Ser His 1 5 Xaa Val cys Xaa \/al Arg Xaa Xaa Asp Leu Cys 10 Arg <210> <211> <212> <213> <220> <221> <222> <223> 222 16

PRT

Conus regius 0* 00 0 0 0 *000 0 00.

0* 0 0* 0000*0 *0 00 0 0 0 0000

SITE

xaa at residues 6 <400> 222 Gly CyS Cys Ser His Xaa 1 5 <210> 223 <211> 16 <212> PRT <213> Conus regius and 13 is Pro or hydroxy-Pro.

Ala Cys Asn Val Asn Asn Xaa His le Cys 10 Page 78 179 PCT-AU rev .APP. txt <220> <221> SITE <222> (12) <223> Xaa at residue 6 is Pro or hydroxy-Pro; xaa at residue 12 is Tyr, nor-Tyr, nor-Tyr, mono-hal 0-Tyr, di -hal 0-Tyr, 0-sul pho-Tyr, 0-phospho-Tyr or nitro-Tyr.

<220> <221> SITE <222> (9) <223> Xaa at residue 9 is Lys, N-methyl-LyS, N,N-dimethyl-LyS or N,N,N-trimethyl-Lys.

<400> 223 Gly Cys cys Ser His Xaa Val cys .xaa Val Arg Xaa Ser ASP met Cys 1 5 10 <210> 224 <211> 17 <212> PRT <213> Conus stercusmuscarum <220> <221> SITE <222> (14) <223> xaa at residues 7 and 14 is Pro or hydroxy-Pro; xaa at residue 10 is Lys, N-methyl-Lys, N,N-dimethyl-LyS or N,N,N-trimethyl-Lys.

<400> 224 Gly Gly Cys Cys Ser His Xaa Ala Cys xaa Val His Phe Xaa His Ser 1 5 10 Cys <210> 225 <211>. <212> PRTu stercusmuscarum <220> <221> SITE <222> (14) <223> xaa at residues 6 and 13 is Pro or hydroxy-Pro; xaa at residue 14 i-s Glu or gamma-carboxy-GlU.

<400> 225 'ial cys Cys Ser Asn Xaa Val Cys His V/al ASP His Xaa Xaa Leu Cys 1 5 10 Ar* Ag <210> 226 <213> conus striatus <220> <221> SITE <222> (13) <223> Xaa at residues 6 and 13 is Pro or hydroxy-Pro.

Page 79 179PCT-Aurev.APP.tt <400> 226 Gly cys cys Ser His Xaa Val CyS Asn Ley Ser Asn xaa ln Ile Cys 1 5 10 Arg <210> <211> <212> <213> <220> <221> <222> <223> 227 18

PRT

conus textile

SITE

Xaa at residue 1 is ln or pyro-GIu; xaa at residues 2 and 15 is lu or gamma-carboxy-GIu; xaa at residues 7 and 14 is Pro or hydroxy-Pro.

<400> 227 xaa xaa Cys Cys Ser 1 5 His xaa Ala CyS Asn Val ASP His 10 xaa xaa Ile CyS Arg <210> <211> <212> <213> <220> <221> <222> <223> 228 17

PRT

conus tulipa

SITE

(6) xaa at residue 6 is Pro or hydroxy-Pro.

<400> 228 Gly CyS CyS Ser Asn 1 5 Xaa Ala CyS Leu Val Asn His Ile Arg Phe Cys 10 I Gly <210> <211> <212> <213> <220> <221> <222> <223> 229 17

PRT

onus virgo

SITE

xaa at residues 6 and <400> 229 Asp'cys Cys ASP ASP Xaa Ala 1 5 13 is Pro or hydroxy-Pro.

CyS Thr Val Asn Asn xaa Gly Leu ys 10 <210> 230 <211> <212> PRT Page 179PCT-AUrev .APP. tXt <213> Conus textile <220> <221> SITE <222> (13) <223> Xaa at residues 6, 7 and 13 is Pro or hydroxy-Pro; Xaa at residue 11 is Lys, N-methyl-LYS, N,N-dimethyl-LyS or N,N,N-trimethyl-Lys.

<400> 230 Gly Cys Cys Ser Asn Xaa Xaa Cysile Ala Xaa Asn Xaa His met Cys 1 5 10 Gly Gly Arg Arg <210> 231 <211> 18 <212> PRT <213> Conus geographus <220> <221> SITE <222> (9) <223> Xaa at residue 5 is Pro or hydroxy-Pro; Xaa at residue 8 is Tyr, nor-Tyr, mono-halo-Tyr, di -hal 0-Tyr, 0-sul pho-Tyr, 0-phospho-Tyr or nitro-Tyr; Xaa at residue 9 is GlU or <220> <221> SITE <222> (14) <223> gamma-carboxy-Glu; xaa at residues 10, 11, 12 and 14 is Lys, N-methyl-LyS, N,N-dimethyl-LyS or N, N,N-tn methyl -Lys.

<400> 231 Cys Cys Thr Ile xaa Ser Cys xaa xaa xaa Xaa xaa Ile xaa Ala Cys 1 5 10 Val Phe <21 SITE <210> 232 1 <211 18 *<212> PRT <213> Cousre8u <22> SITE <222>Pag (6.1(6 179 PCT-Au rev .APP. tXt <213> Conus imperialis <220> <221> CDS <222> (105) <400> 233 tct gat g ga aag agt Ser ASP G ly LYS Ser 1 5 gcc gcg gcc aaa Ala Ala Ala Lys gcc Al a 10 aaa ccg tct cac Lys Pro Ser His ctg acg Leu Thr gct cca ttc Ala Pro Phe agg gac gaa tgc Arg ASP Glu Cys tcc gat tct cgc Ser ASP Ser Arg tgt ggc aag CyS Gly Lys aac tgt ctt tga 108 Asn CyS Leu <210> 234 <211> <212> PRT <213> Conus <400> 234 Ser ASP Gly 1 Ala Pro Phe Asn Cys Leu <210> 235 211> 108 <212> DNA <213> Conus imperialis Lys Ser Ala 5 Ala Ala Lys Ala Lys 10 Pro Ser His Leu Thr Ile Arg ASP Glu Cys cys 25 Ser Asp Ser Arg Cys Gly LYS imperialis Sa 9* so 0 me.

<220> <221> CDS <222> .(105) <400> 235 ttt gat gg a agg aat Phe AS p Gly Arg Asn 1 5 gcc cca gcc gac Ala Pro Ala ASP aaa gcg tct gac Lys Ala Ser ASP ctg atc Leu Ile gct caa atc Ala Gln Ile agg aga gca tgc Arg Arg Ala cys tgt Cy s tcc gat cgt cgc Ser ASP Arg Arg tgt aga tgg CyS Arg Trp *5 9 5 *5*S

S

*5 S S 5* *9*SS* *9 9e S 9

*SS*

agg tgt g t tga 108 Arg Cys G y <210> 236 <211> <212> PRT <213> Conus <400> 236 Phe ASP Gly 1 imperialis Arg Asn Ala Pro Ala ASP ASP Lys Ala Ser ASP Leu Ile 5 10 Page 82 179 PCT-AU rev .APP. tXt Ala Gin Ile Val Arg Arg Ala Cys cys Ser ASP Arg Arg Cys Arg Trp 25 Arg Cys Gly <210> 237 <211> 145 <212> DNA <213> Conus regius <220> <221> CDS <222> (105) <400> 237 tct gat g ga agg aat gcc gca gcc: gac gcc aga gcg tct ccc cgg atc 48 ser ASP Gly Arg Asn Aia Aia Aia ASP Ala Arg Ala Ser Pro Arg Ile 1 .5 10 gct ctt ttc ctc agg ttc aca tgc tgt agg aga. ggt acc tgt tcc: cag 96 Ala Leu Phe Leu Arg Phe Thr Cys Cys Arg Arg Gly Thr Cys Ser Gin 25 cac tgt ggt tgaagacact gctgctccag gaccctctga accacgacgt 145 His Cys G ly <210> 238 <211> <212> PRT <213> Conus regius <400> 238 Ser ASP Giy Arg Asn Ala Ala Ala ASP Ala Arg Ala Ser Pro Arg Ile 1 5 10 Ala Leu Phe Leu Arg Phe Thr Cys Cys Arg Arg Gly Thr Cys Ser Gin 25 His Cys Gly <213 Cou Cg <210>23 <221> CDS <222> (105) <400> 239 ***tct aat g ga agg aat gcc gca gcc: gac gcc aaa. gcg tct caa cgg atc 48 Ser Asn G Iy Arg Asn Ala Ala Ala ASP Ala Lys Ala Ser Gin Arg le 1 5 10 gct cca ttc ctc agg gac tat tgc tgt agg aga cat gcc tgt acg ttg 96 Ala Pro Phe Leu Arg ASP Tyr Cys Cys Arg Arg His Ala Cys Thr Leu 25 att tgt g t tgaagacgct gctgctccag gaccctctga accacgacgt 145 Ile CyS Gly Page 83 179PCT-AU rev. APP .txt <210> 240 <211> <212> PRT <213> Conus regius <400> 240 Ser Asn Gly Arg Asn 1 5 Ala Ala Ala Asp Al a 10 Lys Ala Ser Gin Arg Ile Ala Pro Phe Leu Arg Asp Tyr Cys cys 25 Arg Arg His Ala Cys Thr Leu Ile Cys Gly <210> 241 <211> 145 <212> DNA <213> Conus regius <220> <221> CDS <222> .(105) <400> 241 tct aat g a Ser Asn GBy 1 gct cca ttc Ala Pro Phe att tgt g gt Ilie Cys Gly agg aat Arg Asn 5 gcc gca gcc gac Aia Ala Ala Asp gcc Al a 10 aaa gcg tct caa LYS Ala Ser Gin cgg atc Arg Ile ctc Leu agg gac tat tgc Arg Asp Tyr Cys agg aga cct ccc Arg Arg Pro Pro tgt acg ttg Cys Thr Leu tgaagacgct gctgctccag gaccctctga accacgacgt 145 <210> 242 <211> <212> PRT <213> Conus regius <400> 242 Ser Asn Gly Arg Asn 1 5 Ala Aia Aia Asp Lys Aia Ser Gin Arg Ilie Ala Pro Phe Leu Arg 20 Asp Tyr Cys Cys 25 Arg Arg Pro Pro Cys Thr Leu lie Cys Giy <210> 243 <211> 136 <212> DNA <213> conus regius <220> <221> CDS <222> (96) <400> 243 tct aat aaa agg aag aat gcc gca atg ctt gac atg atc gct caa cac Ser Asn Lys Arg LyS Asn Ala Ala met LeU Asp met Ile Ala Gin His Page 84 179PCT-AU rev .APP .txt 1 5 10 gcc ata agg ggt tgc tgt tcc gat cct cgc tgt aga tat aga tgt cgt 96 Ala Ilie Arg Gly Cys CySsSer ASP Pro Arg Cys Arg Tyr Arg Cys Arg 25 tgaagacgct gctgctccag gaccctctga accacgacgt 136 <210> 244 <211> 32 <212> PRT <213> Conus regius <400> 244 Ser Asn Lys Arg Lys Asn Ala Ala met Leu ASP met le Ala Gin His 1 5 10 Ala Ile Arg Giy Cys CySsSer ASP Pro Arg Cys Arg Tyr Arg Cys Arg 25 <210> 245 <211> 145 <212> DNA <213> Conus regius <220> <221> CDS <222> (105) <400> 245 ttt aat gga agg agt gcc gca gcc gac caa aat gcg cct ggc ctg atc 48 Phe As n GMy Arg Ser Ala Ala Ala ASP Gin Asn Ala Pro GMy Leu Ile 1 5 10 gct caa gtc gtc aga gyga g gg tgc tgt tcc gat ccc cgc tgc gcc tgg 96 Ala Gin Val Val Arg G ly G] y CyS CySsSer ASP Pro Arg CyS Ala Trp 25 aga tgt g gt tgaagacgtt gctgctccag gaccctctga accacgacgt 145 Arg Cys Gy <210> 246 <211> *<212> PRT <213> Conus regius <400> 246 Phe Asn Gly Arg Ser Ala Ala Ala ASP Gin Asn Ala Pro Gly Leu le 1 5 10 Ala Gin Val VIal Arg Gly Gly Cys CySsSer ASP Pro Arg Cys Ala Trp 25 Arg Cys Gly <210> 247 <211> 145 <212> DNA *<213> Conus regius <220> <221> CDS Page 179PCT-AU rev.APP .txt <222> .(105) <400> 247 ttt gat gga agg aat gcc gca gcc gac gcc aaa gtg att aac acg gtc Phe ASP GMy Arg Asn Ala Ala Ala ASp Ala Lys Va 1Ilie Asn Thr Val 1 5 10 gct cga atc gcc tgg gat ata tgc tgt tcc gaa cct gac tgt aac cat Ala Arg Ile Ala Trp ASP Ile Cys Cys Ser Giu Pro ASP Cys Asn His 25 aaa tgt gtt tgaagacgct tctgctccag gaccctctga accacgacgt LYS Cys Val <210> 248 <211> <212> PRT <213> Conus <400> 248 Phe ASP Gly 1 Ala Arg Ile LYS Cys Val regi us Arg Asn Ala Ala Ala ASP Ala LYS V/al Ile Asn Thr Val 5 10 Ala Trp ASP Ilie Cys Cys Ser Giu Pro ASP Cys Asn His 25 <210> 249 <211> 136 <212> DNA <213> Conus regius <220> <221> CDS <222> (96) <400> 249 tct aat aaa agg aag aat gcc gca atg ctt gac atg atc gct caa. cac Ser Asn Lys Arg Lys Asn Ala Ala met Leu ASP met Ile Ala Gin His 1 5 10 gcc ata agg ggt tgc tgt tcc gat cct cgc tgt aaa cat cag tgt ggt Ala lie Arg Gi y Cys Cys Ser ASP Pro Arg Cys Lys His Gin Cys G ly 25 tgaagacgct gctgctccag gaccctctga accacgacgt <210> 250 <211> 32 <212> PRT <213> Conus regius <400> 250 Ser Asn Lys Arg LYS Asn Ala Ala met LeU ASP met Ile Ala Gin His 1 5 10 Ala le Arg Gly Cys Cys Ser ASP Pro Arg Cys Lys His Gin Cys Gly 20 25 48 96 136 <210> 251 <211> 136 Page 86 179 PCT-AU rev. APP .txt <212> DNA <213> Conus musicus <220> <221> CDS <222> (105) <400> 251 atc aag aat aca gca gcc agc aac aaa gcg tct agc ctg gtg gct ctt 48 le Lys Asn Thr Ala Ala Ser Asn Lys Ala Ser ser Leu va IAla Leu 1 5 10 gtt gtc agg gga tgc tgt tac aat cct gtc tgc aag aaa tat tat tgt 96 \'al Val Arg Gi y CyS Cys Tyr Asn Pro Val Cys Lys Lys Tyr Tyr Cys 25 tgg aaa gg c tgatgctcca ggaccctctg aaccacgacg t 136 Trp Lys Gly <210> 252 <211> <212> PRT <213> Conus musicus <400> 252 Ile Lys Asn Thr Ala Ala Ser Asn Lys Ala Ser Ser Leu Val Ala Leu 1 5 10 V/al Val Arg Gly Cys Cys Tyr Asn Pro Val Cys Lys LYS Tyr Tyr Cys 25 Trp Lys Gly <210> 253 <211> 148 <212> DNA <213> Conus purpurascens <220> <220> CDS <222> (117) ~tc g 0 c agg aat gct gaa gcc atc gac aac gcc tta. gac cag agg 48 Ser Gi U GYArg Asn Ala GiU Ala Ile ASP Asn Ala Leu ASP Gin Arg 1 5 10 gat cca aag cga cag gag ccg g g gtgc tgt agg cat cct gcc tgt gyg 96 ASP Pro Lys Arg Gin Glu Pro B]y Cys Cys Arg His Pro Ala Cys G ly 25 aag aac aga tgt g ga aga cgc tgatgctcca ggaccctctg aaccacgacg t 148 LYS Asn Arg CYSGy Arg Arg <210> 254 <211> 39 <212> PRT :0 <213> Conus purpurascens <400> 254 Ser Glu Gly Arg Asn Ala Glu Ala Ilie Asp Asn Ala Leu ASP Gin Arg 1 5 10 Page 87 179 PCT-AU rev. APP.tXt ASP Pro Lys Arg Gin GlU Pro Gly Cys Cys Arg His Pro Ala Cys Gly 25 LyS Asn Arg Cys Gly Arg Arg <210> 255 <211> 156 <212> DNA <213> Conus musicus <220> <221> CDS <222> (102) <400> 255 tct gat ggc agg aat att gca gtc gac gac aga tgg tct ttc tat acg 48 ser ASP G] y Arg Asn Ilie Ala V/al ASP ASP Arg Trp Ser Phe Tyr Thr 1 5 10 ctc ttc cat gct act tgc tgt gcc gat cct gac tgt aga ttc cgg ccc 96 Leu Phe His Ala Thr Cys Cys Ala ASP Pro ASP Cys Arg Phe Arg Pro 25 gyt tgt tgatctttgt tcttcaaaga cgctgctggc ccaggaccct ctgaaccacg 152 GyCyS acgt 156 <210> 256 <211> 34 <212> PRT <213> Conus musicus <400> 256 Ser ASP Gly Arg Asn Ilie Ala Val ASP ASP Arg Trp Ser Phe Tyr Thr 1 5 10 Leu Phe His Ala Thr Cys Cys Ala ASP Pro ASP Cys Arg Phe Arg Pro 25 Gly CyS <210> 257 <211> 142 <212> DNA <213> Conus musicus <220> <221> CDS <222> .(102) *<400> 257 atc aag aat act gca gcc agc aac aaa gcg cct agc ctg gtg gct att 48 lie LyS Asn Thr Ala Ala Ser Asn Lys Ala Pro Ser Leu va] Al a lie 1 5 10 gcc gtc agg g a tgc tgt tac aat cct tcc tgt tgg ccg aaa aca tat 96 Ala Val Arg GIy Cys Cys Tyr Asn Pro Ser Cys Trp Pro Lys Thr Tyr 25 tgt agt tggaaaggct gatgctccag gaccctctga accacgacgt 142 Cys Ser Page 88 179PCT-AUrev .APP.tXt <210> 258 <211> 34 <212> PRT <213> Conus musicus <400> 258 lie Lys Asn Thr Ala Ala Ser Asn LYS Ala Pro Ser Leu Val Ala Ile 1 5 10 Ala Val Arg Gly Cys Cys Tyr Asn Pro Ser Cys Trp Pro Lys Thr Tyr 25 Cys Ser <210> 259 <211> 161 <212> DNA <213> Conus musicus <220> <221> CDS <222> .(108) <400> 259 tct gat agc agg aat gtc gca atc gag gac aga gtg tct gac ctg cac 48 Ser ASP ser Arg Asn Val Ala Ile GlU ASP Arg va ISer ASP Leu His 1 5 10 tct atg ttc ttc gat gtt tct tgc tgt agc aat cct acc tgt aaa gaa 96 Ser met Phe Phe ASP Val Ser Cys Cys Ser Asn Pro Thr Cys Lys Glu 25 acg tat ggt tgt tgatcgttgg ttttgaagac gctgatgctc caggaccctc 148 Thr Tyr Gi y Cys tgaaccacga cgt 161 <210> 260 <211> 36 <212> PRT <213> Conus musicus <400> 260 Ser ASP Ser Arg Asn Val Ala Ile Glu ASP Arg V/al Ser ASP Leu His 1 5 10 Ser met Phe Phe ASP V/al Ser Cys Cys Ser Asn Pro Thr Cys Lys Glu 25 Thr Tyr Gly CyS <210> 261 <212> DNA <213> Conus musicus <220> <221> CDS <222> .(102) Page 89 179 PCT-AU rev. APP. txt <400> 261 tct gtt ggc agg aat att gca gtc gac gac aga ggg att ttc tct acg 48 Ser Val G] yArg Asn lie Ala Val ASP ASP Arg Gly lie Phe ser Thr 1 5 10 ctc ttc cat gct cat tgc tgt gcc aat ccc atc tgt aaa aac acg ccc 96 Leu Phe His Ala His Cys Cys Ala Asn Pro Ilie Cys LYS Asn Thr Pro 25 gyt tgt tgatctttgt tcttcaaaga cgctgctggc ccaggaccct ctgaaccacg 152 G y S acgt 156 <210> 262 <211> 34 <212> PRT <213> Conus musicus <400> 262 Ser Val Gly Arg Asn lie Ala Val ASP ASP Arg Gly Ilie Phe Ser Thr 1 5 10 Leu Phe His Ala His Cys Cys Ala Asn Pro Ile Cys Lys Asn Thr Pro 25 Gly Cys <210> 263 <211> 161 <212> DNA <213> Conus musicus <220> <221> CDS <222> (108) <400> 263 tcc gat ggc agg aat gtc gca atc gac gac: aga gtg tct gac ctg cac 48 Ser ASP Gy~y Arg Asn V/al Ala Ilie ASP ASP Arg Vay ier ASP Leu His 10 tct atg ttc ttc gat att gct tgc tgt aac: aat cct acc tgt aaa gaa 96 Ser met Phe Phe ASP lie Ala Cys Cys Asn Asn Pro Thr CyS Lys GlU 00020 25 acg tat g gt tgt tgatcgttgg ttttgaagac gctgatgctc caggaccctc 148 Thr Tyr GlyCys tgaaccacga cgt 161 <210> 264 <211> 36 <212> PRT <213> Conus musicus <400> 264 Ser ASP Gly Arg Asn Val Ala Ile ASP ASP Arg Val Ser ASP Leu His 1 5 10 Ser met Phe Phe ASP Ilie Ala Cys Cys Asn Asn Pro Thr Cys LYS Giu 25 Page 179PCT-AUrev.APP.tXt Thr Tyr Gly CyS <210> 265 <211> 161 <212> DNA <213> Conus musicus <220> <221> CDS <222> <400> 265 tct gat g c agg aat gtc gca atc gag gac aga. gtq tct gac ctg ctc Ser ASP Gy Arg Asn Val Ala Ile GlU ASP Arg Val Ser Asp Leu Leu 1 5 10 tct atg ctc ttc gat gtt gct tgc tgt agc aat cct gtc tgt aaa gaa Ser met Leu Phe ASP Val Ala Cys Cys Ser Asn Pro Val CYS LYS GlU 25 acg tat g t tgt tgatcgttgg ttttgaagac gctgatgctc caggaccctc Thr Tyr By CyS tgaaccacga cgt <210> 266 <211> 36 <212> PRT <213> conus musicus <400> 266 Ser ASP Gly Arg Asn Val Ala Ile GlU ASP Arg Val Ser ASP LeU Leu 1 5 10 Ser met Leu Phe ASP Val Ala Cys cys Ser Asn Pro Val CyS LYS GlU 25 Thr Tyr Gly CyS <210> 267 <211> 154 <212> DNA <213> conus betulinus <220> <221> CDS <222> <400> 267 tat gat g9c agg aat gct gcc gcc gac gac aaa gct ttt gac ctg ctg Tyr ASP Gly Arg Asn Ala Ala Ala ASP ASP LYS Ala Phe ASP LeU Leu 1 5 10 gct atg acc ata agg g a g a tgc tgt tcc tat cct ccc tgt atc gcg Ala met Thr Ile Arg My Gy CyS CYS Ser Tyr Pro Pro cys Ile Ala 25 agt aat cct aaa tgt gt ga aga cgc tgatgctcca ggaccctctg Ser Asn PrO LYS CyS G Y G y Arg Arg aaccacaacg t Page 91 48 96 148 161 48 96 143 154 179PCT-Aurev.APP .txt <210> 268 <211> 41 <212> PRT <213> Conus betulinus <400> 268 Tyr ASP Gly Arg Asn Ala Ala Ala ASP ASP LYS Ala Phe ASP Leu Leu 1 5 10 Ala met Thr Ile Ang Gly Gly Cys Cys Ser Tyr Pro Pro cys Ile Ala 25 ser Asn Pro LYS Cys Gly Gly Arg Arg <210> 269 <211> 151 <212> DNA <213> Conus lividus <220> <221> CDS <400> 269 ttt gat ggc agg aat gct gca ggc aac gcc aaa atg tcc: gcc ctg atg Phe ASP GMY Arg Asn Ala Ala Gly Asn Ala LYS met Ser Ala Leu met 1 5 10 gcc ctg acc atc agg g ga tgc tgt tcc cat cct gtc: tgt agc gcg atg Ala Leu Thr Ile Arg Gyy Cys Cys Ser His Pro \/al Cys Ser Ala met 25 agt cca atc tgt ggc tgaagacgct gatgccccag gaccctctga accacgacgt Ser Pro Ile Cys Gly a 0 s 09 0 9 0 *0 0 0000 Osseo <210> 270 <211> '37 <212> PRT <213> Conus <400> 270 Phe ASP Gly 1 Ala Leu Thr Ser Pro Ile lividus Arg Asn Ala Ala Gly Asn Ala LYS met Ser Ala Leu Met 5 10 Ile Arg Gly Cys Cys Ser His Pro Val Cys Ser Ala Met 20 25 Cys Gly <210> 271 <211> 196 <212> DNA <213> Conus musicus <220> <221> CDS <222> (165) <400> 271 atc aag aat gct gca gct gac gac aaa gca tct gac: ctg ctc tct cag 48 Page 92 179PCT-Aurev .APP .txt Ile Lys Asn Ala Ala Ala ASP ASP Lys Ala ser Asp Leu Leu Ser Gln 1 5 10 atc gtc agg aat gct gca tcc aat gac aaa ggg tct gac: ctg atg act 96 Ile Val Arg Asn Ala Ala Ser Asn ASP Lys Gly se r ASP Leu met Thr 25 ctt gcc ctc agg gga tgc tgt aaa aat cct tac tgt ggt gcg tcg aaa 144 Leu Ala LeU Arg Gly CyS CyS Lys Asn Pro Tyr Cys G 1y Ala Ser Lys 40 aca tat tgt g gt aga aga cgc tgatgctcca ggaccctctg aaccacgacg t 196 Thr Tyr Cys G ly Arg Arg Arg <210> 272 <211> <212> PRT <213> Conus musicus <400> 272 Ile Lys Asn Ala Ala Ala ASP ASP Lys Ala Ser ASP Leu Leu Ser Gin 1 5 10 Ile Val Arg Asn Ala Ala Ser Asn ASP Lys Gly Ser Asp Leu Met Thr 25 Leu Ala Leu Arg Gly CyS CyS Lys Asn Pro Tyr CyS Gly Ala Ser Lys 40 Thr Tyr Cys Gly Arg Arg Arg <210> 273 <211> 139 <212> DNA <213> Conus omaria <220> <221> CDS <222> (108) <400> 273 tctgatggca ggaatgccgc agcgtctgac ctgatggat ctg acc atc aag gg a 54 Leu Thr Ilie Lys Gly 1 tgc tgt tct tat cct ccc tgt ttc gcg act aat cca. gac tgt ggt cg a 102 Cys Cys Ser Tyr Pro Pro Cys Phe Ala Thr Asn Pro ASP CyS GyIy Arg 15 cga cgc tgatgctcca ggaccctctg aaccacgacg t 139 Arg Arg *<210> 274 <211> 23 <212> Cou omaria <400> 274 Thr Ilie Lys Gly Cys Cys Ser Tyr Pro Pro Cys Phe Ala Thr Asn 1 5 10 Pro ASP CyS Gly Arg Arg Arg Page 93 179PCT-AUrev .APP .txt <210> 275 <211> 126 <212> DNA <213> Conus radiatus <220> <221> CDS <222> (123) <400> 275 ttt gat g c Phe ASP GBy 1 gct atg acc Ala met Thr aat aat cct Asn Asn Pro agg aat Arg Asn 5 gcc gca gcc gac Ala Ala Ala ASP aaa g g gtct gaa Lys G ly Ser Glu ttg ctc Leu Leu agg g ga g ga tgc Arg Gly Gly Cys tgt Cys tcc tat cct ccc Ser Tyr Pro Pro tgt atc gca Cys ile Ala ctt tgt gct g a Leu Cys Ala G y aga cgc tga 126 Arg Arg <210> 276 <211> 41 <212> PRT <213> Conus radiatus <400> 276 Phe ASP Gly 1 Ala met Thr Asn Asn Pro Arg Asn Ala 5 Ala Ala ASP Lys Gly Ser Glu Leu Leu cys ile Ala val Arg Gly Gly Cys Cys 25 Ser Tyr Pro Pro Leu Cys Ala Gly Arg Arg <210> 277 <211> 126 <212> DNA <213> Conus radiatus <220> <221> CDS <222> .(123) <400> 277 ttt gat g~ Phe ASP G 1 c ag gaat y Arg Asn 5 gcc gca gcc gac Ala Ala Ala ASP tac Ty r 10 aaa g g gtct gaa Lys Gly Ser Glu ttg ctc Leu Leu gct atg acc Ala met Thr aat aat cct Asn Asn Pro gtc val 20 agg g ga g ga tgc Argl My Gly Cys tgt Cys 25 tcc tat cct ccc Ser Tyr Pro Pro tgt atc gca cys ile Ala ttt tgt gct Phe CyS Ala g ga aga cgc tga 126 Gly Arg Arg <210> 278 <211> 41 <212> PRT <213> Conus radiatus Page 94 179 PCT-AU rev. APP. tXt <400> 278 Phe ASP Gly Arg Asn Ala Ala Ala ASP Tyr LyS Gly Ser Glu Leu Leu 1 5 10 Ala Met Thr Val Arg Gly Gly Cys Cys Ser Tyr Pro Pro Cys le Ala 25 Asn Asn Pro Phe cys Ala Gly Arg Arg <210> 279 <211> 155 <212> DNA <213> Conus virgo <220> <221> CDS <222> .(114) <400> 279 tct tat gac agg tat gcc tcg ccc gtc gac aga gcg tct gcc ctg atc 48 Ser Tyr ASP Arg Tyr Ala Ser Pro Val ASP Arg Ala Ser Ala Leu Ile 1 5 10 gct cag gcc atc ctt cga gat tgc tgt tcc: aat cct ccc: tgt tcc caa 96 Ala Gin Ala Ilie Leu Arg ASP Cys Cys Ser Asn Pro Pro Cys Ser Gin 25 aat aat cca gac tgt atg taaagacgct gcttgctcca ggaccctctg 144 Asn Asn Pro ASP Cys met aaccacgacg t 155 <210> 280 <211> 38 <212> PRT <213> Conus virgo <400> 280 Ser Tyr ASP Arg Tyr Ala Ser Pro Val ASP Arg Ala Ser Ala Leu Ilie 1 5 10 Ala Gin Ala Ile Leu Arg ASP Cys Cys Ser Asn Pro Pro Cys Ser Gin *20 25 Asn Asn Pro ASP Cys met <210> 281 <211> 155 <212> DNA *<213> Conus virgo <220> <221> CDS .14 <400> 281 tct tat g gc agg tat gcc tca ccc gtc gac aga gcg tct gcc ctg atc 48 Ser Tyr G ly Arg Tyr Ala Ser Pro val ASP Arg Ala Ser Ala Leu lie 1510 gct cag gcc atc ctt cga gat tgc tgc tcc: aat cct cct tgt gcc cat 96 Page 179 PCT-AU rev. APP.tXt Ala Gin Ala Ile Leu Arg ASP Cys CySsSer Asn Pro Pro CyS Ala His 25 aat aat cca gac tgt cgt taaagacgct gcttgctcca ggaccctctg Asn Asn Pro ASP Cys Arg aaccacgacg t <210> 282 <211> 38 <212> PRT <213> Conus Virgo <400> 282 Ser Tyr Gly Arg Ty Ala ser Pro Val ASP Arg Ala Ser Ala Leu Ilie 1 5 10 Ala Gin Ala Ilie Leu Arg ASP Cys CySsSer Asn Pro Pro Cys Ala His 25 Asn Asn Pro ASP Cys Arg <210> 283 <211> 126 <212> DNA <213> Conus achatinus <220> <221> CDS <222> (123) <400> 283 tct gat ggc agg aat gcc gca gcc aac gac aaa gcg tct ggc atg agc Ser ASP GBy Arg Asn Ala Ala Ala Asn ASP LYS Ala Ser G Iy met Ser 1 5 10 gcg ctg gcc gtc aat gaa tgc tgt acc aac cct gtc tgt cac gcg gaa Ala Leu Ala Val Asn Glu Cys Cys Thr Asn Pro \/al CyS His Ala Giu 25 cat caa gaa ctt tgt gct aga aga cgc tga His Gin GiU Leu CyS Ala Arg Arg Arg 48 96 126 <210> 284 <211> 41 <212> PRT <213> Conus <400> 284 Ser ASP Gly 1 Ala Leu Ala His Gin Giu 35 <210> 285 <211> 126 <212> DNA achati nus Arg Asn Ala Ala Ala Asn ASP Lys Ala Ser Gly met Ser 5 10 Val Asn Glu cys Cys Thr Asn Pro Val Cys His Ala Giu 20 25 Leu Cys Ala Arg Arg Arg Page 96 179PCT-AU rev. APP. tXt <213> Conus achatinus <220> <221> CDS <222> .(123) <400> 285 tct gat ggc agg aat gcc gca gcc aac gac aaa gcg tct gac gtg atc Ser ASP Gyy Arg Asn Ala Ala Ala Asn ASP Lys Ala Ser ASP Va] Ilie 1 5 10 acg ctg gcc ctc aag gga tgc tgt tcc aac cct gtc tgt cac ttg gag Thr Leu Ala Leu Lys Gly Cys Cys Ser Asn Pro Val Cys His Leu Glu 25 cat tca aac ctt tgt g gt aga aga cgc tga His Ser Asn Leu Cys Gyy Arg Arg Arg 48 96 126 <210> 286 <211> 41 <212> PRT <213> Conus <400> 286 Ser Asp Gly 1 Thr Leu Ala His Ser Asn achati nus Arg Asn Ala Ala Ala Asn ASP Lys Ala Ser ASP Val Ile 5 10 Leu Lys Gly Cys Cys Ser Asn Pro Val Cys His LeU GlU 25 Leu Cys Gly Arg Arg Arg 0* <210> 287 <211> 126 <212> DNA <213> Conus achatinus <220> <221> CDS <222> (123) <400> 287 tct gat ggc agg aat gcc gca gcc aac gac aaa gcg tct ggc atg agc Ser ASP Gly Arg Asn Ala Ala Ala Asn ASP LYS Ala Ser Gly met Ser 1 5 10 gcg ctg gcc gtc aat gaa tgc tgt acc aac cct gtc tgt cac gtg gaa Ala Leu Ala Val Asn Glu Cys Cys Thr Asn Pro Val Cys His Val Glu 25 cat caa gaa ctt tgt gct aga aga cgc tga His Gln Glu Leu Cys Ala Arg Arg Arg 35 <210> 288 <211> 41 <212> PRT <213> Conus achatinus <400> 288 Ser Asp Gly Arg Asn Ala Ala Ala Asn ASP Lys Ala Ser Gly met Ser 1 5 10 Page 97 48 96 126 179PCT-AUrev .APP .txt Ala Leu Ala Val Asn Glu Cys Cys Thr Asn Pro Val Cys His Val Glu 25 His Gin Glu Leu Cys Ala Arg Arg Arg <210> 289 <211> 220 <212> DNA <213> Conus ammiralis <220> <221> CDS <222> (180) <400> 289 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc 48 met Phe Thr va I Phe Leu Leu Val Val LeU Ala Thr Thr Val Val Ser 1 5 10 ttc act tca gat cgt gca ttt cgt ggc agg aat gcc gca gcc aaa gcg 96 Phe Thr Ser ASP Arg Ala Phe Ar g Gyy A rg Asn Ala Ala Ala LYS Ala 25 tct ggc ctg gtc ggt ctg acc gac aag agg caa gaa tgc tgt tct tat 144 Ser GBY Leu Val G~y Leu Thr ASP Lys Arg Gin Glu Cys Cys Ser Tyr 40 cct gcc tgt aac cta gat cat cca gaa ctt tgt ggt tgaagacgct 190 Pro Ala Cys Asn Leu ASP His Pro Glu Leu Cys G ly 55 gatgctccag gaccctctga accacgacgt 220 <210> 290 <211> <212> PRT <213> Conus ammiralis <400> 290 met Phe Thr Val Phe LeU Leu val Val Leu Ala Thr Thr Val Val ser 1 5 10 Phe Thr Ser ASP Arg Ala Phe Arg Gly Arg Asn Ala Ala Ala Lys Ala 25 Ser Gly Leu Val Gly Leu Thr ASP LYS Arg Gln Glu Cys Cys Ser Tyr 35 40 Pro Ala Cys Asn LeU ASP His Pro Glu Leu Cys Gly 55 <210> 291 *<211> 223 <212> DNA <213> Conus ammiralis <220> <221> cDS <222> (192) <400> 291 atg ttc acc gt gttt ctg ttg gtt gtc ttg gca acc act gtc gtt tcc 48 met Phe Thr va] Phe Le U Leu Val Val LeU Ala Thr Thr Val Val Ser 1 5 10 Page 98 179PCT-AUrev .APP. txt tcc act tca ggt cgt cgt gca ttt cgt ggc agg aat gcc gca gcc aaa 96 ser Thr Ser Gly Arg Arg Ala Phe Arg G]y Arg Asn Ala Ala Ala LYS 25 gcg tct ga ctg gtc ggt ctg act gac agg aga cca gaa tgc tgt agt 144 Ala Ser G] y Leu Val GMy Leu Thr ASP Arg Arg Pro Glu Cys cySsSer 40 gat cct cgc tgt aac tcg act cat cca gaa ctt tgt ggt gga aga cgc 192 ASP Pro Arg Cys Asn Ser Thr His Pro Glu Leu Cys Gly GI y Arg Arg 55 tgatgctcca ggaccctctg aaccacgacg t 223 <210> 292 <211> 64 <212> PRT <213> Conus ammiralis <400> 292 met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val val Ser 1 5 10 Ser Thr Ser Gly Arg Arg Ala Phe Ang Gly Arg Asn Ala Ala Ala Lys 25 Ala Ser Gly Leu Val Gly Leu Thr ASP Arg Arg Pro Glu Cys CySsSer 40 ASP Pro Arg Cys Asn Ser Thr His Pro Glu Leu Cys Gly Gly Arg Arg 55 <210> 293 <211> 151 <212> DNA <213> Conus arenatus <220> <221> CDS <222> (120) 400 293 c g 0 at g c agg aat gcc gca gcc aac gcg ttt gac ctg atc gat ctg 48 Ser ASP GMy Arg Asn Ala Ala Ala Asn Ala Phe ASP Leu Ile ASP Leu 1 5 10 acc gcc agg cta aat tgc tgt atg att ccc ccc tgt tgg aag aaa tat 96 Thr Ala Arg Leu Asn Cys Cys met Ile Pro Pro Cys Trp Lys Lys Tyr 0:20 25 gyga gac aga tgt agt gaa gta cgc tgatgctcca ggaccctctg aaccacgacg 150 Gly ASP Arg Cys Ser Glu Val Arg t 151 <210> 294 <211> <212> PRT <213> Conus arenatus <400> 294 Ser ASP Gly Arg Asn Ala Ala Ala Asn Ala Phe ASP Leu Ile ASP Leu 1 5 10 Page 99 179 PCT-AU rev. APP .txt Thr Ala Arg Leu Asn cys cys met lie Pro Pro Cys Trp Lys Lys Tyr 25 Gly ASP Arg cys Ser Glu \/al Arg <210> 295 <211> 126 <212> DNA <213> Conus arenatus <220> <221> CDS <222> (93) <400> 295 tct gat ggc agg aat gcc gca cgc aaa gcg ttt ggc tgc tgc gac tta 48 Ser ASP GMy Arg Asn Ala Ala Arg Lys Ala Phe Gly Cys Cys ASP Leu 1 5 10 ata ccc tgt ttg gag aga tat ggt aac aga tgt aat gaa gtg cac 93 Ile Pro Cys Leu GlU Arg Tyr GI y Asn Arg Cys Asn GlU va? His 25 tgatgctcca ggaccctctg aaccacgcga cgt 126 <210> 296 <211> 31 <212> PRT <213> Conus arenatus <400> 296 Ser ASP Gly Arg Asn Ala Ala Arg LyS Ala Phe Gly Cys Cys ASP Leu 1 5 10 Ile Pro Cys LeU Glu Arg Tyr Gly Asn Arg Cys Asn GlU Val His 25 <210> 297 211 151 <212> DNA <213> Conus arenatus <220> <221> <22 (1).(20 <400> 297 tct gat ggc agc aat gcc gca gcc aac gag ttt gac ctg atc gct ctg 48 Ser ASP Gly Ser Asn Ala Ala Ala Asn Glu Phe ASP Leu Ile Ala Leu 1 5 10 acc gcc agg cta g gt tgc tgt aac gtt aca ccc tgt tgg gag aaa tat 96 T hr Ala Arg Leu G ly Cys Cys Asn Val Thr Pro Cys Trp Glu LyS Tyr 25 g ga gac aaa tgt aat gaa gta cgc tgatgcttca ggaccctctg aaccacgacg 150 Gly ASP LyS Cys Asn Glu Val Arg t 151 <210> 298 Page 100 179PCT-AUrev.APP. tXt <211> <212> PRT <213> Conus arenatus <400> 298 Ser Asp Gly 1 Thr Ala Arg Gly Asp LyS Ser Asn Ala 5 Leu Gly Cys Ala Ala Asn Cys Asn Val 25 Phe Asp Leu Ile Ala Leu Thr Pro CyS Trp Glu Lys Tyr Cys Asn Glu Val Arg <210> 299 <211> 148 <212> DNA <213> Conus arenatus <220> <221> CDS <222> (117) <400> 299 tct gat g c Ser Asp GMy 1 acc atc agg Thr Ile Arg cca cac gtt Pro His Val agg aat Arg Asn 5 gtc gca gca aaa Val Ala Ala Lys ttt cac cgg atc Phe His Arg Ile PC9 C9cg G ly Arg gaa tgc tgt tcc Glu cys cySsSer aat Asfl cct gcc tgt agg Pro Ala Cys Arg gt g aat aat Val ]Asn A sn tgt aga cga cgc CyS Arg Arg Arg tgatgctcca ggaccctctg aaccacgacg t <210> 300 <211> 39 <212> PRT <213> Conus arenatus 0* 0e <400> 300 Ser Asp Gly 1 Thr Ile Arg Pro His Val Arg Asn Val 5 Asp Glu Cys 20 Ala Ala LyS Ala Phe 10 Cys Ser Asn Pro Ala 25 His Arg Ile Gly Arg CyS Arg Val Asn Asn CyS Arg Arg Arg <210> 301 <211> 151 <212> DNA <213> Conus arenatus <220> <221> CDS <222> (120) <400> 301 tct gat g gc agg aat gcc gca gcc aac Ser Asp Gly A rg Asn Ala Ala Ala Asn 1 5 gcg ttt gac ctg atg cct ctg 48 Ala Phe Asp Leu met Pro Leu 10 Page 101 acc gcc agg Thr Ala Arg aaa gac aga Lys Asp Arg t cta Leu aat tgc tgt Asn Cys cys 179PCT-AUrev.APP. txt agc att ccc gg c tgt tgg aac gaa tat Ser Ilie Pro Gly Cys Trp Asn Glu Tyr 25 tgt agt aaa gta Cys Ser Lys V/al cg c Arg tgatgctcca ggaccctctg aaccacgacg 96 150 151 <210> <211> <212> <213> 302

PRT

Conus arenatus <400> 302 Ser Asp Gly .1 Thr Ala Arg LYS Asp Arg Arg Asn Ala 5 Leu Asn Cys Ala Ala Asn Cys Ser Ilie 25 Al a 10 Phe Asp Leu Met Pro Leu Asn Glu Tyr Pro Gly Cys Trp Cys Ser LYS Val <210> <211> <212> <213> 303 157

DNA

Conus auri siacus <220> <221> CDS <222> (126) <400> 303 tctgatggca ggaatgccgc agccgacgac aaagcgtctg acctggtcgc t ctg gtc Leu VIal 1 tac ttt aat aat cca Tyr Phe Asn Asn Pro @e.0 :0.

4*0 gtc agg gga \/al Arg G ly gy9a tgc tgt tcc G IY Cys Cys Ser cac cct gtc tgt His Pro Val Cys 10 105 157 caa atg Gi n met tgt cgt g ga aga CyS Arg Gly Arg cg c Arg tgatgctcca ggaccctctg aaccacgacg t

AS

5 S

A

*5@A 5 A. S A A S 6S

S

*SSe**

A

*A

0 A 5 <210> 304 <211> <212> PRT <213> Conus <400> 304 Leu Val Val 1 Asn Pro Gin <210> 305 <211> 157 <212> DNA <213> Conus auri siacus Arg Gly Gly Me 5y r l r r cys Cys Ser His Pro Val Cys Tyr Phe Asn 10 20 auri si acus Page 102 179PCT-Aurev.APP .txt <220> <221> CDS <222> (126) <400> 305 tctgatggca ggaatgccgc agccgacgac aaagcgtctg acctggtcgc t ctg gcc Leu Ala 1 gtc agg gga gga tgc tgt tcc cac cct gtc tgt aac ttg aat aat cca Val Arg G y Gly Cys Cys Ser His Pro \/al Cys Asn LeU Asn Asfl Pro 10 caa atg tgt cgt g ga aga cgc tgatgctcca ggaccctctg aaccacgacg t Gin met Cys Arg Gly A rg Arg <210> 306 <211> <212> PRT <213> Conus <400> 306 Leu Ala Val 1 Asn Pro Gin auri siacus Arg Gly Gly Cys Cys Ser His Pro Val Cys Asn Leu Asn 5 10 met Cys Arg Gly Arg Arg 0.00* 0. 0 0.0.

<210> 307 <211> 157 <212> DNA <213> Conus betulinus <220> <221> CDS <222> (117) <400> 307 ttt cgt ggc agg aat ccc gca gcc aac gac aaa agg tct gac ctg gcc Phe Arg GMy Arg Asn Pro Ala Ala Asn Asp Lys Arg ser Asp Leu Ala 1 5 10 gct ctg agc gtc agg gga gga tgc tgt tcc cat cct gcc tgt agc gtg Ala Leu Ser Val Arg GSy GBy Cys Cys Ser His Pro Ala Cys Ser Val 25 act cat cca gag ctt tgt ggc tgaagacgct gatgccccag gaccctctga Thr His Pro Glu Leu Cys Gly accacgacgt <210> 308 <211> 39 <212> PRT <213> Conus betulinus <400> 308 Phe Arg Gly Arg Asn Pro Ala Ala Asn Asp Lys Arg Ser Asp Leu Ala 1 5 10 Ala Leu Ser Val Arg Gly Gly Cys Cys Ser His Pro Ala Cys Ser Val 25 Page 103 48 96 147 157 179 PCT-AU rev. APP .txt Thr His Pro Giu Leu Cys Gly <210> 309 <211> 151 <212> DNA <213> conus betulinus <220> <221> CDS <222> (120) <400> 309 tct gat g c Ser AS p Gly 1 acc atc agg Thr Ilie Arg caa gac ctt Gin ASP Leu t <210> 310 <211> <212> PRT <213> Conus <400> 310 Ser ASP Giy 1 Thr Ilie Arg Gin ASP Leu <210> 311 <211> 114 <212> DNA <213> Conus ggaat Gy Asfl 5 gcc gca gcc aaa Aia Ala Aia Lys gcg Al a 10 tct gac ctg atc Ser ASP Leu Ilie gct cag Ala Gin gya gg a tg ctgt tcc Gi y Cys Cys Ser tat Ty r 25 cct gcc tgt agc Pro Ala Cys Ser gt ggaa cat val GlU His tgt gat g ga aga Cys ASP G ly Arg cg C Arg tgatgctcca ggaccctctg aaccacgacg 150 betul inus Gly Asn Ala 5 Ala Ala LYS Al a 10 Ser ASP Leu Ilie Ala Gin Gly Gly Cys CySsSer Tyr 25 Pro Ala Cys Ser Val GIlU Hi S Cys ASP Gly Arg caracteri sti cus Arg <220> <221> CDS <400> 311 tct tat g Ser Tyr G 1 c ag gaat y Arg Asn 5 gcc gca gcc aaa Ala Ala Ala Lys gcg Al a 10 ttt gaa gtg agt Phe Glu Val ser tgc tgt Cys Cys gtc gtt cgc Val Val Arg ccc Pro 20 tgt tgg att cgc CYS Trp Ile Arg caa gag gaa tgt Gin Glu Glu Cys ctt gaa gca Leu Glu Ala gat ccc agg acc ctc tga ASP Pro Arg Thr Leu Page 104 179 PCT-AU rev .APP. txt <210> 312 <211> 37 <212> PRT <213> Conus caracteristicus <400> 312 ser Tyr Gly Arg Asn Ala Ala Ala Lys Ala Phe Glu Val Ser cys Cys 1 5 10 Val Val Arg Pro Cys Trp Ile Arg Tyr Gln Glu Glu Cys Leu Glu Ala 25 ASP Pro Arg Thr Leu <210> 313 <211> 123 <212> DNA <213> Conus caracteristicus <220> <221> CDS <222> (120) <400> 313 tct gat ggc agg aat gcc gca gcc aac gcc ctt gac ctg atc act ctg Ser ASP GBy A rg Asn Ala Ala Ala Asn Ala Leu ASP Leu Ile Thr Leu 1 5 10 atc gcc agg caa aat tgc tgt agc att ccc ggc: tgt tgg gag aaa tat Ile Ala Arg Gln Asn Cys Cys Ser Ile Pro Gi y Cys Trp Glu Lys Tyr 25 gyJa ga c aaa tgt agt gaa gta cgc tga GyASP Lys CySsSer Glu Val Arg 48 96 123 <210> 314 <211> <212> PRT <213> Conus <400> 314 Ser ASP Gly 1 Ile Ala Arg Gly ASP LYS 35 caracteri sti cus Arg Asn Ala Ala Ala Asn Ala Leu ASP Leu Ile Thr Leu 5 10 Gln Asn cys cys Ser Ile Pro Gly CyS Trp Glu Lys Tyr 25 cys Ser Glu Val Arg <210> 315 <211> 154 <212> DNA <213> Conus catus <220> <221> CDS <222> (123) <400> 315 tct gat ggc agg aat gaa gca gcc aac gac gaa, gcg tct gac gt~ atc Ser ASP Gly Arg Asn Glu Ala Ala Asn ASP GlU Ala Ser ASP va? Ile 1 5 10 Page 105 179PCT-AUrev .APP. txt gag ctg gcc ctc aag gga tgc tgt tcc aac cct gtc tgt cac ttg gag 96 Glu LeU Ala Leu LYS Gly Cys CySsSer Asn Pro Val Cys His Leu Glu 25 cat cca aac gct tgt g gt aga aga cgc tgatgctcca ggaccctctg 143 H-11 Pro Asn Ala Cys G]Y Arg Arg Arg aaccacgacg t 154 <210> 316 <211> 41 <212> PRT <213> Conus catus <400> 316 Ser ASP Gly Arg Asn Glu Ala Ala Asn ASP Glu Ala Ser ASP Val Ile 1 5 10 Glu Leu Ala Leu Lys Gly Cys Cys Ser Asn Pro 'ial Cys His Leu Glu 25 His Pro Asn Ala Cys Gly Arg Arg Arg <210> 317 <211> 154 <212> DNA <213> Conus catus <220> <221> CDS <222> (123) <400> 317 tct gat ggc agg aat gcc gca gcc aac gac aaa gcg tct gac ctg gtc 48 Ser ASP GMY Arg Asn Ala Ala Ala Asn ASP Lys Ala Ser ASP Leu Val 1 5 10 gct ctg gcc gtc agg gga tgc tgt tcc aac cct atc tgt tac ttt aat 96 Ala Leu Ala 'ial Arg Gly Cys CySsSer Asn Pro Ile Cys Tyr Phe Asn 25 aat cca cga att tgt cgt g ga aga cgc tgatgctcca ggaccctctg 143 Asn Pro Arg Ile Cys Arg Gly Arg Arg aaccacgacg t 154 <210> 318 <211> 41 <212> PRT <213> Conus catus *<400> 318 Ser ASP Gly Arg Asn Ala Ala Ala Asn ASP Lys Ala Ser ASP Leu Val 1 5 10 Ala Leu Ala Val Arg Gly Cys CySsSer Asn Pro Ile Cys Tyr Phe Asn 25 Asn Pro Arg Ilie Cys Arg Gly Arg Arg *35 40 Page 106 179PCT-AU rev. APP.txt <210> 319 <211> 111 <212> DNA <213> Conus episcopatus <220> <221> CDS <222> .(108) <400> 319 tct cat ggc agg aat gcc gca cgc aaa gcg tct gac ctg atc gct ctg 48 Ser His Gly Arg Asn Ala Ala Arg Lys Ala Ser ASP Leu le Ala Leu 1 5 10 acc gtc agg gaa tgc tgt tct cag cct ccc tgt cgc tgg aaa cat cca 96 Thr Val Arg Giu Cys CyS Ser Gin Pro Pro Cys Arg Trp LYS His Pro 25 gaa ctt tgt agt tga11 Giu Leu Cys Ser <210> 320 <211> 36 <212> PRT <213> Conus episcopatus <400> 320 Ser His Gly Arg Asn Ala Ala Arg LYS Aia Ser ASP Leu le Aia Leu 1 5 10 Thr Val Arg Giu Cys Cys Ser Gin Pro Pro Cys Arg Trp LYS His Pro 25 Glu Leu Cys Ser <210> 321 <211> 151 <212> DNA <213> Conus geographus <220> <221> CDS <222> .(120) tctgatg cagg aat gac gca gcc aaa gcg ttt gac ctg ata tct tcg 48 Ser ASP M Arg Asn ASP Aia Aia Lys Aia Phe ASP Leu Ilie Ser Ser 1 5 10 acc gtc aag aaa gga tgc tgt tcc cat cct gcc tgt gcg ggg aat aat 96 Thr Val Lys Lys Gy yCYS CySsSer His Pro Ala Cys Aia Gly Asn Asn 25 caa cat att tgt g g c cga aga cgc tgatgctcca ggaccctctg aaccacgacg 150 Gin His Ilie Cys G] y Arg Arg Arg t 151 <210> 322 <211> <212> PRT Page 107 179PCT-AUrev.APP.txt <213> Conus geographus <400> 322 Ser ASP Gly Arg Asn ASP Ala Ala Ls Ala Phe ASP Leu Ile Ser Ser 1 5 10 Thr Val LYS Lys Gly CyS cys Ser His Pro Ala CyS Ala Gly Asn Asn 25 ln His Ile Cys Gly Arg Arg Arg <210> 323 <211> 154 <212> DNA <213> Conus geographus <220> <221> CDS <222> <400> 323 tct gat g c agg aat gcc gca gcc aac gac caa gcg tct gac ctg atg 48 Ser ASP Gyy Arg Asn Ala Ala Ala Asn ASP Gln Ala Ser ASP Leu met 1 5 10 gctgcgac gt ag ga tgc tgt gcc gtt cct tcc tgt cgc ctc cgt 96 Alagc Ala ThrVal Ag Gyqy CyS CyS Ala Val Pro Ser CyS Arg LeU Arg 25 aat cca gac ctt tgt g t gagacctagtcagactt 4 Asn Pro ASP Leu Cys Gyy Gyy Gyy Argca gaccftg14 aaccacgacg t 154 <210> 324 <211> 41 <212> PRT <213> onus geographus Ser ASP Gly Arg Asn40> 2 Ala Ala Ala Asn ASP Gln Ala Ser ASP Leu met 1 5 10 Ala Ala Thr Val Arg Gly CyS Cys Ala Val Pro Ser CYS Arg LeU Arg 25 Asn Pro ASP Leu CyS Gly Gly GlY Arg <210> 325 <211> 120 <212> DNA <213> onus imperialis <220> <221> CDS <222> (1)..117) <400> 325 ctt gat gaa agg aat gcc gca gcc gac gac aaa gcg tct gac ctg atc 48 SLeU ASP GlU Arg Asn Ala Ala Ala ASP ASP LYS Ala Ser ASP Leu Ile 1 5 10 Page 108 gct caa atc Ala Gin lie aat aat cca Asn Asn Pro <210> 326 <211> 39 <212> PRT <213> Conus <400> 326 Leu ASP GlU 1 Ala Gin Ilie Asn Asn Pro 179PCT-Au rev. APP.tXt gtc agg aga g ga tgc tgt tcc cat cct gcc tgt aac gtg 96 Val Arg Arg GMy Cys Cys Ser His Pro Ala CyS Asn vaI 25 cac att tgt ggt tga 120 His Ilie Cys G ly imperialis Arg Asn Ala Ala Ala ASP ASP Lys Ala Ser ASP Leu Ile 5 10 Val Arg Arg Gly Cys CySsSer His Pro Ala Cys Asn Val 25 His Ilie Cys Gly <210> 327 <211> 142 <212> DNA <213> Conus lividus <220> <221> CDS <400> 327 tct gat ggc agg aat act gca gcc aaa gtc aaa tat tct aag acg ccg Ser ASP G~y Arg Asn Thr Ala Ala Lys Val Lys Tyr Ser Lys Thr Pro 1 5 10 gag gaa tgc tgt ccc aat cct ccc tgt ttc gcg aca aat tcg gat att Giu Giu Cys Cys Pro Asn Pro Pro Cys Phe Ala Thr Asn Ser ASP Ilie 25 ggc gya aa cgc tgatgctcca ggaccctctg aaccacgacg t CyS Gly GyAgArg

*S.

SO

S

0 5 <210> 328 <211> 37 <212> PRT <213> Conus <400> 328 Ser Asp Gly 1 Giu Giu Cys CyS Gly Gly lividus Arg Asn Thr Ala Ala Lys Val Lys Tyr Ser LYS Thr Pro 5 10 Cys Pro Asn Pro Pro Cys Phe Ala Thr Asn Ser ASP Ilie 20 25 Arg Arg <210> 329 <211> 157 <212> DNA <213> Conus lividus Page 109 179PCT-AUrev .APP.txt <220> <221> CDS <222> .(117) <400> 329 tct aat ggc agg aat gcc gca gcc aaa ttc aaa gcg cct gcc ctg atg 48 Ser Asn Gly Ang Asn Ala Ala Ala Lys Phe LYS Ala Pro Ala Leu met 1 5 10 aag cgg acc gtc agg gat gct tgc tgt tca gac cct cgc tgt tcc ggg 96 Lys Arg Thr Val Arg ASP Ala Cys Cys Sen ASp Pro Arg Cys Ser G ly 25 aaa cat caa gac ctg tgt ggc tgaagacgct gatgctccag gaccctctga 147 Lys His Gln ASP Leu Cys Gly accacgacgt 157 <210> 330 <211> 39 <212> PRT <213> Conus lividus <400> 330 Ser Asn Gly Arg Asn Ala Ala Ala LYS Phe LYS Ala Pro Ala Leu met 1 5 10 Lys Arg Thr Val Arg ASP Ala Cys Cys Sen ASP Pro Arg Cys Ser Gly 25 LYS His Gln ASP Leu Cys Gly <210> 331 <211> 157 <212> DNA <213> Conus lividus <220>CS <221 <222> (117) <400> 331 tct aat gg c agg aat gcc gca gcc aaa ttc aaa gcg cct gcc ctg atg 48 Sen Asn Gyy Ang Asn Ala Ala Ala LYS Phe Lys Ala Pro Ala Leu met 1 5 10 gag ctg acc gtc agg gaa gat tgc tgt tca gac cct cgc tgt tcc gtg 96 Glu LeU Thr Val Ang Glu ASP Cys Cys Ser ASP Pro Ang Cys Sen Va] 25 gg a cat caa gac ctg tgt ggc tgaagacgct gatgctccag gaccctctga 147 Gly HiS Gln ASPLeu CyS Gly *.00 accacgacgt 157 <210> 332 <211> 39 <212> PRT <213> Conus lividus <400> 332 Page 110 179PCT-AU rev. APP.tXt Ser Asn Gly Arg Asn Ala Ala Ala Lys Phe Lys Ala Pro Ala Leu met 1 5 10 Glu Leu Thr val Arg Glu ASP Cys Cys Ser ASP Pro Arg Cys Ser VIal 25 Gly His Gln ASP Leu Cys Gly <210> 333 <211> 157 <212> DNA <213> Conus lividus <220> <221> CDS <222> .(126) <400> 333 gca ttt gat ggc agg aat gct gca gcc agc gac aaa gcg tcc gag ctg 48 Ala Phe ASP Gyy Arg Asn Ala Ala Ala Ser ASP Lys Ala Ser Glu Leu 1 5 10 atg gct ctg gcc gtc agg gga tgc tgt tcc cat cct gcc tgt gct ggg 96 met Ala Leu Ala Val Arg Gly Cys Cys Ser His Pro Ala Cys Ala G ly 25 agt aat gca cat atc tgt g gc aga aga cgc tgatgctcca ggaccctctg 146 Ser Asn Ala His Ile Cys Gly Arg Arg Arg aaccacgacg t 157 <210> 334 <211> 42 <212> PRT <213> Conus lividus <400> 334 Ala Phe ASP Gly Arg Asn Ala Ala Ala Ser ASP LYS Ala Ser Glu Leu 1 5 10 1 met Ala LeU Ala Val Arg Gly Cys Cys Ser His Pro Ala Cys Ala Gly 25 Ser Asn Ala His Ile Cys Gly Arg Arg Arg <210> 335 <211> 157 <212> DNA <213> Conus lividus <220> <221> CDS <222> .(117) <400> 335 tct aat g c agg aat gcc gca gcc aaa ttc aaa gcg cct gcc ctg atg 48 ser Asn Gly Arg Asn Ala Ala Ala Lys Phe LYS Ala Pro Ala Leu met 1 5 10 aag ctg acc gtc agg gag gat tgc tgt tca gac cct cgc tgt tcc gtg 96 Lys LeU Thr Val Arg Glu ASP Cys Cys Ser ASP Pro Arg Cys Ser Va] 25 Page 111 179PCT-AU rev. APP.tXt gac atg tgt ggc tgaagacgct gatgctccag gaccctctga ASP met Cys Gyy gyga cat caa G ly His Gin atcacgacgt <210> 336 <211> 39 <212> PRT <213> Conus <400> 336 Ser Asn Gly 1 LYS Leu Thr Gly His Gin 147 157 lividus Arg Asn Ala Ala Ala LYS Phe Lys Ala Pro Ala Leu Met 5 10 V/al Arg Glu Asp Cys Cys Ser Asp Pro Arg Cys Ser Val 25 ASP met CyS Gly <210> 337 <211> 154 <212> DNA <213> Conus lividus <220> <221> CDS <222> .(114) <400> 337 ttt gaa tgc agg aat Phe Glu CyS Arg Asn 1 5 gct ctg act gtc agg Ala Leu Thr Val Arg aat cca cat atc tgc Asn Pro His lie Cys accacgacgt <210> 338 <211> 38 <212> PRT <213> Conus lividus <400> 338 Phe Glu Cys Arg Asn 1 5 Ala LeU Thr Val Arg 20 Asn Pro His Ilie Cys gct gca gg c aac gac aaa gcg act gac ctg atg Ala Ala Gly Asn ASP Lys Ala Thr ASP Leu met 10 pga tgc tgt tcc cat cct gcc tgt gct gqgg aat Gi y Cys CySsSer His Pro Ala Cys Al a Gly Asn 25 g~c tgaagacgct gatgctccag gaccctctga Ala Ala Gly Asn ASP Lys Ala Thr ASP Leu met 10 Gly Cys Cys Ser His Pro Ala Cys Ala Gly Asn 25 Gi y <210> 339 <211> 154 <212> DNA Page 112 179 PCT-AU rev. APP.tXt <213> Conus lividus <220> <221> CDS <222> .(114) <400> 339 ttt gat gg c agg aac gcc gca gcc aac aac aaa gcg act gat ctg atg Phe Asp G] y Arg Asn Ala Ala Ala Asn Asn LYS Ala Thr Asp Leu met 1 5 10 gct ctg act gtc aga gga tgc tgt ggc aat cct tca tgt agc atc cat Ala Leu Thr Val Arg Gly cys cys Gly Asn Pro Ser cys Ser Ile His 25 att cct tac gtt tgt aat tagagacact gatgctccag gaccctctga ile Pro Tyr 'ial cys Asn accacgacgt <210> 340 <211> 38 <212> PRT <213> Conus lividus <400> 340 Phe Asp Gly Arg Asn Ala Ala Ala Asn Asn Lys Ala Thr Asp Leu met 1 5 10 Ala Leu Thr Val Arg Gly Cys cys Gly Asn Pro Ser cys Ser Ile His 25 Ile Pro Tyr Val cys Asn <210> 341 <211> 157 <212> DNA <213> Conus lividus <220> <221> CDS <222> (126) <400> 341 tct aat ggc agg aat gcc gca gcc aaa ttc aaa gcg cct gcc ctg atg Ser Asn Gly Arg Asn Ala Ala Ala Lys Phe LYS Ala Pro Ala Leu met 1 5 10 aag cgg acc gac agc gaa gaa tgc tgt tta gac tct cgc tgt gcc ggg Lys Arg Thr Asp Ser GlU GlU Cys Cys Leu Asp Ser Arg Cys Ala Gly 20 25 caa cat caa gac ctg tgt ggc gga aga cgc tgatgctcca ggaccctctg Gln His Gln Asp Leu Cys Gly G] y Arg Arg aaccacgacg t <210> 342 <211> 42 <212> PRT <213> Conus lividus 48 96 144 154 48 96 146 Page 113 179 PCT-AU rev. APP.tXt <400> 342 ser Asn Gly Arg Asn Ala Ala Ala Lys Phe Lys Ala Pro Ala Leu met 1 5 10 Lys Arg Thr ASP ser Glu Glu Cys Cys LeU ASP ser Arg Cys Ala Gly 25 Gin His Gin ASP Leu Cys Gly Gly Arg Arg <210> 343 <211> 126 <212> DNA <213> Conus marmoreus <220> <221> CDS <222> .(123) <400> 343 tct gat ggc agg aat gcc gca gcc aag gac aaa gcg tct gac ctg gtc 48 Ser ASP GNY Arg Asn Ala Ala Ala Lys ASP Lys Ala Ser ASP Leu \Ial 1 5 10 gct ctg acc gtc aag gga tgc tgt tct aat cct ccc tgt tac gcg aat 96 Ala Leu Thr Val LYS Gi y Cys Cys Ser Asn Pro Pro Cys Tyr Ala Asn 25 aat caa gcc tat tgt aat g ga aga cgc tga 126 Asn Gln Ala Tyr CyS Asn G~y Arg Arg <210> 344 <211> 41 <212> PRT <213> Conus marmoreus <400> 344 Ser ASP Gly Arg Asn Ala Ala Ala Lys ASP Lys Ala Ser ASP Leu Val 1 5 10 Ala LeU Thr Val Lys Gly Cys CySsSer Asn Pro Pro CyS Tyr Ala Asn 5.20 25 Asn Gin Ala Tyr Cys Asn Gly Arg Arg <210> 345 <212> DNA <213> Conus marmoreus <220> <221> CDS <222> .(114) <400> 345 tct gat g gc agg aat gcc gca gcc aag gac aaa gcg tct gac ctg gtc 48 Ser ASP GMy Arg Asfl Al a Ala Ala Lys ASP Lys Ala Ser ASP Leu Val 1 5 10 gct ctg acc gtc aag g~ a tgc tgt tct cat cct gcc tgt agc gtg aat 96 Ala Leu Thr Val Lys GMy Cys Cys Ser His Pro Ala Cys Ser Va 1 Asn 25 Page 114 179PCT-AU rev. APP .txt aat cca gac att tgt g gt tga Asn Pro ASP Ile Cys GM1Y <210> 346 <211> 38 <212> PRT <213> Conus marmoreus <400> 346 ser ASP Gly Arg Asn Ala Ala Ala Lys ASP LYS Ala ser ASP Leu VIal 1 5 10 Ala Leu Thr Val Lys Gly CyS Cys Ser His Pro Ala Cys Ser \'al Asn 25 Asn Pro ASP Ile CyS Gly <210> 347 <2 11> 145 <212> DNA <213> Conus musicus <220> <221> CDS <222> .(114) <400> 347 tct gat g gc agg aat Ser ASP GMIY Arg Asn 1 5 agg gg a aaa tgc tgt Arg GlY Lys Cys Cys tac tgt tct g ga aga Tyr Cys Ser Gly Arg

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<210> 348 <211> 38 <212> PRT <213> Conus <400> 348 Ser ASP Gly 1 Arg Gly Lys Tyr Cys Ser musi cus Arg Asn 5 Cys Cys Gly Arg gct gca gcc aac aac: aaa gt ggct ttg acc atg Ala Ala Ala Asn Asn Lys va] Ala Leu Thr met 10 atc aat gat gcg tgt cgc tcg aaa cat cca cag Ile Asn ASP Ala Cys Arg Ser LYS His Pro Gin 25 cgc tgatactcca ggaccctctg aaccacgacg t Arg Ala Ala Ala Asn Asn Lys Val Ala Leu Thr met 10 Ile Asn ASp Ala Cys Arg ser Lys His Pro Gin 25 Arg Page 115 48 96 145 <210> 349 <211> 154 <212> DNA <213> Conus musicus <220> <221> CDS <222> .(123) 179PCT-AUrev .APP. txt <400> 349 tct gat ggc agg aat gct gca gcc aac gac aaa gtg tct gac cag atg Ser ASP G~y Arg Asn Ala Ala Ala Asn ASP LYS va] ser ASP Gin met 1 5 10 gct ctg gtt gtc agg gga tgc tgt tac aat att gcc tgt aga att aat Ala Leu Val Val Arg Gly Cys Cys Tyr Asn Ilie Ala Cys Arg lie Asn 25 aat cca cgg tac tgt cgt g ga aaa cgc tgatgttcca ggaccctctg Asn Pro Arg Tyr Cys Arg G y Lys Arg aaccacgacg t <210> 350 <211> 41 <212> PRT <213> Conus musicus <400> 350 Ser ASP Gly Arg Asn Ala Ala Ala Asn ASP Lys Val Ser ASP Gin met 1 5 10 Ala Leu Val Val Arg Giy Cys Cys Tyr Asn Ile Ala Cys Arg Ile Asn 25 Asn Pro Arg Tyr Cys Arg Giy Lys Arg <210> 351 <211> 154 <212> DNA <213> Conus obscurus <220> <221> CDS <222> (123) <400> 351 tctgaaggca ggaatgccgc agccaacgac aaagcgtctg acctgatggc t ctg aac Leu Asn 1 gtc agg gga tgc tgt tcc cat cct gtc tgt cgc ttc aat tat cca aaa Val Arg Gly Cys Cys Ser His Pro Val Cys Arg Phe Asn Tyr Pro LYS 5 10 tat tgt g gt g ga aga cgc tgatggtcca ggaccctctg aaccacgacg t Tyr CyS Gly G Y Arg Arg 48 96 143 154 9 9 9* 9.

9 99 99 9 9 9 9 99 9 9* 99 9 99 9.

9 9 9 9 <210> 352 <211> 24 <212> PRT <213> Conus <400> 352 Leu Asn 'ial 1 Pro LYS Tyr obscurus Arg Giy cys CySsSer His Pro Val Cys Arg Phe Asn Tyr 5 10 Cys Giy Gly Arg Arg Page 116 179PCT-AU rev .APP.txt <210> 353 <211> 151 <212> DNA <213> Conus obscurus <220> <221> CDS <222> (111) <400> 353 tctgatggcg ggaatgccgc agcaaaagcg tttgatctaa tcact ctg gcc ctc agg LeU Ala Leu Arg 1 gat gaa tgc tgt gcc agt cct ccc tgt cgt ttg aat aat cca tac gta ASP Glu Cys Cys Ala Ser Pro Pro Cys Arg Leu Asn Asn Pro Tyr \/al 10 15 tgt cat tgacgacgct gatgctccag gaccctctga accacgacgt Cys His <210> 354 <211> 22 <212> PRT <213> Conus obscurus <400> 354 LeU Ala Leu Arg ASP Glu Cys Cys Ala Ser Pro Pro Cys Arg LeU Asn 1 5 10 Asn Pro Tyr Val Cys His .0 0 0 a0 .S oo: :*go <210> 355 <211> 217 <212> DNA <213> Conus obscurus <220> <221> CDS <222> (186) <400> 355 atg ttc acc gt gttt ctg ttg gtt gtc ttg gca met Phe Thr val Phe Leu Leu Vial Vial LeU Ala 1 5 10 ccc act tca gat cgt gca tct gat agg agg aat Pro Thr Ser ASP Arg Ala Ser ASP Arg Arg Asn 25 ttt gac ctg aga tat tcg acc gcc aag aga gga Phe ASP LeU Arg Tyr Ser Thr Ala LyS Arg Gly 40 gtc tgt tgg cag aat aa-t gca gaa tac tgt cgt Val cys Trp Gln Asn Asn Ala Glu Tyr Cys Arg rL taatgctcca ggaccctctg aaccacgacg t <210> 356 <211> 62 <212> PRT acc Th r gcc Al a tgc Cys gaa GlU C n v~jL acc gtc gtt tcc Thr Val Val Ser gca gcc aaa gcg Ala Ala Lys Ala tgt tcc aat cct Cys Ser Asn Pro agt g gc Ser M]y 48 96 144 186 217 Page 117 <213> Conus obscurus 19C-ue.P~~ <400> 356 met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 Pro Thr ser ASP Arg Ala Ser ASP Arg Arg Asn Ala Ala Ala Lys Ala 25 Phe ASP LeU Arg Tyr Ser Thr Ala Lys Arg Gly Cys CySsSer Asn Pro 40 Val Cys Trp Gln Asn Asn Ala Glu Tyr Cys Arg Glu Ser Gly 55 <210> 357 <211> 208 <212> DNA <213> Conus obscurus <220> <221> CDS <222> (168) <400> 357 atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc acc gtc gtt tcc met Phe Thr va] Phe Le U Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 ttc act tca gat cgt gca tct gat ggc ggg aat gtc gca gcg tct cac Phe Thr Ser ASP Arg Ala Ser ASP Gly GI y Asn Val Ala Ala Ser His 25 ctg atc gct ctg acc atc aag g ga tgc tgt tct cac cct ccc tgt gcc Leu Ile Ala Leu Thr Ile Lys Gly Cys CySsSer His Pro Pro Cys Ala 40 cag aat aat caa gac tat tgt ggt tgacgacgct gatgctccag gaccctctgz Gln Asn Asn Gln ASP Tyr Cys Gly accacgacgt <210> 358 <211> 56 <212> PRT <213> Conus obscurus <400> 358 met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 1 5 10 Phe Thr Ser ASP Arg Ala Ser ASP Gly Gly Asn Val Ala Ala Ser His 20 25 Leu Ile Ala Leu Thr Ile LYS Gly CyS CySsSer His Pro Pro Cys Ala 35 40 Gini AShi ASn Gifl Asp Ty- Cy Gly 50 <210> 359 <211> 217 <212> DNA <213> Conus obscurus Page 118 48 96 144 198 208

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90 0 0* 9 09 9 99 99 *0 0 9 9 S. S 9* .9 999999 9 9* 99 @9 9 9 9 9 179PCT-AU rev .APP .txt <220> <221> CDS <222> .(186) <400> 359 atg ttc acc gtg ttt ctg ttg gtt gtc tta tca acc acc gtc gtt tcc 48 met Phe Thr va] Phe Leu Leu Val Val Leu Ser Thr Thr Val Val ser 1 5 10 tcc act tca gat cgt gca tct gat agg agg aat gcc gca gcc aaa gcg 96 Ser Thr Ser ASP Arg Ala Ser ASP Arg Arg Asn Ala Ala Ala LYS Ala 25 tct gac ctg atg tat tcg acc gtc aag aaa gga tgt tgt tcc cat cct 144 Ser ASP Leu met Tyr Ser Thr Val Lys Lys G~y Cys CySsSer His Pro 40 gcc tgt tcg g gg aat aat cga gaa tat tgt cgt gaa agt ggc 186 Ala cys Ser G] y Asn Asn Arg Glu Tyr Cys Arg Glu Ser GMY 55 taatgctcca ggaccctctg aaccacgacg t 217 <210> 360 <211> 62 <212> PRT <213> Conus obscurus <400> 360 met Phe Thr Val Phe Leu Leu 'Ial Val Leu Ser Thr Thr Val Val Ser 1 5 10 Ser Thr Ser ASP Arg Ala Ser ASP Arg Arg Asn Ala Ala Ala Lys Ala 25 Ser ASP Leu met Tyr Ser Thr Val Lys Lys Gly Cys CySsSer His Pro 40 Ala cys Ser Gly Asn Asn Arg GlU Tyr Cys Arg Glu Ser Gly 55 <210> 361 <211> 157 <212> DNA <213> Conus omaria <220> <221> CDS <222> .(126) <400> 361 tttgatggca ggaatgcctc agccgacagc aaagtggctg cccggatcgc t cag atc 57 Gln Ile 1 gac agg gat cca tgc tgt tcc tat cct gac tgt g gc gcg aat cat cca 105 ASP Arg ASP Pro Cys Cys Ser Tyr Pro ASP CyS Gly Ala Asn His Pro 1015 gag att tgt g gt gg a aaa cgc tgatgctcca ggaccctctg aaccacgacg t 157 Glu Ile Cys Gly GlY Lys Arg <210> 362 Page 119 179PCT-AU rev. APP. .txt <211> <212> PRT <213> Conus omaria <400> 362 Gin Ilie ASP Arg ASP 1 5 His Pro Giu lie Cys <210> 363 <211> 128 <212> DNA <213> Conus omaria <220> <221> CDS <222> (88) Pro Cys Cys Giy Giy Lys Ser Tyr Pro Asp Cys Giy Ala Asn 10 Arg <400> 363 tctcatggca ggaatgccgc acgct acc gtc agg Thr Val Arg tgc tgt tct cag Cys Cys Ser Gin cct cct tgt Pro Pro Cys cgc tgg aaa cat Arg Trp LYS His 15 cca gaa ctt Pro Giu Leu tgt agt Cys Ser tgaagacgct gatgctccag gaccctctga accacgacgt 128 <210> 364 <211> 21 <212> PRT <213> Conus omaria <400> 364 Leu Thr Val 1 Arg Giu 5 Cys Cys Ser Gin Pro Pro Cys Arg TrP LYS His 10 Pro GIU Leu Cys Ser <210> 365 <211> 154 <212> DNA <213> Conus omaria <220> <221> CDS <222> (123) <400> 365 tttgatggca ggaatgctgc agccagcgac aaagcgtctg agctgatggc t ctg gcc Leu Ala 1 gtc agg gga tgc tgt tcc cat cct gcc tgt gct ggg aat aat cca cat Val Arg Gi y cys Cys Ser His Pro Ala Cys Ala G ly Asfl Asfl Pro His 10 atc tgt Ilie Cys gygc aga aga cgc: tgatgctcca ggaccctctg aaccacgacg t G ly Arg Arg Arg Page 120 179 PCT-AU rev. APP .txt <210> 366 <211> 24 <212> PRT <213> Conus omaria <400> 366 Leu Ala Val Arg Gly 1 5 Cys Cys Ser His Pro Ala Cys Ala Gly Asn Asn 10 Pro His Ile Cys Gl y Arg Arg Arg <210> 367 <211> 142 <212> DNA <213> Conus omaria <220> <221> CDS <222> (102) <400> 367 tctggtgtca ggaaagacgc agcgcctggc ctgatcgct ctg acc atc aag g ga Leu Thr le LyS Gly 1 tgc tgt tct Cys Cys Ser gat cct ASP Pro agc tgt aac ser Cys Asn gt gaat aat Va 1 Asn Asn 15 cca gac tat Pro ASp Tyr 102 142 tgacgacgct gatgctccag gaccctctga accacgacgt <210> 368 <211> 21 <212> PRT <213> Conus omaria <400> 368 Leu Thr Ile 1 Pro ASp Tyr Lys Gly 5 Cys Gl y Cys Cys Ser ASP Pro Ser Cys Asn Val Asn Asn 10 <210> 369 <211> 157 <212> DNA <213> Conus omaria <220> <221> CDS <222> .(117) <400> 369 tctaatggca ggaatgccgc agccaaattc aaagcgcctg gtc agg gaa gaa tgc tgt tca gac cct cgc tgt Val Arg Giu GlU Cys CySsSer ASP Pro Arg Cys 5 10 ccctgatgga g ctg acc Leu Thr 1 tcc gtg gg a cat caa Ser VaiG] y His Gin gat atg tgt cgg tgaagcacgt gatgctccag gaccctctga accacgacgt 157 ASP met Cys Arg Page 121 179PCT-AUrev .APP.tXt <210> 370 <211> 22 <212> PRT <213> Conus omaria <400> 370 Leu Thr Val Arg GiU 1 5 Glu Cys Cys Ser ASP Pro Arg Cys Ser Val Gly 10 His Gin ASP <210> 371 <211> 151 <212> DNA <213> Conus purpurascens <220> <221> CDS <222> (120) <400> 371 act gat ggc Thr AS p Gy 1 gcc gtc agg Ala Val Arg agg aat Arg Asn 5 gct gca gcc ata Ala Ala Ala lie gcg Al a 10 ctt gac ctg atc Leu ASP Leu Ilie gct ccg Ala Pro g~a tg c tgt tcc GYCys Cys Ser cct gcc tgt tta Pro Ala Cys Leu gt gaat cat Va 1 Asn H is cta gaa atg tgt ggt aaa aga cgc Leu Glu met Cys Gly Lys Arg Arg tgatgcccca ggaccctctg aaccacgacg 151 <210> 372 <211> <212> PRT <213> Conus <400> 372 Thr ASP Gly 1 Ala Val Arg Leu Giu met <210> 373 <211> 160 <212> DNA <213> Conus purpurascens Arg Asn Ala Ala 5 Ala Ilie Ala LeU ASP Leu Ilie Ala Pro 10 Gly Gly CYS Cys Ser Asn 20 25 Pro Ala CyS Leu Val Asn Hi S Cys Gly LYS Arg Arg purpurascens <220> <221> CDS <222> (120) <400> 373 tct gat ggc agg gat gcc gca gcc aac gac aaa gcg tct gac ctg atc Page 122 Ser ASP Gly 1 gct ctg acc Ala Leu Thr M g aat aat Asfl Asfl accacgacgt <210> 374 <211> <212> PRT <213> Conus <400> 374 Ser ASP Gly 1 Ala Leu Thr Val Asn Asn <210> 375 <211> 151 <212> DNA <213> Conus <220> <221> CDS <222> <400> 375 tct gat g c Ser ASP G y 1 ccg gaa gac Pro Glu ASP gct tgt act Ala Cys Thr 35 179PCT-AU rev. APP.txt Arg ASP Ala Ala Ala Asn ASP Lys Ala Ser ASP Leu Ile 5 10 gcc agg aga gat cca tgc tgt ttc aat cct gcc tgt aac Ala Arg Arg ASP Pro cys Cys Phe Asn Pro Ala Cys Asn 25 cca cag att tgt gg t tgaagacgct gatgctccag gaccctctga Pro Gin Ile Cys Gy 96 150 160 Pu rpu rascens Arg ASp Ala Ala Ala Asn ASP LYS Ala Ser ASP Leu Ile 5 10 Ala Arg Arg ASP Pro Cys Cys Phe Asn Pro Ala Cys Asn 25 Pro Gin Ile Cys Gly purpurascens (120) agg gat gct gag aaa aca g gc ttt gac acg acc att gtg Arg ASP Ala GlU Lys Thr Gyy Phe ASP Thr Thr Ile va] 5 10 tgc tgt tcg gat cct tcc tgt tgg agg ctg cat agt tta Cys Cys Ser ASP Pro Ser Cys Trp Arg Leu HiSsSer Leu 25 gg a att gta aac cgc tgatgctcca ggaccctctg aaccacgacg Gly Ile \'al Asn Arg 48 96 150 151 <210> 376 <211> <212> PRT <213> Conus <400> 376 Ser ASP Giy 1 Pro Glu ASP Ala CyS Thr purpurascens Arg ASP Ala GlU Lys Thr Gly Phe ASP Thr Thr Ile Val 5 10 Cys Cys Ser ASP Pro Ser Cys Trp Arg Leu HiSsSer Leu 20 25 Giy Ile Val Asn Arg Page 123 179PCT-Au rev. APP .txt <210> 377 <211> 142 <212> DNA <213> Conus purpurascens <220> <221> CDS <400> 377 act gat ggc agg agt gct gca gcc ata gcg ttt gcc ctg atc gct ccg 48 Thr ASP Gly Arg Ser Ala Ala Ala Ile Ala Phe Ala Leu Ile Ala Pro 1 5 10 acc gtc tgc tgt act aat cct gcc tgt ctc gt g aat aat ata cgc ttt 96 Thr Val Cys Cys Thr Asn Pro Ala Cys Leu Val Asn Asn Ile Arg Phe 25 g gt gya aa cgc tgatgcccca ggaccctctg aaccacgacg t 142 CyS G y GyAgArg <210> 378 <211> 37 <212> PRT <213> Conus purpurascens <400> 378 Thr ASP Gly Arg Ser Ala Ala Ala le Ala Phe Ala Leu Ile Ala Pro 1 5 10 Thr Val Cys Cys Thr Asn Pro Ala Cys Leu Val Asn Asn Ile Arg Phe 25 Cys Gly Gly Arg Arg <210> 379 <212> DNA <213> Conus regius <220>CS <222> (117) <400> 379 tct gat g ga aga aat gcc gca agc gac gcc aaa gcg ttt ccc cgg atc 48 Ser ASP Gly Arg Asn Ala Ala Ser ASP Ala LyS Ala Phe Pro Arg le 1 5 10 gct cca atc gtc agg gac gaa tgc tgt agc gat cct agg tgt cac gyg 96 **20 25 aat aat cgg gac cac tgt gct tgaagacgct gctgctccag gaccctctga 147 Asn Asn Arg ASP His Cys Ala accacgacgt 157 *see <210> 380 Page 124 179PCT-Au rev. APP .txt <211> 39 <212> PRT <213> Conus regius <400> 380 Ser ASP GlY Arg Asn Ala Ala ser ASP Ala Lys Ala Phe Pro Arg Ile 1 5 10 Ala Pro Ile Val Arg ASP Glu Cys CySsSer ASP Pro Ang Cys His Gly 25 Asn Asn Arg ASP His Cys Ala <210> 381 <211> 156 <212> DNA <213> Conus regius <220> <221> CDS <222> (117) <400> 381 tct gat ggc agg aat acc gcg gcc gac gaa aaa gcg tcc gac ctg atc ser ASP Gly Arg Asn Thr Ala Ala ASP GIU Lys Ala Ser ASP Leu Ilie 1 5 10 tct caa act gtc aag aga gat tgc tgt tcc cat cct ctc tgt aga tta Ser Gin Thr Val LYS Arg ASP Cys CySsSer HiS1 Pro Leu Cys Arg Leu 25 ttt gtt cca gg a ctt tgt att tgaagacgct gctgctccag gaccctctga Phe Val Pro Gly Leu Cys Ile accacgact <210> 382 <211> 39 <212> PRT <213> Conus regius <400> 382 Ser ASP Gly Arg Asn Thr Ala Ala ASp GIU LYS Ala Ser ASP Leu Ile 1 5 10 Ser Gin Thr Val Lys Arg ASP CyS CySsSer His Pro Leu Cys Arg Leu 25 Phe Val Pro Gly Leu Cys Ile <210> 383 <211> 157 <212> DNA <213> Conus regius <220> <221> CDS <222> .(117) <400> 383 tct gat ggc agg aat gcc gca gcc gac aac aaa gcg tct gac cta atc Ser ASP G~y Arg Asn Ala Ala Ala ASP Asn Lys Ala Ser ASP Leu lie Page 125 48 96 147 156 9 9 .9 999 9* 9.

9 99 99 9 9 9 .9.9 99 9 9.

99 9e*09* 9 99 9* 99 9 .9.9 1 gct caa atc Ala Gin Ile agg tat cca Arg Tyr Pro accacgacgt <210> 384 <211> 39 <212> PRT <213> Conus <400> 384 Ser ASP Gly 1 Ala Gin Ile Arg Tyr Pro 179 PCT-AU rev. APP.txt 5 10 gtc agg aga gga tgc tgt tcc cat cct gtc tgt aaa gtg Val Arg Arg G]y Cys Cys Ser His Pro V/al Cys Lys va I 20 25 gac ctg tgt cgt tgaagacgct gctgctccag gaccctctga ASP Leu Cys Arg 157 regi us Arg Asn Ala Ala Ala ASP Asn Lys Ala Ser ASP Leu Ile 5 10 Val Arg Arg Giy Cys Cys Ser His Pro Vai Cys LYS Val 25 ASP Leu CyS Arg 0 090 0 *0 0 0 0

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0050

S

<2 10> 385 <211> 157 <212> DNA <213> Conus regius <220> <221> CDS <222> .(117) <400> 385 tct gat ggc agg aat gcc gca gcc gac aac aga gcg tct gac cta atc Ser ASP G y Arg Asn Ala Ala Ala ASP Asn Arg Ala Ser ASP Leu Ile 1 5 10 gct caa atc gtc agg aga gga tgc tgt tcc cat cct gcc tgt aat gtg Ala Gin Ile V/al Arg Arg Gly Cys Cys Ser His Pro Ala Cys Asn VaI 20 25 aat aat cca cac att tgt g gt tgaagacgct gctgctccag gaccctctga Asn Asn Pro His Ile Cys Gly accacgacgt <210> 386 <211> 39 <212> PRT <213> Conus regius <400> 386 Ser ASP Giy Arg Asn Ala Ala Ala ASP Asfl Arg Ala Ser ASP Leu Ile 1 5 10 Ala Gin le Val Arg Arg Gly CyS Cys Ser His Pro Ala CyS Asn Val 20 2.5 Asn Asn Pro His le Cys Gly Page 126 48 96 147 157 179PCT-Aurev .APP. tXt <210> 387 <211> 157 <212> DNA <213> Conus regius <220> <221> CDS <222> (117) <400> 387 tct gat ggc agg aat gcc gca gcc gac aac aaa ccg tct gac cta atc ser ASP GMY Arg Asn Ala Ala Ala ASP Asn Lys Pro Ser Asp Leu Ilie 1 5 10 gct caa atc gtc agg aga gga tgc tgt tcg cat cct gtc tgt aaa gtg Ala Gin Ile Val Arg Arg Gi y Cys Cys Ser His Pro Val Cys Lys va] 25 agg tat tca gac atg tgt ggt tgaagacgct gctgctccag gaccctctga Arg Tyr Ser ASP met Cys Gy accacgacgt <210> 388 <211> 39 <212> PRT <213> Conus regius <400> 388 Ser ASP Gly Arg Asn Ala Ala Ala ASP Asn LYS Pro Ser ASP Leu Ilie 1 5 10 Ala Gin Ile Val Arg Arg Gly Cys Cys Ser His Pro Val Cys Lys Val 25 Arg Tyr Ser ASP met Cys Gly <210> 389 <211> 154 <212> DNA <213> Conus stercusmuscarum <220> <221> CDS <222> .(114) <400> 389 tct gat ggc agg aat gca gag cga. cga caa agc gtc tgt cct ggt cgc Ser ASP GMy A rg Asfl Ala Giu Arg Arg Gin Ser Val Cys Pro Gly Arg 1 5 10 tct ggc ccc agg gga gga tgt tgt tcc cac cct gcc tgt aag gtg cat Ser Gly Pro Arg G y G] y Cys Cys Ser His Pro Ala Cys Lys va] His 20 25 ttt cca cac agt tgt ggt tgacgacgct gatgctccag gaccctctga Phe Pro His Ser Cys Gly accacgacgt 48 96 147 157 154 Page 127 179PCT-AU rev. APP.tXt <210> 390 <211> 38 <212> PRT <213> Conus stercusmuscarum <400> 390 ser ASP Gly Arg Asn Ala Glu Arg Arg Gin Ser Vfal Cys Pro Gly Arg 1 5 10 Ser Gly Pro Arg Gly Gly Cys Cys Ser HiS Pro Ala Cys Lys Val His 25 Phe Pro HiSsSer Cys Gly <210> 391 <211> 145 <212> DNA <213> Conus stercusmuscarum <220> <221> CDS <222> (114) <400> 391 tct gat ggc agg aat gcc gca gcc agc gac aga gcg tct gac gcg gcc Ser ASP GMy Arg Asn Ala Ala Ala Ser ASP Arg Ala Ser ASP Ala Ala 1 5 10 cac cag gta tgc tgt tcc aac cct gtc tgt cac gtg gat cat cca gaa His Gln Val Cys Cys Ser Asn Pro Val Cys His va] ASP His Pro Glu 25 ctt tgt cgt aga aga cgc tgatgctcca ggaccctctg aaccacgacg t Leu Cys Arg Arg Arg Arg 48 96 145 <210> 392 <211> 38 <212> PRT <213> Conus <400> 392 Ser ASP Gly 1 His Gin Val Leu CyS Arg stercusmuscarum Arg Asn Ala Ala Ala Ser ASP Arg Ala Ser ASP Ala Ala 5 10 Cys Cys Ser Asn Pro Val Cys His Val ASP His Pro Glu 25 Arg Arg Arg <210> 393 <211> 154 <212> DNA <213> Conus striatus <220> <221> CDS <222> (123) <400> 393 tct gat g c agg aat gcc gcg gcc aac gac aaa gcg tct gac ctg gtc 48 Ser ASP Gly Arg Asn Ala Ala Ala Asn ASP LYS Ala Ser ASP Leu Val 1 5 10 Page 128 179PCT-AU rev. APP.txt gct ccg gcc atc agg gg a tgc tgt tcc cac cct gtc tgt aac ttg agt 96 Ala Pro Ala le Arg GMy Cys Cys Ser His Pro Val Cys Asn Leu Ser 25 aat cca caa att tgt cgt g ga aga cgc tgatgctcca ggaccctctg 143 Asn Pro Gin Ilie Cys Arg Gly Arg Arg aaccacgacg t 154 <210> 394 <211> 41 <212> PRT <213> Conus striatus <400> 394 Ser ASP Gly Arg Asn Ala Ala Ala Asn ASP Lys Ala Ser ASP Leu Val 1 5 10 Aia Pro Aia Ile Arg Gly Cys Cys Ser His Pro \'ai Cys Asn Leu Ser 25 Asn Pro Gin Ile Cys Arg Gly Arg Arg <2 10> 395 <211> 117 <212> DNA <213> Conus textile <220> <221> CDS <222> .(114) <400> 395 ttt cat g gc agg aat Phe His Gly Arg Asn 1 5 acc gac aag agg caa Thr ASP Lys Arg Gin cat cca gaa att tgt His Pro Giu Ilie Cys gcc gca gcc aaa gcg tct gg c ctg gtc gg t ctg Ala Ala Ala Lys Ala Ser Gly Leu Vai Gly Leu 10 gaa tgc tgt tct cat cct gcc tgt aac gta gat Glu Cys Cys Ser His Pro Ala Cys Asn Val ASP 25 cgt tga Arg Ala Ala Ala Lys Ala Ser Gly Leu \fal Gly Leu 10 Glu Cys Cys Ser His Pro Ala Cys Asn Vial ASP 25 Arg 48 96 117 <210> 396 <211> 38 <212> PRT <213> Conus <400> 396 Phe His Giy 1 Thr ASP Lys His Pro Giu <210> 397 textilIe Arg Asn 5 Arg Gi n Ilie Cys Page 129 179PCT-AU rev. APP .txt <211> 151 <212> DNA <213> Conus tulipa.

<220> <221> CDS <222> (120) <400> 397 act gat ggc agg agt gct gca gcc ata gcg ttt gcc ctg atc gct ccg 48 Thr ASP Gly Arg Ser Ala Ala Ala Ilie Ala Phe Ala Leu Ilie Ala Pro 1 5 10 acc gtc tgg gaa gga tgc tgt tct aat cct gcc tgt ctc gtg aat cat 96 Thr Val rrp GiU Gyy Cys CySsSer Asn Pro Ala Cys Leu va] Asn His 25 ata cgc ttt tgt ggt gyga aga cgc tgatgcccca ggaccctctg aaccacgacg 150 Ile Arg Phe Cys G] y G Y Arg Arg t 151 <210> 398 <211> <212> PRT <213> Conus tulipa <400> 398 Thr ASP Gly Arg Ser Ala Ala Ala Ilie Ala Phe Ala Leu Ilie Ala Pro 1 5 10 Thr Val Trp Giu Gly Cys CySsSer Asn Pro Ala Cys Leu \'al Asn His 25 Ile Arg Phe Cys Gly Gly Arg Arg <210> 399 <211> 157 <212> DNA <213> Conus virgo <220> <221> CDS <222> .(117) <400> 399 tct aat g gc atg aat gcc gca gcc atc agg aaa gcg tct gcc ctg gtg 48 Ser Asn Gly Met Asn Ala Ala Ala le Arg LYS Ala Ser Ala Leu VaI gct cag atc gcc cat cga gac tgc tgt gac gat cct gcc tgc acc gtg 96 Ala Gin lie Ala His Arg ASP Cys Cys ASP ASP Pro Ala Cys Thr Va] 25 aat aat cca g gc ctt tgc act tgaagatgct gctgccccag gaccctctga 147 Asn Asn Pro G yLeu CyS Thr accacgacgt 157 <210> 400 <211> 39 <212> PRT Pg 3 179 PCT-AU rev. APP.txt <213> Conus virgo <400> 400 ser Asn Gly met Asn Ala Ala Ala le Arg Lys Ala Ser Ala Leu Val 1 5 10 Ala Gin Ile Ala HiS Arg ASP Cys Cys ASP ASP Pro Ala Cys Thr Val 25 Asn Asn Pro Gly Leu Cys Thr <210> 401 <211> 154 <212> DNA <213> Conus geographus <220> <221> CDS <222> (114) <400> 401 tct gat ggc ggg aat gcc gca gca aaa gag tct gac gtg atc gct ctg 48 Ser ASP GlY Gi y Asn Ala Ala Ala Lys Giu Ser ASP ?a lie Ala Leu 1 5 10 acc gtc tgg aaa tgc tgt acc att cct tcc tgt tat gag aaa aaa aaa 96 Thr Val Trp Lys Cys Cys Thr Ilie Pro Ser Cys Tyr Glu Lys Lys Lys 25 att aaa gca tgt gtc ttt tgacgacgct gatgctccag gaccctctga 144 Ilie Lys Ala Cys \'al Phe accacgacgt 154 <210> 402 <211> 38 <212> PRT <213> Conus geographus <400> 402 Ser ASP Gly Gly Asn Ala Ala Ala Lys GlU Ser ASP Val Ile Ala Leu 1. 5 10 Thr \/al Trp Lys Cys Cys Thr lie Pro Ser Cys Tyr Giu Lys Lys Lys 2025 Ile Lys Ala cys \/al Phe <210> 403 <211> 154 <212> DNA <213> Conus regius <220> <221> CDS <222> .(114) <400> 403 tct gat g gc gca gtc gac gac aaa gcg ttg gat cga atc gct gaa atc 48 Ser ASP Gly Ala V'al ASP ASP LYS Ala Leu ASP Arg lie Ala Glu lie 1 5 10 55*55Page 131 179 PCT-AU rev. APP.tXt gtc agg aga gga tgc tgt ggc aat cct gcc tgt agc ggc tcc tcg aaa 96 Val Arg Arg Gly Cys cys Gi y Asn Pro Ala Cys ser G ly Ser Ser LYS 25 gat gca ccc tct tgt ggt tgaagacgct gctgctccag gaccctctga 144 ASP Ala Pro Ser Cys G~y accacgacgt 154 <210> 404 <211> 38 <212> PRT <213> Conus regius <400> 404 Ser ASP Gly Ala Val ASP ASp Lys Ala Leu ASP Arg Ile Ala Glu Ile 1 5 10 Val Arg Arg Gly Cys CyS Gly Asn Pro Ala Cys Ser Gly Ser Ser Lys 25 ASP Ala Pro Ser Cys Gly 0, o: 0 pp 0 0 *09 PaeP3

Claims (28)

1. A substantially pure a-conotoxin peptide having the generic formula 1: Xaa 1 Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Cys-Cys-Xaa 6 -Xaa 7 -Xaa8-Xaa 9 -Cys-Xaaio-Xaaii-Xaa 2- Cys-Xaal 3 (SEQ ID NOl wherein Xaa 1 is des-Xaal, le, Leu. or Val; Xaa 2 is des-Xaa 2 Ala or Gly; Xaa 3 is des-Xaa 3 Gly, Trp (D or neo-Trp, halo-Trp or any unnatural aromatic amino acid; Xaa 4 is des-Xaa 4 Asp, Phe, Gly, Ala, Glu,,y- carboxy-Glu (Gla) or any unnatural aromatic amino acid; Xaa 5 is Glu, Gla, Asp, Ala, Thr, Ser, Gly, le, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa6 is Ser, Thr, Arg, omnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl- Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 7 is Asp, Glu, Gla, Arg, omnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 8 is 5cr, Thr, Asn, Ala, Gly, Mrg, Lys, omnithine, homoarginine, N-methyi-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid; His, halo-His, Pro or hydroxy-Pro; Xaa 9 is Thr, 5cr, Ala, Asp, Asn, Pro, hydroxy-Pro, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyi-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaaj 0 is Gly, 5cr, Thr, Asn, Arg, omnithine, *0 homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyi-Lys or any unnatural basic amino acid; Xaaj I is Gin, Leu, His, halo-His, Trp (D or L), halo-Trp, neo-Trp, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0- phospho-Tyr, nitro-Tyr, Mrg, omnithine, homoarginine, Lys, N-methyl-Lys, N,N- dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid or any unnatural aromatic amino acid; Xaal2 is Asn, His, halo-His, le, Leu, Val, Gin, Mrg, omnithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N- trimethyl-Lys or any unnatural basic amino acid; Xaa, 13 is des-Xaal3, Val, le, Leu, Mrg, omnithine, homoarginine, Lys, N-methyi-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; and the C-terminus contains a free carboxyl group or an amide group.

2. A substantially pure a-conotoxin peptide of generic formula I selected from the group consisting of: 70 Asp-Xaai -CYs-CYs-Ser-Asp-Ser-Arg-Cys-Gly-Xaa2-Asn-Cys-Leu (SEQ ID NO: 4); Al-y-y-e-s-r-AgCsAgXa-r-y (SEQ ID NO Phe-Thr-Cys-Cys-Arg-Arg-Gly-Thr-Cys-Ser-Gll-His-Cys (SEQ lID NO:6); Asp-Xaas-Cys-Cys-Arg-Arg-His-Ala-Cys-Thr-Leu-Ile-Cys (SEQ lID NO:7); Asp-Xaa 4 -Cys-Cys-Arg-Arg-Xaa 5 -Xaa5-Cys-Thr-Leu-Ile-Cys (SEQ ID NO:8); (SEQ ID NO:9); Gl-l-y-y-e-s-asAgCsAaXa-r-y (SEQ lID NO: Ile-Ala-Xaa 3 -Asp-Ile-Cys-Cys-Ser-Xaai -Xaa 5 -Asp-Cys-Asn-His-Xaa2- Cys-Val (SEQ lID NO: 11); and Gly-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Xaa 2 -His-Gll-Cys (SEQ BD NO: 12), wherein Xaaj is Glu or y-carboxy-Glu (Gla); Xaa 2 is Lys, N-methyl-Lys, N,N- dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa 3 is Trp (D or halo-Trp or neo- Trp; Xaa 4 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0- phospho-Tyr or nitro-Tyr; and Xaa 5 is Pro or hydroxy-Pro; and the C-terminus contains a carboxyl or amide group, or derivatives thereof.

3. The substanially pure cc-conotoxin peptide of claim 2, wherein Xaaj is Glu.

4. The substantially pure a-conotoxin peptide of claim 2, wherein Xaa 2 is Lys. The substantially pure a-conotoxin peptide of claim 2, wherein Xaa 4 is Tyr. The substantially pure a-conotoxin peptide of claim 2, wherein Xaa 4 is mono- iodo-Tyr. The substantially pure a-conotoxin peptide of claim 2, wherein Xaa 4 is di-iodo- Tyr. The substantially pure a-conotoxin peptide of claim 1, which is modified to contain an 0-glycan, an S-glycan or an N-glycan. 70a 9 The substantially pure ax-conotoxin peptide of claim 2 which is modified to contain an 0-glycan, an S-glycan or an N-glycan. A substantially pure ac-conotoxin peptide having the generic formula 11: Xaaj Xaa 2 -Xaa 3 -Xaa 4 -Cys-Cys-Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Cys-Xaa-Xaa 0 -XaaI -Xaal 2- Xaal 3 -Xaal 4 -Cys-Xaal 5 -Xaal 6 -Xaa 1 7 (SEQ IID NO:2), wherein Xaaj is des-Xaal, Asp, Glu or 'y-carboxy-Glu (Gig); WO 00/44776 WO 0044776PCTIUSOO/01979 71 Xaa, is des-Xaa,, Gin, Ala, Asp, Glu, Gla; Xaa 3 is des-Xaa 3 Gly, Ala, Asp, Glu, Gla, Pro or hydroxy-Pro; Xaa, is des-Xaa 4 Gly, Glu, Gla, Gin, Asp, Asn, Pro or hydroxy-Pro; Xaa is Ser, Thr, Gly, Glu, Gla, Asn, Trp (D or neo-Trp, halo-Trp, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, NN-dimethyl-Lys, NNN-trimethyi-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 6 is Asp, Asn, His, halo-His, Thr, Ser, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr, nitro- Tyr or any unnatural hydroxy containing amino acid; Xaa 7 is Pro or hydroxy-Pro; Xaa 8 is Ala, Ser, Thr, Asp, Val, Ie, Pro, hydroxy-Pro, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 9 is Gly, Ie, Leu, Val, Ala, Thr, Ser, Pro, hydroxy-Pro, Phe, Tip (D or neo-Trp, halo- Trp, Arg, omithine, homoarginine, Lys, N-methyl -Lys, N,N-dimethyl-Lys, NN,N-trimethyl- Lys, any unnatural basic amino acid or any unnatural aromatic amino acid; Xaa 1 0 is Ala, Asn, Phe, Pro, hydroxy-Pro, Glu, Gla, Gin, His, halo-His, Val, Ser, Thr, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaaj I is Thr, Ser, His, halo-His, Leu, Ile, Val, Asn, Met, Pro, hydroxy-Pro, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, NN-dimethyl-Lys, NNN- trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa, 2 is Asn, Pro, hydroxy-Pro, Gln, Ser, Thr, Arg, omnithine, homoarginine, Lys, N-methyl- Lys, NN-dimethyi-Lys NN,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 1 3 is des-Xaa 3 Gly, Thr, Ser, Pro, hydroxy-Pro, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 14 is des-Xaa, 1 Ie, Val, Asp, Leu, Phe, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, NN-dimethyl-Lys, NNN-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, 0- phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; and Xaa 1 5 is des- Xaa, 5 Gly, Ala, Met, Ser, Thr, Trp (D or neo-Trp, halo-Trp, any unnatural aromatic amino acid, Arg, omnithine, homoarginine, Lys, N-methyl-Lys, NN-dimethyl-Lys, NNN- trimethyl-Lys or any unnatural basic amino acid; Xaa 1 6 is des-Xaa 1 6 Trp (D or neo-Trp, halo-Trp, any unnatural aromatic amino acid, Arg, ornithine, homoarginine, Lys, N-methyl- WO 00/44776 WO 0044776PCT[USOO/01979 72 Lys, NN-dimethyl-Lys, N,NN-trimethyl-Lys or any unnatural basic amino acid; Xaa, is des-Xaal 7 Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, NNN- trimethyl-Lys or any unnatural basic amino acid; and the C-terminus contains a free carboxyl group or an amide group.

11. A substantially pure a-conotoxin peptide of generic formula Il seleceted from the group consisting of: Cys-Cys-Ser-Asp-Xaa 5 -Ala-Cys-Xaa 2 -Gln-Thr-Xaa 5 -Gly-Cys-Arg (SEQ ID NO: 13); Cys-Cys-Xaal -Asn-Xaa 5 -Ala-Cys-Arg-His-Thr-Gln-Gly-Cys (SEQ ID NO: 14); Gly-Cys-Cys-Xaa 3 -His-Xaa 5 -Ala-Cys-Gly-Arg-His-Xaa 4 -Cys (SEQ ID NO: Ala-Xaa 5 -Cys-Cys-Asn-Asn-Xaa 5 -Ala-Cys-Val-Xaa 2 -His-Arg-Cys (SEQIDNO: 16); Ala-Xaa 5 -Gly-Cys-Cys-Asn-Asn-Xaa 5 -Ala-Cys-Val-Xaa 2 -His-Arg-Cys (SEQ ID NO: 17); Xaa 5 -Xaa 5 -Cys-Cys-Asn-Asn-Xaa 5 -Ala-Cys-Val-Xaa 2 -His-Arg-Cys (SEQ ID NO: 18); Asp-Xaa 1 -Asn-Cys-Cys-Xaa-Asn-Xaa 5 -Ser-Cys-Xaa 5 -Arg-Xaa 5 -Arg-Cys-Thr(SEQ ID NO: 19); Gly-Cys-Cys-Ser-Thr-Xaa 5 -Xaa 5 -Cys-Ala-Val-Leu-Xaa 4 -Cys (SEQ ID NO Gly-Cys-Cys-Gly-Asn-Xaa 5 -Asp-Cys-Thr-Ser-His-Ser-Cys (SEQ ID NO:2 1); Gly-Cys-Cys-Ser-Asn-Xaa 5 -Xaa 5 -Cys-Ala-His-Asn-Asn-Xaa 5 -Asp-Cys-Arg (SEQ ID NO:42); Gly-Cys-Cys-Xaa 4 -Asn-Xaa 5 -Val-Cys-Xaa,-Xaa 2 -Xaa 4 -Xaa 4 -Cys-Xaa 3 -Xaa 2 (SEQ ID NO: 154); Xaa6-Xaa 1 -Xaa 5 -Gly-Cys-Cys-Arg-His-Xaa 5 -Ala-Cys-Gly-Xaa 2 -Asn-Arg-Cys (SEQ ID NO: 155); Cys-Cys-Ala-Asp-Xaa 5 -Asp-Cys-Arg-Phe-Arg-Xaa 5 -Gly-Cys (SEQ ID NO: 156); Gly-Cys-Cys-Xaa 4 -Asn-Xaa 5 -Ser-Cys-Xaa 3 -Xaa 5 -Xaa,-Thr-Xaa 4 -Cys-Ser-Xaa 3 -Xaa, (SEQ ID NO: 157); Cys-Cys-Ser-Asn-Xaa 5 -Thr-Cys-Xaa 2 -Xaa -Thr-Xaa 4 -Gly-Cys (SEQ ID NO: 15 8); Cys-Cys-Ala-Asn-Xaas-Ile-Cys-Xaa 2 -Asn-Thr-Xaas-Gly-Cys (SEQ ID NO: 159); Cys-Cys-Asn-Asn-Xaa 5 -Thr-Cys-Xaa 2 -Xaa 1 -Thr-Xaa 4 -Gly-Cys (SEQ ID NO: 160); Cys-Cys-Ser-Asn-Xaa 5 -Val-Cys-Xaa 2 -Xaa 1 -Thr-Xaa 4 -Gly-Cys (SEQ ID NO: 16 1); WO 00/44776 WO 0044776PCT[USOO/01979

12.

13.

14.

16.

17. Gly-Gly-Cys-Cys-Sr-Xaa 4 -Xaa 5 -Xaa 5 -Cys-Ile-Ala-Ser-Asn-Xaas-Xaa 2 -Cys-Gly (SEQ ID NO: 162); Gly-Cys-Cys-Ser-His-Xaa 5 -Val-Cys-Ser-Ala-Met-Ser-Xaas-Ile-Cys (SEQ ID NO:163); Gly-Cys-Cys-Xaa 2 -Asn-Xaa 5 -Xaa 4 -Cys-Gly-Ala-Ser-Xaa 2 -Thr-Xaa 4 -Cys (SEQ ID NO: 164); Gly-Cys-Cys-Ser-Xaa 4 -Xaa 5 -Xaa 5 -Cys-Phe-Ala-Thr-Asn-Xaa5-Asp-Cys (SEQ ID NO:165); Gly-Gly-Cys-Cys-Ser-Xaa 4 -Xaas-Xaa 5 -Cys-Ie-Ala-Asn-Asn-Xaa 5 -Leu-Cys-Ala (SEQ ID NO: 166); Gly-Gly-Cys-Cys-Ser-Xaa 4 -Xaa 5 -Xaa-Cys-Ile-Ala-Asn-Asn-Xaa 5 -Phe-Cys-Ala (SEQ ID NO: 167); Asp-Cys-Cys-Ser-Asn-Xaa 5 -Xaa 5 -Cys-Ser-Gln-Asn-Asn-Xaa 5 -Asp-Cys-Met (SEQ ID NO: 168); and Asp-Cys-Cys-Ser-Asn-Xaa 5 -Xaa 5 -Cys-Ala-Ilis-Asn-Asfl-Xaa 5 -Asp-Cys-Arg (SEQ ID NO: 169), wherein Xaa 1 is Glu or y-carboxy-Glu (Gla); Xaa 2 is Lys, N-methyl-Lys, NN-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa 3 is Trp (D or halo-Trp or neo-Trp; Xaa 4 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr or nitro-Tyr; and Xaa 5 is Pro or hydroxy-Pro; and the C-terminus contains a carboxyl or amide group, or derivatives thereof. The substantially pure a-conotoxin peptide of claim 11, wherein Xaa 2 is Lys. The substantially pure a-conotoxin peptide of claim 11, wherein Xaaj is Glu. The substantially pure a-conotoxin peptide of claim 11, wherein Xaa 3 is Trp. The substantially pure c-conotoxin peptide of claim 11, wherein Xaa 4 is Tyr. The substantially pure a-conotoxin peptide of claim 11, wherein Xaa 4 is mono-iodo-Tyr. The substantially pure a-conotoxin peptide of claim 11, wherein Xaa 4 is di-iodo-Tyr. WO 00/44776 WO 0044776PCI'/USOO/01979 74

18. The substantially pure a-conotoxin peptide of claim 10, which is modified to contain an 0- glycan, an S-glycan or an N-glycan. 19 The substantially pure c-conotoxin pepti de of claim I11 which is modified to contain an 0- glycan, an S-glycan or an N-glycan.

20. A substantially pure a-conotoxin peptide having the generic formula III: Xaa,-Xaa 2 -Xaa 3 Xaa 4 -Xaa 5 -Cys-Cys-Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Cys-Xaa 0 .XaaI 1 -Xaat 2 -Xaa 13 -Xaa 14 -Xaa, 5 -Xaa 6 Cys-Xaal 7 -Xaalg-Xaa 9 -Xaa 20 -Xaa 21 -Xaa 22 -Xaa 23 -Xaa 24 (SEQ ID NO:3), wherein Xa#t is des- Xaa,, Ser or Thr; Xaa 2 is des-Xaa 2 Asp, Glu, 'y-carboxy-Glu (Gla), Asn, Ser or Thr; Xaa 3 is des-Xaa 3 Ala, Gly, Asn, Ser, Thr, Pro, hydroxy-Pro, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyi-Lys, N,NN-trimethyl-Lys or any unnatural basic amino acid; Xaa 4 is des-Xaa 4 Ala, Val, Leu, le, Gly, Glu, Gla, Gin, Asp, Asn, Phe, Pro, hydroxy-Pro or any unnatural aromatic amino acid; Xaa 5 is des-Xaa 5 Thr, Ser, Asp, Glu, Gla, Gin, Gly, Val, Asp, Asn, Ala, Pro, hydroxy-Pro, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 6 is Thr, Ser, Asp, Asn, Met, Val, Ala, Gly, Leu, le, Phe, any unnatural aromatic amino acid, Pro, hydroxy-Pro, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 7 is le, Leu, Val, Ser, Thr, Gin, Asn, Asp, Arg, His, halo-His, Phe, any unnatural aromatic amino acid, homoarginine, ornithine, Lys, N-methyl-Lys, NN-dimethyl-Lys, NN,N-trimethyi-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr, nitro- Tyr or any unnatural hydroxy containing amino acid; Xaa 8 is Pro, hyroxy-Pro, Ser, Thr, le, Asp, Leu, Val, Gly, Ala, Phe, any unnatural aromatic amino acid, Arg, ornithine, homoarginine, Lys, N-methyi-Lys, NN-dimethyi-Lys, N,NN-trimethyi-Lys or any unnatural basic amino acid; Xaa 9 is Val, Ala, Gly, le, Leu, Asp, Ser, Thr, Pro, hydroxy-Pro, Arg, omithine, homnoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,NN-trimethyl-Lys or any unnatural basic amino acid; Xaa 10 is His, halo-His, Arg, homoarginine, ornithine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Asn, Aia, Ser, Thr, Phe, le, Leu, Gly, Trp (D or neo-Trp, halo-Trp, any unnatural aromatic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho- Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 1 ,I is Leu, Gin, Val, le, Gly, Met, Ala, Lys, N-methyl-Lys, NN-dimethyl-Lys, NNN-trimethyl-Lys, Ser, Thr, Arg, homoarginine, ornithine, any unnatural basic amino acid, Asn, Glu, Gla, Gln, Phe, Trp (D or neo-Trp, halo-Trp or any unnatural aromatic amino acid; Xaa12 is Glu, Gla, Gln, Asn, Asp, Pro, hydroxy-Pro, Ser, Gly, Thr, Lys, N-methyl-Lys, NN-dimethyl-Lys, NNN-trimethyl-Lys, Arg, homoarginine, ornithine, any unnatural basic amino acid, Phe, His, halo-His, any unnatural aromatic amino acid, Leu, Met, Gly, Ala, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa13 is His, halo-His, Asn, Thr, Ser, Ile, Val, Leu, Phe, any unnatural aromatic amino acid, Arg, homoarginine, ornithine, Lys, N-methyl-Lys, NN-dimethyl-Lys, NNN-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa14 is Ser, Thr, Ala, Gln, Pro, hydroxy-Pro, Gly, Ile, Leu, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, NN-dimethyl-Lys, NNN- trimethyl-Lys or any unnatural basic amino acid; Xaaj 5 is Asn, Glu, Gla, Asp, Gly, His, halo-His, A.1a, Leu, Gln, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, NN- dimethyl-Lys, NNN-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-sulpho-Tyr, 0-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa16 is Met, Ile, Thr, Ser, Val, Leu, Pro, hydroxy-Pro, Phe, any unnatural aromatic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0- sulpho-Tyr, 0-phospho-Tyr, nitro-Tyr, any unnatural hydroxy containing amino acid, Glu, Gla, Ala, His, halo-His, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, NN- dimethyl-Lys, NNN-trimethyl-Lys or any unnatural basic amino acid; Xaa17 is des- Xaa17, Gly, Asp, Asn, Ala, Ile, Leu, Ser, Thr, His, halo-His, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, NN-dimethyl-Lys, NNN-trimethyl-Lys or any unnatural basic amino acid; Xaa18 is des-Xaa18, Gly, Glu, Gla, Gln, Trp (D or neo- Trp, halo-Trp, any unnatural aromatic amino acid, Arg, ornithine, homoarginine, Lys, N- methyl-Lys, NN-dimethyl-Lys, NNN-trimethyl-Lys or any unnatural basic amino acid; Xaajq is des-Xaalg, Ser, Thr, Val, Ile, Ala, Arg, ornithine, homoarginine, Lys, N-methyl- Lys, NN-dimethyl-Lys, NNN-trimethyl-Lys or any unnatural basic amino acid; Xaa2O is des-Xaa2o, Val, Asp, His, halo-His, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N-dimethyl-Lys, NNN-trimethyl-Lys or any unnatural basic amino acid; Xaa2i is des-Xaa2l, Asn, Pro or hydroxy-Pro; Xaa22 is des-Xaa22, Arg, ornithine, homoarginine, 75a Lys, N-methyl-Lys, NN-dimethyl-Lys, NNN-trimethyl-Lys or any unnatural basic amino acid; Xaa 23 is des-Xaa 23 S. S S S S S. *SS S S S S 9* S S. 55 S S S S *SSS S S 55 555555 S S. 55 S S S S S S *5S5 WO 00/44776 WO 0044776PCT/USOO/01979 76 Ser or Thr; Xaa 24 is des-Xaa 24 Leu, le or Val; and the C-terminus contains a free carboxyl group or an amide group, with the proviso that Xaa 5 is not Gly, when Xaaj is des-Xaa 1 Xaa 2 is des-Xaa 2 Xaa 3 is des-Xaa 3 Xaa 4 is des-Xaa 4 Xaa 6 is Ser, Xaa 7 is His, Xaa 8 is Pro, Xaa 9 is Ala, Xaaj 0 is Ser, Xaa 12 is Val, Xaal 2 is Asn, Xaa 1 3 is Asn, Xaa, 4 is Pro, Xaa,5 is Asp, Xaa 16 is Ile, Xaa 1 7 is des-Xaal 7 Xaa, 8 is des-Xaa, 8 Xaa 19 is des-Xaa 19 Xaa 2 0 is des-Xaa 20 Xaa 2 is des-Xaa 2 Xaa 22 is des-Xaa 22 Xaa 23 is des-Xaa 23 and Xaa 24 is des-Xaa 24

21. A substantially pure a-conotoxin pe ptide of generic forumula III selected from the group consisting of: Gly-Cys-Cys-Ser-Asn-Xaa-Val-Cys-His-Leu-Xaa-His-Ser-Asn-Met-Cys (SEQ ID NO:22); Gly-Cys-Cys-Ser-Asn-Xaa 5 -Val-Cys-Arg-Gln-Asn-Asn-Ala-Xaa-Xaa 4 -Cys-Arg (SEQ ID NO:23); Xaa%-Gln-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaas-Xaa,-Ile-Gys-Arg (SEQ ID NO:24); Xaa-t-Xaa,-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Xaa 1 -Ile-Cys-Arg (SEQ ID 5 -Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Xaa 1 -Ile-Cys-Asp (SEQ ID NO:26); Xaa 5 (SEQ ID NO:27); Xaa 5 -Gln-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Gly-Ile-Cys-Arg (SEQ ID NO:28); Xaa 5 -Gln-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Xaal-Thr-Cys-Arg (SEQ ID NO:29); Xaa 5 -Gln-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaas-Xaa 1 -Val-Cys-Arg (SEQ ID Xaa 5 -Gln-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Ile-Asp--is-Xaa-Xaa -Ile-Cys-Arg (SEQ ID NO:3 1); Xaa 5 -Gln-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaas-Xaa,-Ile-Cys-Arg- Arg-Arg-Arg (SEQ ID NO:32); WO 00/44776 WO 0044776PCTIUSOO/01979 77 y-l-a-s-i-a5X a-Leu-Cys (SEQ ID 3); (SEQ ID NO:34); Gl-y-y-e-i-a5AaCsAs-a-s-i-a5Xa-l-y (SEQ ID 2 -Thr-Gfln-Xaa -Xaa 5 -Cys-Arg- Xaa 1 -Ser (SEQ ID NO:36); (SEQ ID NO:37); sSrGl-s-s-a5X a-h-y-r-l (SEQ ID NO:38); (SEQ ID NO:3 9); Gl-y-y-e-i-a5Xa-y-h-e-s-s-a5ApXa-y (SEQ ID a-y-l-l-a2A nX a-i- e-y-l (SEQ ID NO:4 (SEQ ID NO:43); (SEQ ID NO:44); Gl-y-y-e-s-asVlCsHs-a-aHsXa-alLuCsAg Arg-Arg-Arg (SEQ ID Gl-l-y-y-e-h-a5AaCsAgXa-a5AgXa-alM tCs Gly (SEQ ID NO:46); Xa-Leu-Cys- Gly (SEQ ID NO:47); Xaa 5 GlCysCysSerAspXaaAgCyssalGysnaas-Xa-erys Gly (SEQ ID NO:48); Xa6VlCsCsSrApXa-r-y-s-a-l-i-asXa-l-y-l (SEQ ID NO:49); WO 00/44776 WO 0044776PCT/USOO/01979 78 Gly-Cys-Cys-Ser-Arg-Xaa 5 -Xaa 5 -Cys-Ile-Ala-Asn-Asn-Xaa 5 -Asp-Leu-Cys (SEQ ID Xaas-Gln-Cys-Cys-Ser-His-Leu-Ala-Cys-Asn-Va-Asp-His-Xaa 5 -Xaa -Ile-Cys-Arg (SEQ ID NO:5 1); Gly-Cys-Cys-Ser-Xaa 4 -Phe-Asp-Cys-Arg-Met-Met-Phe-Xaa 5 -Xaa -Met-Cys-Gly- Xaa 3 -Arg (SEQ ID NO:52); Gly-Gly-Cys-Cys-Ser-Phe-Ala-Ala-Cys-Arg-Xaa 2 -Xaa 4 -Arg-Xaa 5 -Xaa -Met-Cys- Gly (SEQ ID NO:53); Gly-Gly-Cys-Cys-Phe-His-Xaa 5 -Val-Cys-Xaa 4 -Ile-Asn-Leu-Leu-Xaa,-Met-Cys-Arg- Gln-Arg (SEQ ID NO:54); Ser-Ala-Thr-Cys-Cys-Asn-Xaa 4 -Xaa 5 -Xaa-Cys-Xaa 4 -Xaal-Thr-Xaa 4 -Xaas-Xaa,-Ser- Cys-Leu (SEQ ID NO:5 Ala-Cys-Cys-Ala-Xaa 4 -Xaa5-Xaa 5 -Cys-Phe-Xaal-Ala-Xaa 4 -Xaa 5 -Xaa-Arg-Cys-Leu (SEQ ID NO:56); Asn-Ala-Xaa 1 -Cys-Cys-Xaa 4 -Xaa 4 -Xaa 5 -Xaa 5 -Cys-Xaa 4 -Xaal-Ala-Xaa 4 -Xaa 5 -Xaa Ile-Cys-Leu (SEQ ID NO:57); Xaa 1 -Cys-Cys-Thr-Asn-Xaa 5 -Val-Cys-His-Ala-Xaa -His-Gln-Xaa 1 -Leu-Cys-Ala- Arg-Arg-Arg (SEQ ID NO: 170); Gly-Cys-Cys-Ser-Asn-Xaa,-Val-Cys-His-Leu-Xaa 1 -His-Ser-Asn-Leu-Cys (SEQ ID NO: 17 1); Xaa 2 -Cys-Cys-Thr-Asn-Xaa 5 -Val-Cys-His-Val-Xaa -His-Gln-Xaa 1 -Leu-Cys-Ala- Arg-Arg-Arg (SEQ ID NO: 172); Xaa 6 -Xaa-Cys-Cys-Ser-Xaa 4 -Xaa 5 -Ala-Cys-Asn-Leu-Asp-His-Xaa 5 -Xaa -Leu-Cys (SEQ ID NO: 173); Xaa 5 -Xaa-Cys-Cys-Ser-Asp-Xaa-Arg-Cys-Asn-Ser-Thr-His-Xaa 5 -Xaal-Leu-Cys- Gly (SEQ ID NO: 174); Leu-Asn-Cys-Cys-Met-Ile-Xaa 5 -Xaa 5 -Cys-Xaa 3 -Xaa 2 -Xaa 2 -Xaa 4 -Gly-Asp-Arg-Cys- Ser-Xaa 1 -Val-Arg (SEQ ID NO: 175); Ala-Phe-Gly-Cys-Cys-Asp-Leu-Ile-Xaa 5 -Cys-Leu-Xaal-Arg-Xaa 4 -Gly-Asn-Arg- Cys-Asn-Xaa, -Val-His (SEQ ID NO: 176); Leu-Gly-Cys-Cys-Asn-Val-Thr-Xaa 5 -Cys-Xaa 3 -Xaa-Xaa 2 -Xaa 4 -Gly-Asp-Xaa 2 -Cys- Asn-Xaal-Val-Arg (SEQ ID NO: 177); WO 00/44776 WO 0044776PCT/USOO/01979 79 Asp-Xaa 1 -Cys-Cys-Ser-Asn-Xaa 5 -Ala-Cys-Arg-Val-Asn-Asn-Xaa 5 -His-Val-Cys- Arg-Arg-Arg (SEQ ID NO: 178); Leu-Asn-Cys-Cys-Ser-le-Xaa 5 -Gly-Cys-Xaa 3 -Asn-Xaa -Xaa 4 -Xaa,-Asp-Arg-Cys- Ser-Xaa 2 -Val-Arg (SEQ ID NO: 179); Gly-Gly-Cys-Cys-Ser-His-Xaa 5 -VaI-Cys-Xaa 4 -Phe-Asn-Asn-Xaa 5 -Gln-Met-Cys-Arg (SEQ ID NO: 180); Gly-Gly-Cys-Cys-Ser-His-Xaa 5 -VaI-Cys-Asn-Leu-Asn-Asn-Xaa 5 -Gln-Met-Cys-Arg (SEQ ID NO: 18 1); Gly-Cys-Cys-Ser-His-Xaa 5 -Xaa 5 -Cys-Xaa 4 -Ala-Asn-Asn-Gln-Ala-Xaa 4 -Cys-Asn (SEQ ID NO: 182); Gly-Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ser-Val-Thr-His-Xaa 5 -Xaa 1 -Leu-Cys(SEQ ID NO: 183); Gly-Gly-Cys-Cys-Ser-Xaa 4 -Xaa 5 -Ala-Cys-Ser-VaI-Xaal-His-Gln-Asp-Leu-Cys-Asp (SEQ ID NO: 184); Val-Ser-Cys-Cys-Va-Va-Arg-Xaa 5 -Cys-Xaa 3 -1e-Arg-Xa 4 -Gln-Xaa -Xaa 1 -Cys- Leu-Xaa,-Ala-Asp-Xaa 5 -Arg-Thr-L eu (SEQ ID NO: 185); Xaa 6 -Asn-Cys-Cys-Ser-Ile-Xaa 5 -Gly-Cys-Xaa 3 -Xaa 1 -Xaa 2 -Xaa 4 -Gly-Asp-Xaa 2 -Cys- Ser-Xaa 1 -Val-Arg (SEQ ID NO: 186); Gly-Cys-Cys-Ser-Asn-Xaas-Val-Cys-His-Leu-Xaa 1 -His-Xaas-Asn-Ala-Cys (SEQ ID NO: 187); Gly-Cys-Cys-Ser-Asn-Xaa 5 -Ile-Cys-Xaa 4 -Phe-Asn-Asn-Xaas-Arg-Ile-Cys-Arg(SEQ ID NO: 188); Xaa,-Cys-Cys-Ser-Gln-Xaa 5 -Xaa 5 -Cys-Arg-Xaa 3 -Xaa 2 -His-Xaa 5 -Xaa -Leu-Cys-Ser (SEQ ID NO: 189); Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ala-Gly-Asn-Asn-Gln-His-Ile-Cys (SEQ ID NO: 190); Gly-Cys-Cys-Ala-Va-Xaa 5 -Ser-Cys-Arg-Leu-Arg-Asn-Xaa 5 -Asp-Leu-Cys-Gly-Gly (SEQ ID NO: 19 1); Gly-Cys-Cys-Ser-His-Xaas-Ala-Cys-Asn-Val-Asn-Asn-Xaa 5 -His-Ile-Cys (SEQ ID NO: 192); Thr-Xa 5 -Xaa-Xaa 1 -Cys-Cys-Xaas-Asn-Xaa 5 -Xaa 5 -Cys-Phe-Ala-Thr-Asn-Ser-Asp- Ile-Cys-Gly (SEQ ID NO: 193); WO 00/44776 WO 0044776PCT/USOO/01 979 Asp-Ala-Cys-CYS-Ser-Asp-Xaa 5 -Arg-Cys-Ser-Gly-Xaa 2 -His-Gln-Asp-Leu-Cys(SEQ ID NO: 194); Xaal-Asp-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Leu-Cys(SEQ ID NO: 195); Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ala-Gly-Ser-Asn-Ala-His-Ile-Cys (SEQ ID NO: 196); Xaa Asp-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Ser-VaI-Gly-His-Gln-Asp-Met-Cys (SEQ ID NO: 197); Gly-Cys-Cys-Ser-His-Xaa,-Ala-Cys-Ala-Gly-Asn-Asn-Xaa 5 -His-Ile-Cys (SEQ ID NO: 198); Gly-Cys-Cys-Gly-Asn-Xaa 5 -Ser-Cys-Ser-Ile-His-JIe-Xaa 5 -Xaa 4 -VaI-Cys-Asn (SEQ ID NO: 199); Thr-Asp-Ser-Xaa,-Xaa,-Cys-Cys-Leu-Asp-Ser-Arg-Cys-Ala-Gly-Gln-His-Gln-Asp- Leu-Cys-Gly (SEQ ID NO:200); Gly-Cys-Cys-Ser-Asn-Xaa,-Xaas-Cys-Xaa 4 -Ala-Asn-Asn-Gln-Ala-Xaa 4 -Cys-Asn (SEQ ID NO:201); Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ser-Val-Asn-Asn-Xaa 5 -Asp-Ile-Cys (SEQ ID NO:202); Gly-Xaa 2 -Cys-Cys-Ile-Asn-Asp-Ala-Cys-Arg-Ser-Xaa 2 -His-Xaa 5 -Gln-Xaa 4 -Cys-Ser (SEQ ID NO:203); Gly-Cys-Cys-Xaa 4 -Asn-Ile-Ala-Cys-Arg-Ile-Asn-Asn-Xaa 5 -Arg-Xaa 4 -Cys-Arg(SEQ ID NO:204); Gly-Cys-Cys-Ser-His-Xaa 5 -Val-Cys-Arg-Phe-Asn-Xaa 4 -Xaa 5 -Xaa 2 -Xaa 4 -Cys-Gly (SEQ ID NO:205); Asp-Xaa,-Cys-Cys-Ala-Ser-Xaa 5 -Xaa,-Cys-Arg-Leu-Asn-Asn-Xaa 5 -Xaa 4 -Val-Cys- His (SEQ ID NO:206); Gly-Cys-Cys-Ser-Asn-Xaa 5 -Val-Cys-Xaa 3 -Gln-Asn-Asn-Ala-Xaa, -Xaa 4 -Cys-Arg- Xaal-Ser (SEQ ID NO:207); Gly-Cys-Cys-Ser-His-Xaa,-Xaa 5 -Cys-Ala-Gln-Asn-Asn-Gln-Asp-Xaa 4 -Cys (SEQ ID NO:208); Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys- Ser-Gly-Asn-Asn-Arg-Xaa, -Xaa 4 -Cys-Arg- Xaa 1 -Ser (SEQ ID NO:209); WO 00/44776 PCT/USOO/01979 81 Asp-Xaa 5 -Cys-Cys-Ser-Xaa 4 -Xaa 5 -Asp-Cys-Gly-Ala-Asf-His-Xaa-Xaa,-Ile-Cys- Gly (SEQ ID NO:2 XalCsCsSrGnXa-asCy-r-a3Xa-i-a Xa-Leu-Cys-Ser (SEQ ID NO:21 1); Gly.Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ala-Gly-Asfl-Asfl-Xaa-His-Ile-Cys (SEQ ID NO:212); (SEQ ID NO:213); Xaa,-a 1 CsCsSrApXa AgCsSrVlGy-i-i-s-e-y-r (SEQ ID NO:214); Gl-l-y-y-e-AnXa-l y-e-VlAnHsLuXa-Met-Cys (SEQ ID NO:215); (SEQ ID NO:2 16); Cy-y-e-s-asSrCsXa-r-LuHsSrLuAaCsTrGyIe Val-Asn-Arg (SEQ ID NO:2 17); (SEQ ID NO:21 8); As-aC sC sSrApX a-r-y-i-l-s-s-r-s-i-y-l (SEQ ID NO:2 19); ID NO:220); Gl-y-y-e-i-aV lC sX a-a-r-a4Xa-s-e-y-r (SEQ ID NO:22 1); Gl-y-y-e-i-a5AaCsAnVlAnAnXa-i-l-y (SEQ ID NO:222); Gl-y-y-e-i-a5VlCsXa2VlAgXa-e-s-e-y(SEQ ID NO:223); Gl-l-y-y-e-i-a5AaCsXa2VlHsPeXa-i-e-y(E ID NO :224); Arg-Arg (SEQ ID NO:225); WO 00/44776 WO 0044776PCT/USOO/01979 82 Gly-Cys-Cys-Ser-His-Xaa 5 -Val-Cys-Asn-Leu-Ser-Asn-Xaa 5 -Gln-Ile-Cys-Arg (SEQ ID NO:226); Xaa6-Xaa 1 -Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Va1-Asp-His-Xaa 5 -Xaal-Ile-Cys-Arg (SEQ ID NO:227); Gly-Cys-Cys-Ser-Asn-Xaa 5 -Ala-Cys-Leu-Val-Asn-His-Ile-Arg-Phe-Cys-Gly (SEQ ID NO:228); Asp-Cys-Cys-Asp-Asp-Xaa 5 -Ala-Cys-Thr-VaI-Asn-Asn-Xaa 5 -Gly-Leu-Cys-Thr (SEQ ID NO:229); and Gly-Cys-Cys-Ser-Asn-Xaa 5 -Xaa 5 -Cys-Ile-Ala-Xaa 2 -Asn-Xaas-His-Met-Cys-Gly- Gly-Arg-Arg (S.EQ ID NO:230), wherein Xaa I is Glu or y-carboxy-Glu (Gla); Xaa 2 is Lys, N-methyl-Lys, NN-dimethyl-Lys or N,NN-trimethyl-Lys; Xaa 3 is Trp (D or halo-Trp or neo-Trp; Xaa 4 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, 0-suipho-Tyr, 0-phospho-Tyr or nitro-Tyr; and Xaa 5 is Pro or hydroxy-Pro; Xaa 6 is Gin or pyro-Glu; and the C-terminus contains a carboxyl or amide group, or derivatives thereof.

22. The substantially pure a-conotoxin peptide of claim 21, wherein Xaa 2 is Lys.

23. The substantially pure a-conotoxin peptide of claim 2 1, wherein Xaa, is Glu.

24. The substantially pure a-conotoxin peptide of claim 21, wherein Xaa 3 is Trp. The substantially pure a-conotoxin peptide of claim 21, wherein Xaa 4 is Tyr.

26. The substantially pure a-conotoxin peptide of claim 2 1, wherein Xaa 4 is mono-iodo-Tyr.

27. The substantially pure a-conotoxin peptide of claim 21, wherein Xaa 4 is di-iodo-Tyr.

28. The substantially pure a-conotoxin peptide of claim 20, which is modified to contain an 0- glycan, an S-glycan or an N-glycan. WO 00/44776 PCT/US00/01979 83 29 The substantially pure a-conotoxin peptide of claim 21 which is modified to contain an O- glycan, an S-glycan or an N-glycan. A substantially pure a-conotoxin peptide seleceted from the group consisting of: Cys-Cys-Thr-Ile-Xaas-Ser-Cys-Xaa4-Xaai-Xaa2-Xaa2-Xaa2-Ile-Xaa2-Ala-Cys-Val- Phe (SEQ ID NO:231) and Gly-Cys-Cys-Gly-Asn-Xaas-Ala-Cys-Ser-Gly-Ser-Ser-Xaa2-Asp-Ala-Xaas-Ser-Cys (SEQ ID NO:232), wherein Xaa, is Glu or y-carboxy-Glu (Gla); Xaa 2 is Lys, N-methyl-Lys, N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa 4 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaas is Pro or hydroxy-Pro; and the C-terminus contains a carboxyl or amide group, or derivatives thereof.

31. The substantially pure a-conotoxin peptide of claim 30, wherein Xaa 2 is Lys.

32. The substantially pure a-conotoxin peptide of claim 30, wherein Xaa, is Glu.

33. The substantially pure a-conotoxin peptide of claim 30, wherein Xaa 4 is Tyr.

34. The substantially pure a-conotoxin peptide of claim 30, wherein Xaa 4 is mono-iodo-Tyr. The substantially pure a-conotoxin peptide of claim 30, wherein Xaa 4 is di-iodo-Tyr.

36. The substantially pure a-conotoxin peptide of claim 30, which is modified to contain an O- glycan, an S-glycan or an N-glycan.

37. An isolated nucleic acid comprising a nucleic acid coding for an a-conotoxin precursor comprising an amino acid sequence selected from the group of amino acid sequences set forth in Tables 1-134. 84

38. The nucleic acid of claim 37 wherein the nucleic acid comprises a nucleotide sequence selected from the group of nucleotide sequences set forth in Tables 1- 134 or their complements.

39. A substantially pure a-conotoxin protein precursor comprising an amino acid sequence selected from the group of amino acid sequences set forth in Tables 1-

134. A substantially pure a-conotoxin peptide, substantially as herein described with reference to any one of the examples but excluding comparative examples. 41. An isolated nucleic acid, substantially as herein described with reference to any one of the examples but excluding comparative examples. 42. A substainally pure a-conotoxin protein precursor, substantially as herein described with reference to any one of the examples but excluding comparative examples. DATED this 2 nd day of December 2003 BALDWIN SHELSTON WATERS Attorneys for: Cognextix, Inc. and University Of Utah Research Foundation 0 0 *S 0..0 SO. :0 S *o S 0* s 0o *oo 0** I