WO2000044776A1

WO2000044776A1 - Alpha-conotoxin peptides

Info

Publication number: WO2000044776A1
Application number: PCT/US2000/001979
Authority: WO
Inventors: Maren Watkins; Baldomero M. Olivera; David R. Hillyard; J. Michael Mcintosh; Robert M. Jones
Original assignee: University Of Utah Research Foundation; Cognetix, Inc.
Priority date: 1999-01-29
Filing date: 2000-01-28
Publication date: 2000-08-03
Also published as: AU2973500A; CA2361534A1; EP1147130A4; CA2743116A1; AU770076B2; CA2361534C; CA2743116C; JP2002534996A; EP1147130A1

Abstract

The invention relates to relatively short peptides (termed α -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.

Description

TITLE OF THE INVENTION ALPHA-CONOTOXIN PEPTIDES

This invention was made with Government support under Grant No. PO 1 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

The invention relates to relatively short peptides (termed α-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 neuromuscular receptors and may be equivalent in their pharmacological diversity to the 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 normally 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 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 α-, μ- and ω-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 α-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 α-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 application Serial No. 09/ , filed 21 January 2000 (Attorney Docket No. 2314-178. A) and international patent application No.

PCT/US00/ , filed 21 January 2000 (Attorney Docket No. 2314-138.PCT), each incorporated by reference herein. Additional α-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 α-conotoxins are described in U.S. Serial No. 09/219,446, filed 22

December 1998, incorporated herein by reference. In this application, α-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.

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

SUMMARY OF THE INVENTION

The invention relates to relatively short peptides (termed α-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.

More specifically, the present invention is directed to α-conotoxin peptides having the general formula I:

Xaa₁-Xaa₂-Xaa₃-Xaa₄-Xaa₅-Cys-Cys-Xaa₆-Xaa₇-Xaa₈-Xaa₉-Cys-Xaa₁o-Xaa₁₁-Xaa₁₂-Cys- Xaa₁₃ (SEQ ID NOl :), wherein Xaa, is des-Xaa„ He, Leu or Val; Xaa₂ is des-Xaa₂, Ala or Gly; Xaa₃ is des-Xaa₃, Gly, Trp (D or L), neo-Trp, halo-Trp or any unnatural aromatic amino acid; Xaa₄ is des- Xaa₄, Asp, Phe, Gly, Ala, Glu,γ-carboxy-Glu (Gla) or any unnatural aromatic amino acid; Xaa₅ is Glu, Gla, Asp, Ala, Thr, Ser, Gly, He, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O- phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa₆ 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; Xaa₇ 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; Xaa₈ is Ser, Thr, Asn, Ala, Gly, His, halo-His, Pro or hydroxy-Pro; Xaaα 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; Xaa₁₀ is Gly, Ser, Thr, Ala, Asn, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N-N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid;

Xaa,, 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-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,₂ is Asn, His, halo-His, He, 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,₃ is des-Xaa₁₃, Val, He, Leu, 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 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 L). 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, e.g., tetrazolyl derivatives of Gly and Ala.

More specifically, the present invention is directed to α-conotoxin peptides having the general formula II:

Xaa₁-Xaa₂-Xaa₃-Xaa₄-Cys-Cys-Xaa₅-Xaa₅-Xaa₇-Xaa_g-Cys-Xaa₉-Xaa]₀-Xaa,₁-Xaa,₂-Xaa₁₃- Xaa,₄-Cys-Xaa,₅-Xaa,₆-Xaa,₇ (SEQ ID NO:2), wherein Xaa, is des-Xaa,, Asp, Glu or γ-carboxy-Glu (Gla); Xaa₂ is des-Xaa₂, Gin, Ala, Asp, Glu, Gla; Xaa₃ is des-Xaa₃, Gly, Ala, Asp, Glu, Gla, Pro or hydroxy-Pro; Xaa₄ is des-Xaa₄, Gly, Glu, Gla, Gin, Asp, Asn, Pro or hydroxy-Pro; Xaa₅ is Ser, Thr, Gly, Glu, Gla, Asn, Trp (D or L), neo-Trp, halo-Trp, 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; Xaa₆ 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; Xaa₇ is Pro or hydroxy-Pro; Xaa_g is Ala, Ser, Thr, Asp, Val, He, 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, He, Leu, Val, Ala, Thr, Ser, Pro, hydroxy-Pro, Phe, Trp (D or L), neo-Trp, halo-Trp, 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; Xaa₁₀ 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; Xaa, , is Thr, Ser, His, halo-His, Leu, He, Val, Asn, Met, Pro, hydroxy-Pro, 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,₂ is Asn, Pro, hydroxy-Pro, Gin, 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-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa,₃ is des-Xaa₁₃, 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; Xaa₁₄ is des-Xaa₁₄, He, 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, O-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 L), 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-Xaa₁₆, Trp (D or L), 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 L). 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, e.g., tetrazolyl derivatives of Gly and Ala.

More specifically, the present invention is directed to α-conotoxin peptides having the general formula III: Xaa₁-Xaa₂-Xaa₃-Xaa₄-Xaa₅-Cys-Cys-Xaa₆-Xaa₇-Xaa₈-Xaa₉-Cys-Xaa,₀-Xaa_n-Xaa]₂-Xaa,₃-

Xaa,₄-Xaa,₅-Xaa,₆-Cys-Xaa,₇-Xaaι_g-Xaa,₉-Xaa₂₀-Xaa₂,-Xaa₂₂-Xaa₂₃-Xaa₂₄ (SEQ ID NO:3), wherein Xaa, is des-Xaa,, Ser or Thr; Xaa₂ is des-Xaa₂, Asp, Glu, γ-carboxy-Glu (Gla), Asn, Ser or Thr; Xaa₃ is des-Xaa₃, Ala, Gly, Asn, Ser, Thr, 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; Xaa₄ is des-Xaa₄, Ala, Val, Leu, He, Gly, Glu, Gla, Gin, Asp, Asn, Phe, Pro, hydroxy-Pro or any unnatural aromatic amino acid; Xaa₅ is des-Xaa₅, 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; Xaas is Thr, Ser, Asp, Asn, Met, Val, Ala, Gly, Leu, He, Phe, any unnatural aromatic amino acid, 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; Xaa₇ is He, 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 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; Xaa₈ is Pro, hyroxy-Pro, Ser, Thr, He, 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_*, is Val, Ala, Gly, He, 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 unnatural basic amino acid; Xaa,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, Ala, Ser, Thr, Phe, He,

Leu, Gly, Trp (D or L), 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; Xaa, , is Leu, Gin, Val, He, 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 L), neo-Trp, halo-Trp or any unnatural aromatic amino acid; Xaa,₂ 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,₃ is His, halo-His, Asn, Thr, Ser, He, 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-Try, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-

Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa,₄ is Ser, Thr, Ala, Gin, Pro, hydroxy-Pro, Gly, He, Leu, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N-N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa,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; Xaa₁₆ is Met, He, Thr, Ser, Val, Leu, Pro, hydroxy-Pro, Phe, any unnatural aromatic amino acid, Tyr, nor-Tyr, mono- halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, any unnatural hydroxy containing amino acid, Glu, Gla, Ala, His, halo-His, 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, Gly, Asp,

Asn, Ala, He, Leu, Ser, Thr, His, halo-His, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N-N- dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa,₈ is des-Xaa, ₈, Gly, Glu, Gla, Gin, Trp (D or L), neo, 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,₉ is des-Xaa,₉, Ser, Thr, Val, He, Ala, Arg, ornithine, homoarginine, Lys, N-methyl-

Lys, N-N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa₂₀ is des-Xaa₂₀. Val, Asp, His, halo-His, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N-N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa₂, is des-Xaa₂,, Asn, Pro or hydroxy- Pro; Xaa₂₂ is des-Xaa₂₂, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N-N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa₂₃ is des-Xaa₂₃, Ser or Thr; Xaa₂₄ is des- Xaa₂₄, Leu, He or Val; with the proviso that (a) Xaa₅ is not Gly, when Xaa, is des-Xaa,, Xaa₂ is des- Xaa₂, Xaa₃ is des-Xaa₃, Xaa₄ is des-Xaa₄, Xaa₆ is Ser, Xaa₇ is His, Xaa₈ is Pro, Xaa<, is Ala, Xaa,₀ is Ser, Xaa,, is Val, Xaa,₂ is Asn, Xaa,₃ is Asn, Xaa,₄ is Pro, Xaa,₅ is Asp, Xaa,₆ is He, Xaa,₇ is des- Xaa,₇, Xaa,₈ is des-Xaa,₈, Xaa,₉ is des-Xaa,₉, Xaa₂₀ is des-Xaa₂₀, Xaa₂, is des-Xaa₂,, Xaa₂₂ is des- Xaa₂₂, Xaa₂₃ is des-Xaa₂₃, and Xaa₂₄ is des-Xaa₂₄. 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 L). 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, e.g., tetrazolyl derivatives of Gly and Ala. The present invention is also directed to novel specific α-conotoxin peptides of general formula I having the formulas:

Asp-Xaa,-Cys-Cys-Ser-Asp-Ser-Arg-Cys-Gly-Xaa₂-Asn-Cys-Leu (SEQ ID NO:4);

Ala-Cys-Cys-Ser-Asp-Arg-Arg-Cys-Arg-Xaa₃-Arg-Cys (SEQ ID NO:5);

Phe-Thr-Cys-Cys-Arg-Arg-Gly-Thr-Cys-Ser-Gln-His-Cys (SEQ ID NO:6); Asp-Xaa₄-Cys-Cys-Arg-Arg-His-Ala-Cys-Thr-Leu-He-Cys (SEQ ID NO:7);

Asp-Xaa₄-Cys-Cys-Arg-Xaa₅-Xaa₅-Cys-Thr-Leu-Ile-Cys (SEQ ID NO:8);

Gly-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Arg-Xaa₄-Arg-Cys-Arg (SEQ ID NO:9);

Gly-Gly-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ala-Xaa₃-Arg-Cys (SEQ ID NO: 10);

He- Ala-Xaa₃- Asp-Ile-Cys-Cys-Ser-Xaa, -Xaa₅-Asp-Cys-Asn-His-Xaa₂-Cy s- Val (SEQ ID NOJ 1); and

Gly-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Xaa₂-His-Gln-Cys (SEQ ID NO: 12), wherein Xaa, is Glu or γ-carboxy-Glu (Gla); Xaa₂ is Lys, N-methyl-Lys, N-N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa₃ is Trp (D or L), halo-Trp or neo-Trp; Xaa₄ is Tyr, nor-Tyr, mono-halo- Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa₅ 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 Trp. In addition, the His residues may be substituted with halo-His; the Arg residues may be substituted by Lys, ornithine, homoargine, 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, ornithine, homoargine, 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 L). 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, e.g., tetrazolyl derivatives of Gly and Ala. More specifically, the present invention is directed to the following α-conotoxin peptides of general formula I:

Iml J : SEQ ID NO:4, wherein Xaa, is Glu and Xaa₂ is Lys;

Iml .2: SEQ ID NO:5, wherein Xaa₃ is Trp; Rgl .2: SEQ ID NO.6;

Rgl .6: SEQ ID NO:7, wherein Xaa₄ is Tyr;

Rgl .6A: SEQ ID NO:8, wherein Xaa₄ is Tyr and Xaa₅ is Pro;

Rgl .7: SEQ ID NO:9, wherein Xaa₄ is Tyr and Xaa₅ is Pro;

Rgl .9: SEQ ID NOJ 0, wherein Xaa₃ is Trp and Xaa₅ is Pro; Rgl J 0: SEQ ID NOJ 1 , wherein Xaa, is Glu, Xaa₂ is Lys, Xaa₃ is Trp and Xaa₅ is

Pro; and Rgl.l 1 : SEQ ID NOJ2, wherein Xaa₂ is Lys and Xaa₅ is Pro.

The C-terminus of Iml J, Rgl.7 an Rgl JO preferably contains a free carboxyl group. The C- terminus of Iml.2, Rgl.2, Rgl.6, Rgl.6A, Rgl.9 and Rgl.l 1 preferably contains an amide group. The present invention is further directed to novel specific α-conotoxin peptides of general formula II having the formulas:

Cys-Cys-Ser-Asp-Xaa₅-Ala-Cys-Xaa₂-Gln-Thr-Xaa₅-Gly-Cys-Arg (SEQ ID NO: 13); Cys-Cys-Xaa,-Asn-Xaa₅-Ala-Cys-Arg-His-Thr-Gln-Gly-Cys (SEQ ID NO: 14); Gly-Cys-Cys-Xaa₃-His-Xaa₅-Ala-Cys-Gly-Arg-His-Xaa₄-Cys (SEQ ID NO: 15); Ala-Xaa₅-Cys-Cys-Asn-Asn-Xaa₅-Ala-Cys-Val-Xaa₂-His-Arg-Cys (SEQ ID NO: 16);

Ala-Xaa₅-Gly-Cys-Cys-Asn-Asn-Xaa₅-Ala-Cys-Val-Xaa₂-His-Arg-Cys (SEQ ID NO: 17); Xaa₅-Xaa₅-Cys-Cys-Asn-Asn-Xaa₅-Ala-Cys-Val-Xaa₂-His-Arg-Cys (SEQ ID NO: 18); Asp-Xaa,-Asn-Cys-Cys-Xaa₃-Asn-Xaa₅-Ser-Cys-Xaa₅-Arg-Xaa₅-Arg-Cys-Thr (SEQ ID NO: 19); Gly-Cys-Cys-Ser-Thr-Xaa₅-Xaa₅-Cys-Ala-Val-Leu-Xaa₄-Cys (SEQ ID NO:20);

Gly-Cys-Cys-Gly-Asn-Xaa₅-Asp-Cys-Thr-Ser-His-Ser-Cys (SEQ ID NO:21); Gly-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ala-His-Asn-Asn-Xaa₅-Asp-Cys-Arg (SEQ ID NO:42);

Gly-Cys-Cys-Xaa₄-Asn-Xaa₅-Val-Cys-Xaa₂-Xaa₂-Xaa₄-Xaa₄-Cys-Xaa₃-Xaa₂ (SEQ ID NOJ54);

Xaa₆-Xaa, -Xaa₅-Gly-Cys-Cys- Arg-His-Xaa₅-Ala-Cys-Gly-Xaa₂- Asn- Arg-Cys (SEQ ID NO.155); Cys-Cys-Ala-Asp-Xaa₅-Asp-Cys-Arg-Phe-Arg-Xaa₅-Gly-Cys (SEQ ID NO: 156);

Gly-Cys-Cys-Xaa₄-Asn-Xaa₅-Ser-Cys-Xaa₃-Xaa₅-Xaa₂-Thr-Xaa₄-Cys-Ser-Xaa₃-Xaa₂ (SEQ ID NO: 157);

Cys-Cys-Ser-Asn-Xaa₅-Thr-Cys-Xaa₂-Xaa,-Thr-Xaa₄-Gly-Cys (SEQ ID NO: 158); Cys-Cys-Ala-Asn-Xaa₅-Ile-Cys-Xaa₂-Asn-Thr-Xaa Gly-Cys (SEQ ID NO: 159);

Cys-Cys-Asn-Asn-Xaa₅-Thr-Cys-Xaa₂-Xaa,-Thr-Xaa₄-Gly-Cys (SEQ ID NO: 160);

Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-Xaa₂-Xaa,-Thr-Xaa₄-Gly-Cys (SEQ ID NO: 161);

Gly-Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Xaa₅-Cys-Ile-Ala-Ser-Asn-Xaa₅-Xaa₂-Cys-Gly (SEQ ID NO: 162); Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Ser-Ala-Met-Ser-Xaa₅-He-Cys (SEQ ID NOJ 63);

Gly-Cys-Cys-Xaa₂-Asn-Xaa₅-Xaa₄-Cys-Gly-Ala-Ser-Xaa₂-Thr-Xaa₄-Cys(SEQIDNO:164);

Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Xaa₅-Cys-Phe-Ala-Thr-Asn-Xaa₅-Asp-Cys (SEQ ID NOJ 65);

Gly-Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Xaa₅-Cys-Ile-Ala-Asn-Asn-Xaa₅-Leu-Cys-Ala (SEQ ID NOJ66); Gly-Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Xaa₅-Cys-Ile-Ala-Asn-Asn-Xaa₅-Phe-Cys-Ala (SEQ ID

NO: 167);

Asp-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ser-Gln-Asn-Asn-Xaa₅-Asp-Cys-Met (SEQ ID NO: 168); and

Asp-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ala-His-Asn-Asn-Xaa₅-Asp-Cys-Arg (SEQ ID NO: 169), wherein Xaa, is Glu or γ-carboxy-Glu (Gla); Xaa₂ is Lys, N-methyl-Lys, N-N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa₃ is Trp (D or L), halo-Trp or neo-Trp; Xaa₄ is Tyr, nor-Tyr, mono-halo- Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa₅ 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 Trp. In addition, the His residues may be substituted with halo-His; the Arg residues may be substituted by Lys, ornithine, homoargine, 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, ornithine, homoargine, 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 L). 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, e.g., tetrazolyl derivatives of Gly and Ala. More specifically, the present invention is directed to the following α-conotoxin peptides of general formula II:

Snl .1 : SEQ ID NO: 13, wherein Xaa₂ is Lys and Xaa₅ is Pro;

Snl .2: SEQ ID NOJ4, wherein Xaa, is Glu and Xaa₅ is Pro;

SI 1.3 : SEQ ID NO: 15, wherein Xaa₃ is Trp, Xaa₄ is Tyr and Xaa₅ is Pro; A1.2: SEQ ID NOJ6, wherein Xaa₂ is Lys and Xaa₅ is Pro;

Bui J : SEQ ID NOJ 7, wherein Xaa₂ is Lys and Xaa₅ is Pro;

Bui .2: SEQ ID NO: 18, wherein Xaa₂ is Lys and Xaa₅ is Pro;

Bui .3 : SEQ ID NO: 19, wherein Xaa, is Glu, Xaa₃ is Trp and Xaa₅ is Pro;

Bui .4: SEQ ID NO:20, wherein Xaa₄ is Tyr and Xaa₅ is Pro ; Crl.3: SEQ ID NO.21, wherein Xaa₅ is Pro;

Di 1 J : SEQ ID NO:42 wherein Xaa₅ is Pro;

Msl .7: SEQ ID NO: 154, wherein Xaa₂ is Lys, Xaa₃ is Trp, Xaa₄ is Tyr and Xaa₅ is

Pro; P1.7: SEQ ID NO: 155, wherein Xaa, is Glu, Xaa₂ is Lys, Xaa₅ is Pro and Xaa,; is Gin;

Msl.2: SEQ ID NO: 156, wherein Xaa₅ is Pro;

Msl .3 : SEQ ID NO: 157, wherein Xaa₂ is Lys, Xaa₃ is Trp, Xaa₄ is Tyr and Xaa₅ is

Pro; Msl .4: SEQ ID NOJ58, wherein Xaa, is Glu, Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ is Pro;

Ms 1.5: SEQ ID NO: 159, wherein Xaa₂ is Lys and Xaa₅ is Pro;

Msl .8: SEQ ID NO: 160, wherein Xaa, is Glu, Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ is

Pro; Msl .9: SEQ ID NOJ61, wherein Xaa, is Glu, Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ is Pro;

Btl.7: SEQ ID NOJ62, wherein Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ is Pro;

Lvl .5: SEQ ID NO: 163, wherein Xaa₅ is Pro; Msl J 0: SEQ ID NO: 164, wherein Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ is Pro;

Oml J : SEQ ID NO: 165, wherein Xaa₄ is Tyr and Xaa₅ is Pro;

R1.6: SEQ ID NO: 166, wherein Xaa₄ is Tyr and Xaa₅ is Pro;

R1.7: SEQ ID NO: 167, wherein Xaa₄ is Tyr and Xaa₅ is Pro; Vrl J : SEQ ID NO: 168, wherein Xaa₅ is Pro; and

Vrl .2: SEQ ID NO: 169, wherein Xaa₅ is Pro.

The C-terminus preferably contains a carboxyl group for the peptides SnlJ, Snl.2, Crl.3, DilJ, Msl .2, Msl .4, Msl .5, Msl.8, Msl.9, Vrl .l and Vrl .2. The C-terminus of the other peptides preferably contains an amide group. The present invention is also directed to novel specific α-conotoxin peptides of general formula III having the formulas:

Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Leu-Xaa,-His-Ser-Asn-Met-Cys(SEQIDNO:22);

Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-Arg-Gln-Asn-Asn-Ala-Xaa,-Xaa₄-Cys-Arg (SEQ ID NO:23); Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa,-He-Cys-Arg (SEQ

ID NO:24);

Xaas-Xaai-Cys-Cys-Ser-His-Xaas-Ala-Cys-Asn-Val-Asp-His-Xaaj-Xaai-Ile-Cys-Arg (SEQ ID NO.25);

Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa,-Ile-Cys-Asp (SEQ ID NO:26);

Xaa₅-Arg-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa,-Ile-Cys-Arg (SEQ ID NO.27);

Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-AsnNal-Asp-His-Xaa₅-Gly-πe-Cys-Arg (SEQ ID ΝO.28); Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa,-Thr-Cys-Arg (SEQ

ID NO:29);

Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa,-Val-Cys-Arg (SEQ ID NO:30);

Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Ile-Asp-His-Xaa₅-Xaa,-Ile-Cys-Arg (SEQ ID NO:31);

Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa|-Ile-Cys-Arg-Arg- Arg-Arg (SEQ ID NO:32); Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Val-Asn-His-Xaa₅-Xaa,-Leu-Cys (SEQ ID NO:33);

Gly-Cys-Cys-Ser-His-Xaa Ala-Cys-Ser-Val-Asn-His-Xaa₅-Xaa,-Leu-Cys(SEQIDNO:34);

Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-AsnNal-Asp-His-Xaa₅-Xaa,-Ile-Cys(SEQIDNO:35); Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Gly-Xaa₂-Thr-Gln-Xaa,-Xaa₅-Cys-Arg-Xaa,-Ser (SEQ ID NO:36);

Xaa₅-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Gly-Asn-Asn-Xaa₅-Xaa,-Phe-Cys-Arg-Gln(SEQ IDNO:37);

Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Gly-Asn-Asn-Xaa₅-Xaa,-Phe-Cys-Arg-Gln(SEQ IDNO:38);

Gly-Cys-Cys-Ser-His-Xaa₅-Xaa₅-Cys-Ala-Met-Asn-Asn-Xaa₅-Asp-Xaa₄-Cys (SEQ ID NO:39);

Gly-Cys-Cys-Ser-His-Xaa₅-Xaa₅-Cys-Phe-Leu-Asn-Asn-Xaa₅-Asp-Xaa₄-Cys (SEQ ID NO:40); Gly-Cys-Cys-Ser-Asn-Xaa_rXaa₅-Cys-Ile-Ala-Xaa₂-Asn-Xaa₅-His-Met-Cys-Gly (SEQ ID NO:41);

Gly-Cys-Cys-Ser-Asn-Xaa₅-Ala-Cys-Ala-Gly-Asn-Asn-Xaa₅-His-Val-Cys-Arg-Gln(SEQ IDNO:43);

Gly-Cys-Cys-Ser-Arg-Xaa₅-Ala-Cys-He-Ala-Asn-Asn-Xaa₅-Asp-Leu-Cys(SEQIDNO:44); Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Val-Xaa,-His-Xaa₅-Xaa,-Leu-Cys-Arg-Arg-Arg- Arg (SEQ ID NO:45);

Gly-Gly-Cys-Cys-Ser-Phe-Xaa₅-Ala-Cys-Arg-Xaa₂-Xaa₅-Arg-Xaa₅-Xaa,-Met-Cys-Gly(SEQ ID NO:46);

Xaa₅-Xaa,-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Asn-Ser-Ser-His-Xaa₅-Xaa,-Leu-Cys-Gly(SEQ ID NO:47);

Xaa₅-Gln-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Asn-Val-Gly-His-Xaa₅-Xaa,-Leu-Cys-Gly(SEQ IDNO:48);

Xaa₆-Val-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-AsnNal-Gly-His-Xaa₅-Xaa,-He-Cys-Gly (SEQ ID ΝO:49); Gly-Cys-Cys-Ser-Arg-Xaa₅-Xaa₅-Cys-Ile-Ala-Asn-Asn-Xaa₅-Asp-Leu-Cys (SEQ ID NO:50); Xaa₅-Gln-Cys-Cys-Ser-His-Leu-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa,-Ile-Cys-Arg(SEQ IDNO.51);

Gly-Cys-Cys-Ser-Xaa₄-Phe-Asp-Cys-Arg-Met-Met-Phe-Xaa₅-Xaa,-Met-Cys-Gly-Xaa₃-Arg (SEQIDNO:52); Gly-Gly-Cys-Cys-Ser-Phe-Ala-Ala-Cys-Arg-Xaa₂-Xaa₄-Arg-Xaa₅-Xaa,-Met-Cys-Gly(SEQ IDNO:53);

Gly-Gly-Cys-Cys-Phe-His-Xaa₅-Val-Cys-Xaa₄-Ile-Asn-Leu-Leu-Xaa,-Met-Cys-Arg-Gln- Arg (SEQ ID NO:54);

Ser-Ala-Thr-Cys-Cys-Asn-Xaa₄-Xaa₅-Xaa₅-Cys-Xaa₄-Xaa₁-Thr-Xaa₄-Xaa₅-Xaa_]-Ser-Cys- Leu(SEQIDNO:55);

Ala-Cys-Cys-Ala-Xaa₄-Xaa₅-Xaa₅-Cys-Phe-Xaa,-Ala-Xaa₄-Xaa₅-Xaa|-Arg-Cys-Leu (SEQ IDNO:56);

Asn-Ala-Xaa,-Cys-Cys-Xaa₄-Xaa₄-Xaa₅-Xaa₅-Cys-Xaa₄-Xaa,-Ala-Xaa₄-Xaa₅-Xaa,-Ile-Cys- Leu (SEQ ID NO:57); Xaa,-Cys-Cys-Thr-Asn-Xaa₅-Val-Cys-His-Ala-Xaa,-His-Gln-Xaa,-Leu-Cys-Ala-Arg-Arg- Arg (SEQ ID NO:170);

Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Leu-Xaa,-His-Ser-Asn-Leu-Cys (SEQ ID NOJ71);

Xaa,-Cys-Cys-Thr-Asn-Xaa₅-Val-Cys-His-Val-Xaa,-His-Gln-Xaa,-Leu-Cys-Ala-Arg-Arg- Arg (SEQ ID NO:172);

Xaa₆-Xaa,-Cys-Cys-Ser-Xaa₄-Xaa₅-Ala-Cys-Asn-Leu-Asp-His-Xaa₅-Xaa,-Leu-Cys (SEQ ID NOJ73);

Xaa₅-Xaa,-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Asn-Ser-Thr-His-Xaa₅-Xaa,-Leu-Cys-Gly(SEQ ID NO:174); Leu-Asn-Cys-Cys-Met-Ile-Xaa₅-Xaa₅-Cys-Xaa₃-Xaa₂-Xaa₂-Xaa₄-Gly-Asp-Arg-Cys-Ser- Xaa,-Val-Arg (SEQ ID NO:175);

Ala-Phe-Gly-Cys-Cys-Asp-Leu-Ile-Xaa₅-Cys-Leu-Xaa,-Arg-Xaa₄-Gly-Asn-Arg-Cys-Asn- Xaa,-Val-His (SEQ ID NO:176);

Leu-Gly-Cys-Cys-Asn-Val-Thr-Xaa₅-Cys-Xaa₃-Xaa,-Xaa₂-Xaa₄-Gly-Asp-Xaa₂-Cys-Asn- Xaa,-Val-Arg (SEQ ID NO:177);

Asρ-Xaa,-Cys-Cys-Ser-Asn-Xaa₅-Ala-Cys-Arg-Val-Asn-Asn-Xaa₅-His-Val-Cys-Arg-Arg- Arg (SEQ ID NO:178); Leu-Asn-Cys-Cys-Ser-He-Xaa₅-Gly-Cys-Xaa₃-Asn-Xaa,-Xaa₄-Xaa₂-Asp-Arg-Cys-Ser-Xaa₂- Val-Arg (SEQ ID NOJ79);

Gly-Gly-Cys-Cys-Ser-His-Xaa_rVal-Cys-Xaa₄-Phe-Asn-Asn-Xaa₅-Gln-Met-Cys-Arg(SEQ ID NO:180); Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Asn-Leu-Asn-Asn-Xaa₅-Gln-Met-Cys-Arg(SEQ ID NOJ81);

Gly-Cys-Cys-Ser-His-Xaa₅-Xaa₅-Cys-Xaa₄-Ala-Asn-Asn-Gln-Ala-Xaa₄-Cys-Asn(SEQID NO:182);

Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Val-Thr-His-Xaa₅-Xaa,-Leu-Cys (SEQ ID NOJ83);

Gly-Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Ala-Cys-Ser-Val-Xaa,-His-Gln-Asp-Leu-Cys-Asp(SEQ ID NO:184);

Val-Ser-Cys-Cys-Val-Val-Arg-Xaa₅-Cys-Xaa₃-Ile-Arg-Xaa₄-Gln-Xaa,-Xaa,-Cys-Leu-Xaa,- Ala-Asp-Xaa₅-Arg-Thr-Leu (SEQ ID NO:185); Xaa₆-Asn-Cys-Cys-Ser-Ile-Xaa₅-Gly-Cys-Xaa₃-Xaa_rXaa₂-Xaa₄-Gly-Asp-Xaa₂-Cys-Ser- Xaa,-Val-Arg (SEQ ID NOJ86);

Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Leu-Xaa,-His-Xaa₅-Asn-Ala-Cys (SEQ ID NOJ87);

Gly-Cys-Cys-Ser-Asn-Xaa₅-He-Cys-Xaa₄-Phe-Asn-Asn-Xaa₅-Arg-He-Cys-Arg (SEQ ID NOJ88);

Xaa,-Cys-Cys-Ser-Gln-Xaa₅-Xaa₅-Cys-Arg-Xaa₃-Xaa₂-His-Xaa₅-Xaa,-Leu-Cys-Ser (SEQ ID NO:189);

Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Gly-Asn-Asn-Gln-His-He-Cys (SEQ ID NO:190);

Gly-Cys-Cys-Ala-Val-Xaa₅-Ser-Cys-Arg-Leu-Arg-Asn-Xaa₅-Asp-Leu-Cys-Gly-Gly(SEQ ID NOJ91);

Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asn-Asn-Xaa₅-His-He-Cys(SEQIDNO:192);

Thr-Xaa₅-Xaaι-Xaa,-Cys-Cys-Xaa₅-Asn-Xaa₅-Xaa₅-Cys-Phe-Ala-Thr-Asn-Ser-Asp-Ile-Cys- Gly (SEQ ID NO:193);

Asp-Ala-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ser-Gly-Xaa₂-His-Gln-Asp-Leu-Cys (SEQ ID NO:194);

Xaa,-Asp-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Leu-Cys (SEQ ID NOJ95); Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Gly-Ser-Asn-Ala-His-He-Cys (SEQ ID NOJ96);

Xaa,-Asp-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Met-Cys (SEQ ID NO:197);

Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Gly-Asn-Asn-Xaa₅-His-He-Cys(SEQIDNOJ98); Gly-Cys-Cys-Gly-Asn-Xaa₅-Ser-Cys-Ser-Ile-His-Ile-Xaa₅-Xaa₄-Val-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-Xaa₅-Xaa₅-Cys-Xaa₄-Ala-Asn-Asn-Gln-Ala-Xaa₄-Cys-Asn(SEQID NO.201);

Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Val-Asn-Asn-Xaa₅-Asp-He-Cys(SEQIDNO:202);

Gly-Xaa₂-Cys-Cys-Ile-Asn-Asp-Ala-Cys-Arg-Ser-Xaa₂-His-Xaa₅-Gln-Xaa₄-Cys-Ser(SEQ ID NO:203);

Gly-Cys-Cys-Xaa₄-Asn-Ile-Ala-Cys-Arg-Ile-Asn-Asn-Xaa₅-Arg-Xaa₄-Cys-Arg (SEQ ID NO:204);

Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Arg-Phe-Asn-Xaa₄-Xaa₅-Xaa₂-Xaa₄-Cys-Gly(SEQID NO:205);

Asp-Xaa_rCys-Cys-Ala-Ser-Xaa₅-Xaa₅-Cys-Arg-Leu-Asn-Asn-Xaa₅-Xaa₄-Val-Cys-His (SEQ ID NO:206); Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-Xaa₃-Gln-Asn-Asn-Ala-Xaa,-Xaa₄-Cys-Arg-Xaa,-Ser (SEQ ID NO:207);

Gly-Cys-Cys-Ser-His-Xaa₅-Xaa_rCys-Ala-Gln-Asn-Asn-Gln-Asp-Xaa₄-Cys (SEQ ID NO:208);

Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Gly-Asn-Asn-Arg-Xaa,-Xaa₄-Cys-Arg-Xaa,-Ser (SEQ ID NO:209);

Asp-Xaa₅-Cys-Cys-Ser-Xaa₄-Xaa₅-Asp-Cys-Gly-Ala-Asn-His-Xaa₅-Xaa,-Ile-Cys-Gly(SEQ IDNO:210);

Xaa,-Cys-Cys-Ser-Gln-Xaa₅-Xaa₅-Cys-Arg-Xaa₃-Xaa₂-His-Xaa₅-Xaa,-Leu-Cys-Ser (SEQ IDNO:211); Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Gly-Asn-Asn-Xaa₅-His-He-Cys(SEQIDNO:212);

Gly-Cys-Cys-Ser-Asp-Xaa₅-Ser-Cys-Asn-Val-Asn-Asn-Xaa₅-Asp-Xaa₄-Cys (SEQ ID NO:213); Xaa,-Xaa,-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Met-Cys-Arg(SEQ IDNO.214);

Gly-Gly-Cys-Cys-Ser-Asn-Xaa₅-Ala-Cys-Leu-Val-Asn-His-Leu-Xaa,-Met-Cys (SEQ ID NO:215); Arg-Asp-Xaa₅-Cys-Cys-Phe-Asn-Xaa₅-Ala-Cys-Asn-Val-Asn-Asn-Xaa₅-Gln-Ile-Cys (SEQ IDNO:216);

Cys-Cys-Ser-Asp-Xaa₅-Ser-Cys-Xaa₃-Arg-Leu-His-Ser-Leu-Ala-Cys-Thr-Gly-Ile-Val-Asn- Arg(SEQIDNO:217);

Cys-Cys-Thr-Asn-Xaa₅-Ala-Cys-LeuNal-Asn-Asn-Ile-Arg-Phe-Cys-Gly(SEQIDNO:218); Asp-Xaa,-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-His-Gly-Asn-Asn-Arg-Asp-His-Cys-Ala (SEQ IDNO.219);

Asp-Cys-Cys-Ser-His-Xaa₅-Leu-Cys-Arg-Leu-Phe-Val-Xaa₅-Gly-Leu-Cys-Ile (SEQ ID NO:220);

Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Xaa₂-Val-Arg-Xaa₄-Xaa₅-Asp-Leu-Cys-Arg(SEQID NO:221);

Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asn-Asn-Xaa₅-His-fie-Cys(SEQIDNO:222);

Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Xaa₂-Val-Arg-Xaa₄-Ser-Asp-Met-Cys (SEQ ID NO:223);

Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Xaa₂-Val-His-Phe-Xaa₅-His-Ser-Cys (SEQ ID NO:224);

Val-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Val-Asp-His-Xaa₅-Xaa_rLeu-Cys-Arg-Arg-Arg- Arg (SEQ ID NO:225);

Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Asn-Leu-Ser-Asn-Xaa₅-Gln-Ile-Cys-Arg (SEQ ID NO:226); Xaa₆-Xaa,-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa,-Ile-Cys-Arg(SEQ ID NO:227);

Gly-Cys-Cys-Ser-Asn-Xaa₅-Ala-Cys-Leu-Val-Asn-His-Ile-Arg-Phe-Cys-Gly (SEQ ID NO:228);

Asp-Cys-Cys-Asp-Asp-Xaa₅-Ala-Cys-ThrNal-Asn-Asn-Xaa₅-Gly-Leu-Cys-Thr (SEQ ID ΝO:229); and

Gly-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ile-Ala-Xaa₂-Asn-Xaa₅-His-Met-Cys-Gly-Gly-Arg- Arg (SEQ ID NO:230), wherein Xaa, is Glu or γ-carboxy-Glu (Gla); Xaa₂ is Lys, N-methyl-Lys, N-N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa₃ is Trp (D or L), halo-Trp or neo-Trp; Xaa₄ is Tyr, nor-Tyr, mono-halo- Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa₅ is Pro or hydroxy-Pro; Xaa₆ 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, homoargine, 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, ornithine, homoargine, 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 L). 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, e.g., tetrazolyl derivatives of Gly and Ala.

More specifically, the present invention is directed to the following α-conotoxin peptides of general formula III:

Sml: SEQ ID NO:22, wherein Xaa, s Glu and Xaa₅ is Pro;

OB-29: SEQ ID NO:23, wherein Xaa, s Glu, Xaa₃ is Tyr and Xaa₅ is Pro;

TxlJ: SEQ ID NO:24, wherein Xaa, s Glu and Xaa₅ is Pro;

R1JA: SEQ ID NO:25, wherein Xaa, s Glu and Xaa₅ is Pro;

R1JB: SEQ ID NO:26, wherein Xaa, s Glu and Xaa₅ is Pro;

Om-9: SEQ ID NO:27, wherein Xaa, s Glu and Xaa₅ is Pro;

Om-10 SEQ ID NO:28, wherein Xaa₅ s Pro;

Om-21 SEQ ID NO:29, wherein Xaa, s Glu and Xaa₅ is Pro;

Om-25 SEQ ID NO:30, wherein Xaa, s Glu and Xaa₅ is Pro;

Om-27 SEQ ID NO:31, wherein Xaa, s Glu and Xaa₅ is Pro;

Om-28 SEQ ID NO:32, wherein Xaa, s Glu and Xaa₅ is Pro;

Btl.2: SEQ ID NO:33, wherein Xaa, s Glu and Xaa₅ is Pro;

Btl.4: SEQ ID NO:34, wherein Xaa, s Glu and Xaa₅ is Pro;

Dal.l : SEQ ID NO:35, wherein Xaa, s Glu and Xaa₅ is Pro; OB-20: SEQ ID NO:36, wherein Xaa, is Glu, Xaa₂ is Lys and Xaa₅ is Pro;

TI: SEQ ID NO:37, wherein Xaa, is Glu and Xaa₅ is Pro;

TIB: SEQ ID NO:38, wherein Xaa, is Glu and Xaa₅ is Pro;

Pnl J : SEQ ID NO:39, wherein Xaa₅ is Pro;

Pnl.2: SEQ ID NO:40, wherein Xaa, is Glu and Xaa₅ is Pro;

Tl : SEQ ID NO.41 , wherein Xaa₂ is Lys and Xaa₅ is Pro;

TIA: SEQ ID NO:43, wherein Xaa₅ is Pro;

Dal .2: SEQ ID NO:44, wherein Xaa₅ is Pro;

Crl .2: SEQ ID NO:45, wherein Xaa, is Glu and Xaa₅ is Pro;

Sll .2: SEQ ID NO:46, wherein Xaa, is Glu, Xaa₂ is Lys and Xaa₅ is Pro;

Txl .3 : SEQ ID NO:47, wherein Xaa, is Glu and Xaa₅ is Pro;

Dal .3 : SEQ ID NO:48, wherein Xaa, is Glu and Xaa₅ is Pro;

Dal A: SEQ ID NO:49, wherein Xaa, is Glu, Xaa₅ is Pro and Xaa₆ is Gin;

Txl .2: SEQ ID NO:50, wherein Xaa₅ is Pro;

Om-35: SEQ ID NO:51, wherein Xaa, is Glu and Xaa₅ is Pro;

Sll J : SEQ ID NO:52, wherein Xaa, is Glu, Xaa₃ is Trp, Xaa₄ is Tyr and Xaa₅ is

Pro; Sll.6: SEQ ID NO:53, wherein Xaa, is Glu, Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ is

Pro; S SI111..77:: SEQ ID NO:54, wherein Xaa, is Glu Xaa₄ is Tyr and Xaa₅ is Pro;

Btl .l : SEQ ID NO:55, wherein Xaa, is Glu Xaa₄ is Tyr and Xaa₅ is Pro;

Bt:1.3: SEQ ID NO:56, wherein Xaa, is Glu Xaa₄ is Tyr and Xaa₅ is Pro;

Btl .5: SEQ ID NO:57, wherein Xaa, is Glu Xaa₄ is Tyr and Xaa₅ is Pro;

A1.4: SEQ ID NO: 170, wherein Xaa, is Glu and Xaa₅ is Pro; A A11..55:: SEQ ID NOJ71, wherein Xaa, is Glu and Xaa₅ is Pro;

A1.6: SEQ ID NO: 172, wherein Xaa, is Glu and Xaa₅ is Pro;

Afl .l : SEQ ID NO: 173, wherein Xaa, is Glu Xaa₄ is Tyr, Xaa₅ is Pro and Xaa₆ is

Gin;

Afl .2: SEQ ID NO: 174, wherein Xaa, is Glu and Xaa₅ is Pro; A Arrll ..22:: SEQ ID NOJ 75, wherein Xaa, is Glu, Xaa₂ is Lys, Xaa₃ is Tφ, Xaa₄ is Try and Xaa₅ is Pro; Ar 1.3 : SEQ ID NO: 176, wherein Xaa, is Glu, Xaa₄ is Tyr and Xaa₅ is Pro; Arl A: SEQ ID NO: 177, wherein Xaa, is Glu, Xaa₂ is Lys, Xaa₃ is Tφ, Xaa₄ is Try and Xaa₅ is Pro;

Arl.5: SEQ ID NO: 178, wherein Xaa, is Glu and Xaa₅ is Pro;

Arl .6: SEQ ID NO: 179, wherein Xaa, is Glu, Xaa₂ is Lys, Xaa₃ is Tφ, Xaa₄ is Try and Xaa₅ is Pro;

Ayl .2: SEQ ID NOJ 80, wherein Xaa₄ is Tyr and Xaa₅ is Pro;

Ay 1.3: SEQ ID NO: 181, wherein Xaa₅ is Pro;

Bnl A: SEQ ID NO: 182, wherein Xaa₄ is Tyr and Xaa₅ is Pro;

Btl .8: SEQ ID NOJ 83, wherein Xaa, is Glu and Xaa₅ is Pro; Btl .9: SEQ ID NO: 184, wherein Xaa, is Glu, Xaa₄ is Tyr and Xaa₅ is Pro;

Cal.3: SEQ ID NOJ 85, wherein Xaa, is Glu, Xaa₃ is Tφ, Xaa₄ is Try and Xaa₅ is

Pro;

Cal A: SEQ ID NOJ 86, wherein Xaa, is Glu, Xaa₂ is Lys, Xaa₃ is Tφ, Xaa₄ is Try,

Xaa₅ is Pro and Xaaa is Gin; C1.2: SEQ ID NO:187, wherein Xaa, is Glu and Xaaj is Pro;

C1.3: SEQ ID NO: 188, wherein Xaa₄ is Tyr and Xaa₅ is Pro;

Epl .2: SEQ ID NOJ 89, wherein Xaa, is Glu, Xaa₂ is Lys, Xaa₃ is Tφ and Xaa₅ is

Pro;

Gl .l : SEQ ID NO: 190, wherein Xaa₅ is Pro; G1.3: SEQ ID NO-191, wherein Xaa₅ is Pro;

Iml .3: SEQ ID NO: 192, wherein Xaa₅ is Pro;

Lvl.2: SEQ ID NO: 193, wherein Xaa, is Glu and Xaa₅ is Pro;

Lvl .3 : SEQ ID NO: 194, wherein Xaa₂ is Lys and Xaa₅ is Pro;

Lvl A: SEQ ID NO: 195, wherein Xaa, is Glu and Xaa₅ is Pro; Lvl .6: SEQ ID NO: 196, wherein Xaa₅ is Pro;

Lvl .7: SEQ ID NO: 197, wherein Xaa, is Glu and Xaa₅ is Pro;

Lvl .8: SEQ ID NO: 198, wherein Xaa₅ is Pro;

Lvl .9: SEQ ID NO: 199, wherein Xaa₄ is Tyr and Xaa₅ is Pro;

Lvl JO: SEQ ID NO:200, wherein Xaa, is Glu; Mr 1.3: SEQ ID NO-201, wherein Xaa₄ is Tyr and Xaa₅ is Pro;

Mrl .4: SEQ ID NO:202, wherein Xaa₅ is Pro;

Msl J : SEQ ID NO:203, wherein Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ is Pro; Msl .6: SEQ ID NO:204, wherein Xaa₄ is Tyr and Xaa₅ is Pro;

O1 J : SEQ ID NO:205, wherein Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ is Pro;

Ol .2: SEQ ID NO:206, wherein Xaa, is Glu, Xaa₄ is Tyr and Xaa₅ is Pro;

Ol A SEQ ID NO:207, wherein Xaa, is Glu, Xaa₃ is Tφ, Xaa₄ is Tyr and Xaa₅ is

Pro;

O1.7: SEQ ID NO:208, wherein Xaa₄ is Tyr and Xaa₅ is Pro; O1.8: SEQ ID NO:209, wherein Xaa, is Glu, Xaa₄ is Tyr and Xaa₅ is Pro; Oml.2: SEQ ID NO:210, wherein Xaa, is Glu, Xaa₄ is Tyr and Xaa₅ is Pro; Oml .3: SEQ ID NO:211, wherein Xaa, is Glu, Xaa₂ is Lys, Xaa₃ is Tφ and Xaa₅ is Pro;

Oml .4 SEQ ID NO:212, wherein Xaa₅ is Pro;

Oml.5 SEQ ID NO:213, wherein Xaa₄ is Tyr and Xaa₅ is Pro;

Oml.6 SEQ ID NO:214, wherein Xaa, is Glu and Xaa₅ is Pro;

P1.4: SEQ ID NO:215, wherein Xaa, is Glu and Xaa₅ is Pro;

P1.5: SEQ ID NO:216, wherein Xaa₅ is Pro;

P1.6: SEQ ID NO:217, wherein Xaa₃ is Tφ and Xaa₅ is Pro;

P1.8: SEQ ID NO:218, wherein Xaa₅ is Pro;

Rgl .l SEQ ID NO:219, wherein Xaa, is Glu and Xaa₅ is Pro; Rgl .3 SEQ ID NO:220, wherein Xaa₅ is Pro; Rgl.4 SEQ ID NO:221, wherein Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ is Pro; Rgl.5 SEQ ID NO:222, wherein Xaa₅ is Pro; Rgl.8 SEQ ID NO:223, wherein Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ is Pro; Sml .4: SEQ ID NO:224, wherein Xaa₂ is Lys and Xaa₅ is Pro; Sml.5: SEQ ID NO:225, wherein Xaa, is Glu and Xaa₅ is Pro; SSI1..55:: SEQ ID NO:226, wherein Xaa₅ is Pro; Txl .5: SEQ ID NO:227, wherein Xaa, is Glu, Xaa₅ is Pro and Xaa₆ is Gin; Tl .l: SEQ ID NO:228, wherein Xaa₅ is Pro; Vrl.3: SEQ ID NO:229, wherein Xaa₅ is Pro; and Tb: SEQ ID NO:230, wherein Xaa₂ is Lys and Xaa₅ is Pro. The C-terminus preferably contains a carboxyl group for the peptides OB-29, TxlJ, RIJA, RIJB,

Om-9, Om-10, Om-21, Om-25, Om-27, Om-28, Crl .2, Om-35, Btl .l, Btl.3, Btl.5, A1.4, A1.6, Arl.2, Arl.3, Arl.4, Arl .5, Arl.6, Cal.3, Cal.4, Epl.2, Lvl.9, O1.2, Oml.3, Oml.6, P1.6, Rgl.l, Rgl .3, Rgl A, 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 α-contoxin peptides having the formulas: Cys-Cys-Thr-Ile-Xaa₅-Ser-Cys-Xaa₄-Xaa,-Xaa₂-Xaa₂-Xaa₂-He-Xaa₂-Ala-Cys-Val-Phe(SEQ

ID NO:231) and

Gly-Cys-Cys-Gly-Asn-Xaa₅-Ala-Cys-Ser-Gly-Ser-Ser-Xaa₂-Asp-Ala-Xaa₅-Ser-Cys (SEQ ID NO:232), wherein Xaa, is Glu or γ-carboxy-Glu (Gla); Xaa₂ is Lys, N-methyl-Lys, N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa₄ is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-

Tyr or nitro-Tyr; and Xaa₅ 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. In addition, the His residues may be substituted with halo-His; the Arg residues may be substituted by Lys, ornithine, homoargine, 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, ornithine, homoargine, 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 L). 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, e.g., tetrazolyl derivatives of Gly and Ala.

More specifically, the present invention is directed to the following α-conotoxin peptides: Gl .2: SEQ ID NO:231 , wherein Xaa, is Glu, Xaa₂ is Lys, Xaa₄ is Tyr and Xaa₅ is

Pro; and RglJ2: SEQ ID NO:232, wherein Xaa₂ is Lys and Xaa₅ is Pro.

The C-terminus of G1.2 preferably contains a carboxyl group, and the C-terminus of RglJ2 preferably contains an amide group. Examples of unnatural aromatic amino acid include, but are not limited to, such as nitro-Phe,

4-substituted-Phe wherein the substituent is C,-C₃ alkyl, carboxyl, hyrdroxymethyl, sulphomethyl, halo, phenyl, -CHO, -CN, -SO₃H and -NHAc. Examples of unnatural hydroxy containing amino acid, include, but are not limited to, such as 4-hydroxymethyl-Phe, 4-hydroxyphenyl-Gly, 2,6- dimethyl-Tyr and 5-amino-Tyr. Examples of unnatural basic amino acids include, but are not limited to, N- 1 -(2 -pyrazolinyl)-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 N-, S- or O-linked mono-, di-, tri-, poly- or 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, D-mannose, D-gulose, D-idose, D-galactose, D-talose, D- galactosamine, D-glucosamine, D-N-acetyl-glucosamine (GlcNAc), D-N-acetyl-galactosamine (GalNAc), D-fucose or D-arabinose. These saccharides may be structurally modified, e.g., with one or more O-sulfate, O-phosphate, O-acetyl or acidic groups, such as sialic acid, including combinations thereof. The gylcan 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), incoφorated 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 monosaccharide 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 further in U.S. Serial No. 09/420,797, filed 19 October 1999 and in PCT Application No. PCT/US99/24380, filed 19 October 1999, both incoφorated herein by reference. A preferred glycan is Gal(βl^→3)GalNAc(αl-). 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.

DETAILED DESCRIPTION OF THE INVENTION

The present invention, in another aspect, relates to a pharmaceutical composition comprising an effective amount of an α-conotoxin peptide. Such a pharmaceutical composition has the capability of acting as antagonists for nicotinic acetylcholine receptors. In one aspect, the α- 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 application Serial No. 09/ , filed 21 January 2000 (Attorney Docket No. 2314-178.A) and international patent application No. PCT/US00/ , filed 21 January 2000 (Attorney Docket No.

2314-138. PCT), each incoφorated by reference herein. In a second aspect, additional α-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 incoφorated herein by reference.

In a third aspect additional uses for α-conotoxins are described in U.S. Serial No. 09/219,446, filed 22 December 1998, incorporated herein by reference. In this application, α- 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 α-conotoxin peptides described herein are sufficiently small to be chemically synthesized. General chemical syntheses for preparing the foregoing α-conotoxin peptides are described hereinafter. Various ones of the α-conotoxin peptides can also be obtained by isolation 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 α-conotoxin peptides of the present invention can be obtained by purification from cone snails, because the amounts of α-conotoxin peptides obtainable from individual snails are very small, the desired substantially pure α-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 α-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 α-conotoxin peptides depends of course upon correct determination of the amino acid sequence.

The α-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, e.g., dicyclohexylcarbodiimide or diisopropylcarbonyldimidazole, various active esters, e.g., esters of N-hydroxyphthalimide or N- hydroxy-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. 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 γ-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 α-amino group on an amino acid or a fragment while that entity reacts at the carboxyl group, followed by the selective removal of the α-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 α-amino groups during the synthesis. However, for some amino acids, e.g., 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: (a) the protecting group preferably retains its protecting properties and is not split off under coupling conditions, (b) the protecting group should be stable under the reaction conditions selected for removing the α-amino protecting group at each step of the synthesis, and (c) 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 α-amino acid to a suitable resin. Such a starting material can be prepared by attaching an α-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 para- methylbenzhydrylamine (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-CH₂-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 (Komreich 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°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 BOC- protected amino acid to the resin support, the α-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 HCl in dioxane, and conditions for removal of specific α-amino protecting groups may be used as described in Schroder & Lubke (1965). After removal of the α-amino-protecting group, the remaining α-amino- and side chain- protected 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). 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):CH₂C1₂ (1 J) or in DMF or CH₂C1₂ alone. In cases where intermediate coupling occurs, the coupling procedure is repeated before removal of the α-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 α-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 S- alkylation. 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- terminus using an Advanced Chemtech 357 Automatic Peptide Synthesizer. Couplings are carried out using 1,3-diisopropylcarbodimide in N-methylpyrrolidinone (NMP) or by 2-(lH-benzotriazole- l-yl)-lJ,3,3-tetramethyluronium hexafluorophosphate (HBTU) and diethylisopro- pylethylamine (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, e.g., 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, 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 of 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 spealists, 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 Parmaceutical 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 a bout 0J mg/kg to about 75 mg/kg. A suitable dose can be administered in multiple sub-doses per day. Typically, a dose or sub-dose may contain from about 0J mg to about 500 mg of the active ingredient per unit dosage form. A more preferred dosage will contain from about 0.5 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 would 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 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 α-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,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,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 α3β4 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; Shon et al., 1994).

In accordance with this method, peptides Mil, AuIA, AuIB, AuIC, MAR-1, MAR-2, TI, OB- 29, Epl, S1J, Bnl J, Bnl.2, CalJ, Cal.2, CnlJ, 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 Cartier et al. (1996). Briefly, the linear chains were built on Rink amide resin by Fmoc procedures with 2-(l H-benzotriol- l-yl)-lJ,3,3,-tetramethyluronium tetrafluoroborated coupling using an ABI model 430 A peptide sythesizer with amino acid derivatives purchased from Bachem (Torrence CA). Orthogonal protection was used on cysteines: Cys³ and Cys¹⁶ were protected as the stable Cys(S- acetamidomethyl), while Cys² and Cys⁸ 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°C methyl t-butyl ether, which removed the protecting groups except on Cys³ and Cys¹⁶. The peptides were dissolved in 0.1% TFA and 60% acetonitrile and purified by RPLC on a Vydac C,₈ 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 Cys² and Cys⁸ 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,₈ prepartive 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 Cys³ and Cys¹⁶ was carried out simultaneously be iodine oxidation. The cyclic peptides were purified by

RPLC on a Vydac C₁₈ prepartive column (22 x 250 mm) and eluted with a gradient of acetonitrile in 0.1% TFA.

EXAMPLE 3 Isolation of DNA Encoding α-Conotoxins DNA coding for α-conotoxins was isolated and cloned in accordance with conventional techniques using general procedures well known in the art, such as 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 the Ml 3 universal priming site and the Ml 3 reverse universal priming site. Clones having a size of approximately 300 nucleotides were sequenced and screened for similarity in sequence to known α-conotoxins. The DNA sequences and encoded propeptide or peptide sequences are set forth in Tables 1-134.

TABLE 1

DNA Sequence (SEQ ID NO:58) and Protein Sequence (SEQ ID NO:59) of Mil atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec

Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc cct tea gat cgt gca tet gat ggc agg aat gee gca gee aac gac Phe Pro Ser Asp Arg Ala Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp aaa gcg tet gac gtg ate acg ctg gcc etc aag gga tgc tgt tec aac Lys Ala Ser Asp Val lie Thr Leu Ala Leu Lys Gly Cys Cys Ser Asn cct gtc tgt cac ttg gag cat tea aac ctt tgt ggt aga aga cgc Pro Val Cys His Leu Glu His Ser Asn Leu Cys Gly Arg Arg Arg tgatgctcca ggaccctctg aaccacgacg ttcgagca

TABLE 2

DNA Sequence (SEQ ID NO:60) and Protein Sequence (SEQ ID NO:61) of AuIA atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace ace gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tea gat cgt gca tet gat ggc agg aag gac gca gcg tet ggc Phe Thr Ser Asp Arg Ala Ser Asp Gly Arg Lys Asp Ala Ala Ser Gly ctg ate get ctg ace ate aag gga tgc tgt tet tat cct ccc tgt ttc Leu lie Ala Leu Thr He Lys Gly Cys Cys Ser Tyr Pro Pro Cys Phe gcg act aat tea 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) ofAuIB atg ttc ace gtg ttt ctg ttg gtc gtc ttg gca ace ace gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tea gat cgt gca tet gat ggc agg aag gac gca gcg tet ggc Phe Thr Ser Asp Arg Ala Ser Asp Gly Arg Lys Asp Ala Ala Ser Gly ctg att get ctg ace atg aag gga tgc tgt tet tat cct ccc tgt ttc

Leu He 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) ofTxl.3 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace ace gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc tet tea 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 tet 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 teg 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 TABLE 5

DNA Sequence (SEQ ID NO:66) and Protein Sequence (SEQ ID NO:67) ofTxl .2 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace gcc gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Ala Val Val Ser ttc act tea gat cgt gca tet gat gac ggg aaa gcc get gcg tet gac

Phe Thr Ser Asp Arg Ala Ser Asp Asp Gly Lys Ala Ala Ala Ser Asp ctg ate act ctg ace ate aag gga tgc tgt tet cgt cct ccc tgt ate Leu He Thr Leu Thr He Lys Gly Cys Cys Ser Arg Pro Pro Cys He 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) ofTxl J atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace ace gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tea 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 tet ggc ctg gtc agt ctg act gac agg aga cca caa tgc tgt tet 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 He Cys Arg gatgctccag gaccctctga accacgacgt

TABLE 7

DNA Sequence (SEQ ID NO:70) and Protein Sequence (SEQ ID NO-71) ofRl.lA atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace ace gtc gtt tec

Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tea 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 tet ggc ctg gtc agt ctg act gac agg aga cca gaa tgc tgt tet 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 He Cys Arg gatgctccag gaccctctga accacgacgt

TABLE 8 DNA Sequence (SEQ ID NO:72) and Protein Sequence (SEQ ID NO:73) of RIJB atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace ace gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tea 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 tet ggc ctg gtc agt ctg act gac agg aga cca caa tgc tgt tet

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 He Cys Asp gatgctccag gaccctctga accacgacgt

TABLE 9

DNA Sequence (SEQ ID NO:74) and Protein Sequence (SEQ ID NO:75) ofS1.1 atg ttc act gtg ttt ctg ttg gtt gtc ttg gca ate act gtc gtt tec

Met Phe Thr Val Phe Leu Leu Val Val Leu Ala He Thr Val Val Ser ttc cct tta gat cgt gaa tet gat ggc gcg aat gcc gaa gcc cgc ace 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 egg 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 age cac aga tgt ggt tgacgacgct gatgctccag Pro Ala Cys Glu Ser His Arg Cys Gly gaccctctga accacgacgt tcgagca

TABLE 10 DNA Sequence (SEQ ID NO:76) and Protein Sequence (SEQ ID NO:77) of BnlJ atg ttc ace atg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec Met Phe Thr Met Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc get tea gat cgt gca tet 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 tet gac ctg gtc get ctg ace gtc aag gga tgc tgt tet cat

Lys Ala Ser Asp Leu Val Ala Leu Thr Val Lys Gly Cys Cys Ser His cct gcc tgt age gtg aat aat cca gac att tgt ggt tgaagacgct Pro Ala Cys Ser Val Asn Asn Pro Asp He Cys Gly gatgctccag gaccctctga accacgacgt tcgagca

TABLE 11

DNA Sequence (SEQ ID NO:78) and Protein Sequence (SEQ ID NO:79) ofBnl.2 aaa gaa tgc tgt act cat cct gcc tgt cac gtg agt cat cca gaa etc 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 TABLE 12 DNA Sequence (SEQ ID NO:80) and Protein Sequence (SEQ ID NO:81) of BnlJ atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca act get 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 tet 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 ate gcg cca ttc ate agg gat tat tgc tgt cat Lys Thr Pro Arg Leu He Ala Pro Phe He 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 CalJ atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtg gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tea gat cgt get tet 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 ate get ctg ate gcc agg caa aat tgc tgt age att ccc Phe Asp Leu He Ala Leu He Ala Arg Gin Asn Cys Cys Ser He Pro age tgt tgg gag aaa tat aaa tgt agt taa

Ser Cys Trp Glu Lys Tyr Lys Cys Ser

TABLE 14 DNA Sequence (SEQ ID NO:84) and Protein Sequence (SEQ ID NO:85) ofCal.2 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtg gtt tec

Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tea gat cgt gcg tet gaa ggc agg aat get gca gcc aag gac Phe Thr Ser Asp Arg Ala Ser Glu Gly Arg Asn Ala Ala Ala Lys Asp aaa gcg tet gac ctg gtg get ctg aca gtc agg gga tgc tgt gcc att Lys Ala Ser Asp Leu Val Ala Leu Thr Val Arg Gly Cys Cys Ala He cgt gaa tgt cgc ttg cag aat gca gcg tat tgt ggt gga ata tac Arg Glu Cys Arg Leu Gin Asn Ala Ala Tyr Cys Gly Gly He Tyr tgatgctcca ggaccctctg aaccacgacg

TABLE 15 DNA Sequence (SEQ ID NO:86) and Protein Sequence (SEQ ID NO:87) ofTIB atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc cct tea gat att gca act gag ggc agg aat gcc gca gcc aaa gcg

Phe Pro Ser Asp He Ala Thr Glu Gly Arg Asn Ala Ala Ala Lys Ala ttt gac ctg ata tet teg ate gtc aag aaa gga tgc tgt tec cat cct

Phe Asp Leu He Ser Ser He Val Lys Lys Gly Cys Cys Ser His Pro gcc tgt teg ggg aat aat cca gaa ttt tgt cgt caa ggt cgc

Ala Cys Ser Gly Asn Asn Pro Glu Phe Cys Arg Gin Gly Arg tgatgctcca ggaccctctg aaccacgacg t

TABLE 16 DNA Sequence (SEQ ID NO:88) and Protein Sequence (SEQ ID NO:89) ofTIA atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec

Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc cct tea gat ata gca act gag ggc agg aat gcc gca gcc aaa gcg Phe Pro Ser Asp He Ala Thr Glu Gly Arg Asn Ala Ala Ala Lys Ala ttt gac ctg ata tet teg ate gtc agg aaa gga tgc tgt tec aat ccc Phe Asp Leu He Ser Ser He Val Arg Lys Gly Cys Cys Ser Asn Pro 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 Gly Arg tgatgctcca ggaccctctg aaccacgacg t

TABLE 17 DNA Sequence (SEQ ID NO:90) and Protein Sequence (SEQ ID NO:91) ofSll.1 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace ace gtc gtt tec

Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc aat tea gat cgt gat cca gca tta ggt ggc agg aat get gca gcc

Phe Asn Ser Asp Arg Asp Pro Ala Leu Gly Gly Arg Asn Ala Ala Ala aaa gcg tet gac aag ate get teg ace etc aag aga aga gga tgc tgt

Lys Ala Ser Asp Lys He Ala Ser Thr Leu Lys Arg Arg Gly Cys Cys teg tat ttt gac tgt aga atg atg ttt cca gaa atg tgt ggt tgg cga

Ser Tyr Phe Asp Cys Arg Met Met Phe Pro Glu Met Cys Gly Trp Arg ggc tgatgctcca ggaccctctg aaccacgacg t Gly

TABLE 18

DNA Sequence (SEQ ID NO:92) and Protein Sequence (SEQ ID NO:93) ofSll.2 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace ace gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc aat tea gat cgt gat cca gca tta ggt ggc agg aat get gca gcc

Phe Asn Ser Asp Arg Asp Pro Ala Leu Gly Gly Arg Asn Ala Ala Ala ata gcg tet gac aag ate get teg ace etc agg aga gga gga tgc tgt

He Ala Ser Asp Lys He Ala Ser Thr Leu Arg Arg Gly Gly Cys Cys tet 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 IDNO:94) and Protein Sequence (SEQ ID NO:95) ofSll.3 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace ace gtc gtt tec

Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tea gat cat gaa tet gat cgc ggt gat gcc caa ace ate caa Phe Thr Ser Asp His Glu Ser Asp Arg Gly Asp Ala Gin Thr He Gin gaa gtg ttt gag atg ttc get ctg gac age gat gga tgc tgt tgg cat

Glu Val Phe Glu Met Phe Ala Leu Asp Ser Asp Gly Cys Cys Trp His cct get tgt ggc aga cac tat tgt ggt cga aga cgc tgatgctcca Pro Ala Cys Gly Arg His Tyr Cys Gly Arg Arg Arg ggaccctctg aaccacgacg t

TABLE 20

DNA Sequence (SEQ ID NO:96) and Protein Sequence (SEQ ID NO:97) ofSll.6 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace ace gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc aat tea gat cgt gat cca gca tta ggt ggc agg aat get gca gcc

Phe Asn Ser Asp Arg Asp Pro Ala Leu Gly Gly Arg Asn Ala Ala Ala ata gcg tet gac aag ate get teg ace etc agg aga gga gga tgc tgt He Ala Ser Asp Lys He Ala Ser Thr Leu Arg Arg Gly Gly Cys Cys tet ttt get 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) ofSll.7 atg ttc ace gtg ttt ctg ttg gtt etc ttg gca ace ace gtc gtt tec

Met Phe Thr Val Phe Leu Leu Val Leu Leu Ala Thr Thr Val Val Ser ttc aat tea gat cgt gca tta ggt ggc agg aat get gca gcc aaa gcg Phe Asn Ser Asp Arg Ala Leu Gly Gly Arg Asn Ala Ala Ala Lys Ala tet gac aag ate ctt teg aac etc agg aga gga gga tgc tgt ttt cat Ser Asp Lys He Leu Ser Asn Leu Arg Arg Gly Gly Cys Cys Phe His cct gtc tgt tac ate aat ctt eta gaa atg tgt cgt caa cga ggc Pro Val Cys Tyr He Asn Leu Leu Glu Met Cys Arg Gin Arg Gly tgatcgtcca ggaccctctg aaccacgacg t TABLE 22

DNA Sequence (SEQ ID NO:100) and Protein Sequence (SEQ ID NO:101) ofCn1.1 atg ttc ace gtg ttt ctg ttg gtt gtc ttg aca ace act gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Thr Thr Thr Val Val Ser ttc cct tea gat agt gca tet 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 tet gac atg tac aaa teg aaa egg 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) ofSml atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser tec cct tea gat cgt gca tet 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 tet gac gtg ate gcg ctg gcc etc aag gga tgc tgt tec aac Lys Ala Ser Asp Val He Ala Leu Ala Leu Lys Gly Cys Cys Ser Asn cct gtc tgt cac ctg gag cat tea 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

TABLE 24

DNA Sequence (SEQ ID NO:104) and Protein Sequence (SEQ ID NO:105) ofBtl J atg ttc tec gtg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec

Met Phe Ser Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser tec act tea ggt ggt gca tet ggt ggc agg aag get gca gcc aaa gcg Ser Thr Ser Gly Gly Ala Ser Gly Gly Arg Lys Ala Ala Ala Lys Ala tet aac egg ate get ctg ace gtc agg agt gca aca tgc tgt aat tat Ser Asn Arg He 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 25 DNA Sequence (SEQ ID NOJ06) and Protein Sequence (SEQ ID NOJ07) ofBtl.2 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtg gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser 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 tet gac ctg gcc get ctg age gtc agg gga gga tgc tgt tec

Lys Arg Ser Asp Leu Ala Ala Leu Ser Val Arg Gly Gly Cys Cys Ser cat cct gcc tgt gcg gtg aat cat cca gag ctt tgt ggc tgaagacgct

His Pro Ala Cys Ala Val Asn His Pro Glu Leu Cys Gly gatgccccag gaccctctga accacgacgt

TABLE 26 DNA Sequence (SEQ ID NO:108) and Protein Sequence (SEQ ID NO:109) ofBtl.3 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec

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 get gca gcc aaa gcg Phe Thr Ser Gly Arg Ala Ser Gly Gly Arg Asn Ala Ala Ala Lys Ala tet aac egg ate get atg gcc ate age agt gga gca tgc tgt gca tat Ser Asn Arg He Ala Met Ala He Ser Ser Gly Ala Cys Cys Ala Tyr cct ccc tgt ttc gag get tat cca gaa aga tgt ctg taacgtgaat Pro Pro Cys Phe Glu Ala Tyr Pro Glu Arg Cys Leu catccagacc tttgtggctg aagacgctga tgccccagga ccctctgaac cacgacgt

TABLE 27 DNA Sequence (SEQ ID NOJ 10) and Protein Sequence (SEQ ID NOJ 11) ofBtl.4 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tea gat cgt gca ttt cgt ggc agg aat tec gca gcc aac gac Phe Thr Ser Asp Arg Ala Phe Arg Gly Arg Asn Ser Ala Ala Asn Asp aaa agg tet gac ctg gcc get ctg age gtc agg aga gga tgc tgc tec

Lys Arg Ser Asp Leu Ala Ala Leu Ser Val Arg Arg Gly Cys Cys Ser cat ccc gcc tgt age 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 tgatgcccca ggaccctctg aaccacgacg t

TABLE 28

DNA Sequence (SEQ ID NOJ 12) and Protein Sequence (SEQ ID NOJ 13) ofBtl.5 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec

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 get gca gcc aaa gcg Phe Thr Ser Gly Arg Ala Ser Gly Gly Arg Asn Ala Ala Ala Lys Ala tet aac egg ate get ctg ate gtc agg aat gca gaa tgc tgt tat tat

Ser Asn Arg He Ala Leu He Val Arg Asn Ala Glu Cys Cys Tyr Tyr cct ccc tgt tac gag get tat cca gaa att tgt ctg taacgtgaat Pro Pro Cys Tyr Glu Ala Tyr Pro Glu He Cys Leu catccagacc tttgtggctg aagaccctga tgctccagga ccctctgaac cacgacgt

TABLE 29 DNA Sequence (SEQ ID NOJ 14) and Protein Sequence (SEQ ID NOJ 15) of PnlJ atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace ace gtc att tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val He Ser ttc act tea gat cgt gca tet gat ggc ggg aat gcc gca gcg tet gac Phe Thr Ser Asp Arg Ala Ser Asp Gly Gly Asn Ala Ala Ala Ser Asp ctg ate get ctg ace ate aag gga tgc tgt tet cat cct ccc tgt gcc

Leu He Ala Leu Thr He 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 30

DNA Sequence (SEQ ID NOJ 16) and Protein Sequence (SEQ ID NOJ17) ofPnl.2 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace ace gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tea gat cgt gca tet gat ggc ggg aat gcc gca atg tet gac Phe Thr Ser Asp Arg Ala Ser Asp Gly Gly Asn Ala Ala Met Ser Asp ctg ate get ctg ace ate aag gga tgc tgt tet cat cct ccc tgt ttc Leu He Ala Leu Thr He 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

TABLE 31

DNA Sequence (SEQ ID NOJ 18) and Protein Sequence (SEQ ID NOJ 19) ofSml.3 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc cct tea gat cgt gaa tet gat ggc gcg aat gac gaa gcc cgc ace

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 age cac aga tgt ggt tgacgacgct gatgctccag Pro Ala Cys Glu Ser His Arg Cys Gly gaccctctga accacgacg TABLE 32

DNA Sequence (SEQ ID NOJ20) and Protein Sequence (SEQ ID NOJ21) ofCrl.2 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc cct tea gat cgt gca tet gat ggc agg aat gcc gca gcc age gac

Phe Pro Ser Asp Arg Ala Ser Asp Gly Arg Asn Ala Ala Ala Ser Asp aga gcg tet gac gcg gcc cac cag gga tgc tgt tec aac cct gtc tgt Arg Ala Ser Asp Ala Ala His Gin Gly Cys Cys Ser Asn Pro Val Cys cac gtg gaa cat cca gaa ctt tgt cgt aga aga cgc tgatgctcca His Val Glu His Pro Glu Leu Cys Arg Arg Arg Arg ggaccctctg aaccacgacg

TABLE 33

DNA Sequence (SEQ ID NO:122) and Protein Sequence (SEQ ID NO:123) ofCrl.3 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc cct tea aat cgt gaa tet gat ggc gcg aat gcc gaa gtc cgc ace Phe Pro Ser Asn Arg Glu Ser Asp Gly Ala Asn Ala Glu Val Arg Thr gac gag cct gag gag cac gac gaa ctg ggc ggg aat gga tgc tgt ggg Asp Glu Pro Glu Glu His Asp Glu Leu Gly Gly Asn Gly Cys Cys Gly aat cct gac tgt acg age cac agt tgt gat tgacgacgct gatgctccag

Asn Pro Asp Cys Thr Ser His Ser Cys Asp gaccctctga accacgacg

TABLE 34

DNA Sequence (SEQ ID NOJ24) and Protein Sequence (SEQ ID NOJ25) ofEpl atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace ace gtc gtt tec

Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tea gat cgt gca tet gat age agg aag gac gca gcg tet ggc Phe Thr Ser Asp Arg Ala Ser Asp Ser Arg Lys Asp Ala Ala Ser Gly ctg ate get ctg ace ate aag gga tgc tgt tet gat cct cgc tgt aac Leu He Ala Leu Thr He Lys Gly Cys Cys Ser Asp Pro Arg Cys Asn atg aat aat cca gac tat tgt ggt tgacgacgct gatgctccag gaccctctga Met Asn Asn Pro Asp Tyr Cys Gly accacgacg

TABLE 35 DNA Sequence (SEQ ID NOJ26) and Protein Sequence (SEQ ID NOJ27) of SnlJ atg tec ace gtg ttt ctg ttg gtt gtc etc gca ace ace gtc gtt tec Met Ser Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ' ttc act gta gat cgt gca tet gat ggc agg gat gtc gca ate gac gac

Phe Thr Val Asp Arg Ala Ser Asp Gly Arg Asp Val Ala He Asp Asp aga ttg gtg tet etc cct cag ate gcc cat get gac tgt tgt tec gat

Arg Leu Val Ser Leu Pro Gin He 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) ofSnl.2 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace ace gtc get tec

Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Ala Ser ttc att ate gat gat cca tet gat ggc agg aat att gca gtc gac gac Phe He He Asp Asp Pro Ser Asp Gly Arg Asn He Ala Val Asp Asp aga ggg ctt ttc tet acg etc ttc cat get 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 tgatctttgt tcttcaaaga cactgctggc Ala Cys Arg His Thr Gin Gly Cys ccaggaccct ctgaaccacg acg

TABLE 37 DNA Sequence (SEQ ID NO:130) and Protein Sequence (SEQ ID NO:131) ofDal J atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace ace gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tea 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 tet ggc ctg gtc ggt ctg ace gac aag acg cga gga tgc tgt tet cat

Ser Gly Leu Val Gly Leu Thr Asp Lys Thr Arg Gly 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 He Cys Gly gatgctccag gaccctctga accacgacgt

TABLE 38

DNA Sequence (SEQ ID NOJ32) and Protein Sequence (SEQ ID NO:133) ofDal.2 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace ace gtc gtt tec

Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tea gat ggt gca tet gat gac agg aaa gcc get gcg tet gac Phe Thr Ser Asp Gly Ala Ser Asp Asp Arg Lys Ala Ala Ala Ser Asp ctg ate act ctg ace ate aag gga tgc tgt tet cgt cct ccc tgt ate

Leu He Thr Leu Thr He Lys Gly Cys Cys Ser Arg Pro Pro Cys He gcg aat aat cca gac ttg tgt ggt cga cga cgc tgatgctcca ggaccctctg Ala Asn Asn Pro Asp Leu Cys Gly Arg Arg Arg

TABLE 39

DNA Sequence (SEQ ID NO:134) and Protein Sequence (SEQ ID NO:135) ofDal.3 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec

Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser tec act tea ggt cgt cgt gca ttt cat ggc agg aat gcc gca gcc aaa Ser Thr Ser Gly Arg Arg Ala Phe His Gly Arg Asn Ala Ala Ala Lys gcg tet gga ctg gtc ggt ctg act gac agg aga cca caa tgc tgt agt Ala Ser Gly Leu Val Gly Leu Thr Asp Arg Arg Pro Gin Cys Cys Ser gat cct cgc tgt aac gta ggt cat cca gaa ctt tgt ggt gga aga cgc Asp Pro Arg Cys Asn Val Gly His Pro Glu Leu Cys Gly Gly Arg Arg tgatgctcca ggaccctctg aaccacaacg t

TABLE 40 DNA Sequence (SEQ ID NO:136) and Protein Sequence (SEQ ID NO:137) ofDal.4 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec

Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser tec act tea 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 tet ggc ctg gtc ggt ctg ace 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 He Cys Gly Gly Arg Arg tgatgctcca ggaccctctg aaccacgacg t

TABLE 41

DNA Sequence (SEQ ID NOJ38) and Protein Sequence (SEQ ID NO-139) ofA1.2 atg ttc ace gtg ttt ctg ttg gtt gtc ttg aca ace act gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Thr Thr Thr Val Val Ser ttc cct tea gat agt gca tet ggt ggc agg gat gac gag gcc aaa gac Phe Pro Ser Asp Ser Ala Ser Gly Gly Arg Asp Asp Glu Ala Lys Asp gaa agg tet gac atg tac gaa ttg aaa egg aat gga cgc tgt tgc cat Glu Arg Ser Asp Met Tyr Glu Leu Lys Arg Asn Gly Arg Cys Cys His cct gcc tgt ggt ggc aaa tac gtt aaa tgt gga cgc tgatgctcca Pro Ala Cys Gly Gly Lys Tyr Val Lys Cys Gly Arg ggaccctctc gaaccacg TABLE 42

DNA Sequence (SEQ ID NOJ40) and Protein Sequence (SEQ ID NOJ41) ofBui J atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc tet aca gat gat gaa tet gat ggc teg aat gaa gaa ccc age gcc

Phe Ser Thr Asp Asp Glu Ser Asp Gly Ser Asn Glu Glu Pro Ser Ala gac cag act gcc agg tec tea 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 cct gcc tgt gtg aag cac aga tgt gga tgacgctgat gctccaggac Asn Pro Ala Cys Val Lys His Arg Cys Gly cctctgaacc acgacgt

TABLE 43

DNA Sequence (SEQ ID NO:142) and Protein Sequence (SEQ ID NO:143) ofBui.2 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc tet aca gat gat gaa tet gat ggc teg aat gaa gaa ccc age gcc Phe Ser Thr Asp Asp Glu Ser Asp Gly Ser Asn Glu Glu Pro Ser Ala gac cag get gcc agg tec 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 cct gcc tgt gtg aag cac aga tgt ggt gga tgacgctgat gctccaggac

Asn Pro Ala Cys Val Lys His Arg Cys Gly Gly cctctgaacc acgacgt

TABLE 44 DNA Sequence (SEQ ID NOJ44) and Protein Sequence (SEQ ID NOJ45) ofBui.3 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec

Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc cct tea gat cgt gac tet gat ggc gcg gat gcc gaa gcc agt gac Phe Pro Ser Asp Arg Asp Ser Asp Gly Ala Asp Ala Glu Ala Ser Asp gag cct gtt gag ttc gaa agg gac gag aat gga tgc tgt tgg aat cct Glu Pro Val Glu Phe Glu Arg Asp Glu Asn Gly Cys Cys Trp Asn Pro tec tgt ccg agg ccc aga tgt aca gga cga cgc taatgctcca ggaccctctg Ser Cys Pro Arg Pro Arg Cys Thr Gly Arg Arg aaccacgacg t

TABLE 45 DNA Sequence (SEQ ID NOJ46) and Protein Sequence (SEQ ID NOJ70) ofBul.4 atg ttc ace gtg ttt ctg ttg gtt gtc ttg aca ace act gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Thr Thr Thr Val Val Ser ttc cct tea gat cgt gca tet 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 tet gac gtg gtc acg ctg gtc etc aag gga tgc tgt tec ace

Lys Ala Ser Asp Val Val Thr Leu Val Leu Lys Gly Cys Cys Ser Thr cct ccc tgt get gtg ctg tat tgt ggt aga aga cgc tgatgctcca

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 DilJ atg ttc ace gtg ttt ctg ttg gtt gtc ttc gca tec tet gtc ace tta

Met Phe Thr Val Phe Leu Leu Val Val Phe Ala Ser Ser Val Thr Leu gat cgt gca tet tat ggc agg tat gcc tea ccc gtc gac aga gcg tet Asp Arg Ala Ser Tyr Gly Arg Tyr Ala Ser Pro Val Asp Arg Ala Ser gcc ctg ate get cag gcc ate ctt cga gat tgc tgc tec aat cct cct Ala Leu He Ala Gin Ala He Leu Arg Asp Cys Cys Ser Asn Pro Pro tgt gcc cat aat aat cca gac tgt cgt taaagacgct gcttgctcca Cys Ala His Asn Asn Pro Asp Cys Arg ggaccctctg aaccacgacg t

TABLE 47 DNA Sequence (SEQ ID NO: 150) and Protein Sequence (SEQ ID NO: 151 ) of Tl gga tgc tgt tet aat cct ccc tgt ate gcg aag aat cca cac atg tgt Gly Cys Cys Ser Asn Pro Pro Cys He 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) ofCnl.2 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc cct tea gat cgt gca tet 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 tet gac gtg ate acg ctg gcc etc aag gga tgc tgt tec aac Lys Ala Ser Asp Val He Thr Leu Ala Leu Lys Gly Cys Cys Ser Asn cct gtc tgt cac ttg gag cat tea aac ctt tgt ggt aga aga cgc Pro Val Cys His Leu Glu His Ser Asn Leu Cys Gly Arg Arg Arg tgatgctcca ggaccctctg aaccacgacg t TABLE 49

DNA Sequence (SEQ ID NO:233) and Protein Sequence (SEQ ID NO:234) ofIml J tet gat gga aag agt gcc gcg gcc aaa gcc aaa ccg tet cac ctg acg Ser Asp Gly Lys Ser Ala Ala Ala Lys Ala Lys Pro Ser His Leu Thr get cca ttc ate agg gac gaa tgc tgt tec gat tet cgc tgt ggc aag

Ala Pro Phe He Arg Asp Glu Cys Cys Ser Asp Ser Arg Cys Gly Lys aac tgt ctt tga Asn Cys Leu

TABLE 50 DNA Sequence (SEQ ID NO:235) and Protein Sequence (SEQ ID NO:236) ofIml.2 ttt gat gga agg aat gcc cca gcc gac gac aaa gcg tet gac ctg ate Phe Asp Gly Arg Asn Ala Pro Ala Asp Asp Lys Ala Ser Asp Leu He get caa ate gtc agg aga gca tgc tgt tec gat cgt cgc tgt aga tgg Ala Gin He Val Arg Arg Ala Cys Cys Ser Asp Arg Arg Cys Arg Trp agg tgt ggt tga

Arg Cys Gly

TABLE 51 DNA Sequence (SEQ ID NO:237) and Protein Sequence (SEQ ID NO:238) ofRgl.2 tet gat gga agg aat gcc gca gcc gac gcc aga gcg tet ccc egg ate Ser Asp Gly Arg Asn Ala Ala Ala Asp Ala Arg Ala Ser Pro Arg He get ctt ttc etc agg ttc aca tgc tgt agg aga ggt ace tgt tec cag Ala Leu Phe Leu Arg Phe Thr Cys Cys Arg Arg Gly Thr Cys Ser Gin cac tgt ggt tgaagacact gctgctccag gaccctctga accacgacgt His Cys Gly

TABLE 52

DNA Sequence (SEQ ID NO:239) and Protein Sequence (SEQ ID NO:240) ofRgl.6 tet aat gga agg aat gcc gca gcc gac gcc aaa gcg tet caa egg ate Ser Asn Gly Arg Asn Ala Ala Ala Asp Ala Lys Ala Ser Gin Arg He get cca ttc etc agg gac tat tgc tgt agg aga cat gcc 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 accacgacgt He Cys Gly

TABLE 53

DNA Sequence (SEQ ID NO:241) and Protein Sequence (SEQ ID NO:242) ofRgl.όA tet aat gga agg aat gcc gca gcc gac gcc aaa gcg tet caa egg ate Ser Asn Gly Arg Asn Ala Ala Ala Asp Ala Lys Ala Ser Gin Arg He get cca ttc etc agg gac tat tgc tgt agg aga cct 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 accacgacgt He Cys Gly

TABLE 54

DNA Sequence (SEQ ID NO:243) and Protein Sequence (SEQ ID NO:244) ofRgl.7 tet aat aaa agg aag aat gcc gca atg ctt gac atg ate get caa cac Ser Asn Lys Arg Lys Asn Ala Ala Met Leu Asp Met He Ala Gin His gcc ata agg ggt tgc tgt tec gat cct cgc tgt aga tat aga tgt cgt

Ala He Arg Gly Cys Cys Ser Asp Pro Arg Cys Arg Tyr Arg Cys Arg tgaagacgct gctgctccag gaccctctga accacgacgt

TABLE 55

DNA Sequence (SEQ ID NO:245) and Protein Sequence (SEQ ID NO:246) ofRgl.9 ttt aat gga agg agt gcc gca gcc gac caa aat gcg cct ggc ctg ate

Phe Asn Gly Arg Ser Ala Ala Ala Asp Gin Asn Ala Pro Gly Leu He get caa gtc gtc aga gga ggg tgc tgt tec gat ccc cgc tgc gcc tgg Ala Gin Val Val Arg Gly Gly Cys Cys Ser Asp Pro Arg Cys Ala Trp aga tgt ggt tgaagacgtt gctgctccag gaccctctga accacgacgt Arg Cys Gly

TABLE 56

DNA Sequence (SEQ ID NO:247) and Protein Sequence (SEQ ID NO:248) of RglJO ttt gat gga agg aat gcc gca gcc gac gcc aaa gtg att aac acg gtc Phe Asp Gly Arg Asn Ala Ala Ala Asp Ala Lys Val He Asn Thr Val get cga ate gcc tgg gat ata tgc tgt tec gaa cct gac tgt aac cat

Ala Arg He Ala Trp Asp He Cys Cys Ser Glu Pro Asp Cys Asn His aaa tgt gtt tgaagacgct tctgctccag gaccctctga accacgacgt Lys Cys Val

TABLE 57 DNA Sequence (SEQ ID NO:249) and Protein Sequence (SEQ ID NO:250) ofRgl J 1 tet aat aaa agg aag aat gcc gca atg ctt gac atg ate get caa cac Ser Asn Lys Arg Lys Asn Ala Ala Met Leu Asp Met He Ala Gin His gcc ata agg ggt tgc tgt tec gat cct cgc tgt aaa cat cag tgt ggt Ala He Arg Gly Cys Cys Ser Asp Pro Arg Cys Lys His Gin Cys Gly tgaagacgct gctgctccag gaccctctga accacgacgt TABLE 58 DNA Sequence (SEQ IDNO:251) and Protein Sequence (SEQ ID NO:252) ofMsl.7 ate aag aat aca gca gcc age aac aaa gcg tet age ctg gtg get ctt He Lys Asn Thr Ala Ala Ser Asn Lys Ala Ser Ser Leu Val Ala Leu gtt gtc agg gga tgc tgt tac aat cct gtc tgc 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) ofP1.7 tet gaa ggc agg aat get gaa gcc ate gac aac gcc tta gac cag agg Ser Glu Gly Arg Asn Ala Glu Ala He Asp Asn Ala Leu Asp Gin Arg gat cca aag cga cag gag ccg ggg tgc tgt agg cat cct gcc tgt ggg Asp Pro Lys Arg Gin Glu Pro Gly Cys Cys Arg His Pro Ala Cys Gly aag aac aga tgt gga aga cgc tgatgctcca ggaccctctg aaccacgacg t

Lys Asn Arg Cys Gly Arg Arg

TABLE 60

DNA Sequence (SEQ ID NO:255) and Protein Sequence (SEQ ID NO:256) of Msl .2 tet gat ggc agg aat att gca gtc gac gac aga tgg tet ttc tat acg Ser Asp Gly Arg Asn He Ala Val Asp Asp Arg Trp Ser Phe Tyr Thr etc ttc cat get act tgc tgt gcc gat cct gac tgt aga ttc egg ccc Leu Phe His Ala Thr Cys Cys Ala Asp Pro Asp Cys Arg Phe Arg Pro ggt tgt tgatctttgt tcttcaaaga cgctgctggc ccaggaccct ctgaaccacg Gly Cys acgt

TABLE 61

DNA Sequence (SEQ ID NO:257) and Protein Sequence (SEQ ID NO:258) ofMsl.3 ate aag aat act gca gcc age aac aaa gcg cct age ctg gtg get att He Lys Asn Thr Ala Ala Ser Asn Lys Ala Pro Ser Leu Val Ala He gcc gtc agg gga tgc tgt tac aat cct tec tgt tgg ccg aaa aca tat

Ala Val Arg Gly Cys Cys Tyr Asn Pro Ser Cys Trp Pro Lys Thr Tyr tgt agt tggaaaggct gatgctccag gaccctctga accacgacgt Cys Ser TABLE 62 DNA Sequence (SEQ ID NO:259) and Protein Sequence (SEQ ID NO:260) ofMsl.4 tet gat age agg aat gtc gca ate gag gac aga gtg tet gac ctg cac Ser Asp Ser Arg Asn Val Ala He Glu Asp Arg Val Ser Asp Leu His tet atg ttc ttc gat gtt tet tgc tgt age aat cct ace tgt aaa gaa

Ser Met Phe Phe Asp Val Ser Cys Cys Ser Asn Pro Thr Cys Lys Glu acg tat ggt tgt tgatcgttgg ttttgaagac gctgatgctc caggaccctc Thr Tyr Gly Cys

TABLE 63 DNA Sequence (SEQ ID NO:261) and Protein Sequence (SEQ ID NO:262) ofMsl.5 tet gtt ggc agg aat att gca gtc gac gac aga ggg att ttc tet acg Ser Val Gly Arg Asn He Ala Val Asp Asp Arg Gly He Phe Ser Thr etc ttc cat get cat tgc tgt gcc aat ccc ate tgt aaa aac acg ccc Leu Phe His Ala His Cys Cys Ala Asn Pro He Cys Lys Asn Thr Pro ggt tgt tgatctttgt tcttcaaaga cgctgctggc ccaggaccct ctgaaccacg

Gly Cys acgt

TABLE 64

DNA Sequence (SEQ ID NO:263) and Protein Sequence (SEQ ID NO:264) ofMsl.8 tec gat ggc agg aat gtc gca ate gac gac aga gtg tet gac ctg cac

Ser Asp Gly Arg Asn Val Ala He Asp Asp Arg Val Ser Asp Leu His tet atg ttc ttc gat att get tgc tgt aac aat cct ace tgt aaa gaa Ser Met Phe Phe Asp He Ala Cys Cys Asn Asn Pro Thr Cys Lys Glu acg tat ggt tgt tgatcgttgg ttttgaagac gctgatgctc caggaccctc Thr Tyr Gly Cys tgaaccacga cgt

TABLE 65

DNA Sequence (SEQ ID NO:265) and Protein Sequence (SEQ ID NO:266) of Msl.9 tet gat ggc agg aat gtc gca ate gag gac aga gtg tet gac ctg etc Ser Asp Gly Arg Asn Val Ala He Glu Asp Arg Val Ser Asp Leu Leu tet atg etc ttc gat gtt get tgc tgt age aat cct gtc 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 gctgatgctc caggaccctc Thr Tyr Gly Cys tgaaccacga cgt TABLE 66 DNA Sequence (SEQ ID NO:267) and Protein Sequence (SEQ ID NO:268) ofBtl.7 tat gat ggc agg aat get gcc gcc gac gac aaa get ttt gac ctg ctg Tyr Asp Gly Arg Asn Ala Ala Ala Asp Asp Lys Ala Phe Asp Leu Leu get atg ace ata agg gga gga tgc tgt tec tat cct ccc tgt ate gcg

Ala Met Thr He Arg Gly Gly Cys Cys Ser Tyr Pro Pro Cys He 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) ofLvl.5 ttt gat ggc agg aat get gca ggc aac gcc aaa atg tec gcc ctg atg Phe Asp Gly Arg Asn Ala Ala Gly Asn Ala Lys Met Ser Ala Leu Met gcc ctg ace ate agg gga tgc tgt tec cat cct gtc tgt age gcg atg Ala Leu Thr He Arg Gly Cys Cys Ser His Pro Val Cys Ser Ala Met agt cca ate tgt ggc tgaagacgct gatgccccag gaccctctga accacgacgt Ser Pro He Cys Gly

TABLE 68

DNA Sequence (SEQ ID NO:271) and Protein Sequence (SEQ ID NO:272) ofMsl.10 ate aag aat get gca get gac gac aaa gca tet gac ctg etc tet cag

He Lys Asn Ala Ala Ala Asp Asp Lys Ala Ser Asp Leu Leu Ser Gin ate gtc agg aat get gca tec aat gac aaa ggg tet gac ctg atg act He Val Arg Asn Ala Ala Ser Asn Asp Lys Gly Ser Asp Leu Met Thr ctt gcc etc agg gga tgc tgt aaa aat cct tac t.gt ggt gcg teg 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) ofOml.l tctgatggca ggaatgccgc agcgtctgac ctgatggat ctg ace ate aag gga

Leu Thr He Lys Gly tgc tgt tet 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 TABLE 70 DNA Sequence (SEQ ID NO:275) and Protein Sequence (SEQ ID NO:276) of R1.6 ttt gat ggc agg aat gcc gca gcc gac tac aaa ggg tet gaa ttg etc Phe Asp Gly Arg Asn Ala Ala Ala Asp Tyr Lys Gly Ser Glu Leu Leu get atg ace gtc agg gga gga tgc tgt tec tat cct ccc tgt ate gca

Ala Met Thr Val Arg Gly Gly Cys Cys Ser Tyr Pro Pro Cys He Ala aat aat cct ctt tgt get gga aga cgc tga Asn Asn Pro Leu Cys Ala Gly Arg Arg

TABLE 71 DNA Sequence (SEQ ID NO:277) and Protein Sequence (SEQ ID NO:278) ofR1.7 ttt gat ggc agg aat gcc gca gcc gac tac aaa ggg tet gaa ttg etc Phe Asp Gly Arg Asn Ala Ala Ala Asp Tyr Lys Gly Ser Glu Leu Leu get atg ace gtc agg gga gga tgc tgt tec tat cct ccc tgt ate gca Ala Met Thr Val Arg Gly Gly Cys Cys Ser Tyr Pro Pro Cys He Ala aat aat cct ttt tgt get 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 J tet tat gac agg tat gcc teg ccc gtc gac aga gcg tet gcc ctg ate Ser Tyr Asp Arg Tyr Ala Ser Pro Val Asp Arg Ala Ser Ala Leu He get cag gcc ate ctt cga gat tgc tgt tec aat cct ccc tgt tec caa Ala Gin Ala He' 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) ofVrl.2 tet tat ggc agg tat gcc tea ccc gtc gac aga gcg tet gcc ctg ate Ser Tyr Gly Arg Tyr Ala Ser Pro Val Asp Arg Ala Ser Ala Leu He get cag gcc ate ctt cga gat tgc tgc tec aat cct cct tgt gcc cat

Ala Gin Ala He Leu Arg Asp Cys Cys Ser Asn Pro Pro Cys Ala His aat aat cca gac tgt cgt taaagacgct gcttgctcca ggaccctctg Asn Asn Pro Asp Cys Arg aaccacgacg t TABLE 74

DNA Sequence (SEQ ID NO:283) and Protein Sequence (SEQ ID NO:284) ofA1.4 tet gat ggc agg aat gcc gca gcc aac gac aaa gcg tet ggc atg age

Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala Ser Gly Met Ser gcg ctg gcc gtc aat gaa tgc tgt ace aac cct 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 get aga aga cgc tga His Gin Glu Leu Cys Ala Arg Arg Arg

TABLE 75 DNA Sequence (SEQ ID NO:285) and Protein Sequence (SEQ ID NO:286) ofA1.5 tet gat ggc agg aat gcc gca gcc aac gac aaa gcg tet gac gtg ate

Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala Ser Asp Val He acg ctg gcc etc aag gga tgc tgt tec aac cct gtc tgt cac ttg gag

Thr Leu Ala Leu Lys Gly Cys Cys Ser Asn Pro Val Cys His Leu Glu cat tea aac ctt 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) of A1.6 tet gat ggc agg aat gcc gca gcc aac gac aaa gcg tet ggc atg age Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala Ser Gly Met Ser gcg ctg gcc gtc aat gaa tgc tgt ace aac cct gtc tgt cac gtg gaa

Ala Leu Ala Val Asn Glu Cys Cys Thr Asn Pro Val Cys His Val Glu cat caa gaa ctt tgt get aga aga cgc 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) ofAfl.l atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace ace gtc gtt tec

Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tea gat cgt gca ttt cgt ggc agg aat gcc gca gcc aaa gcg Phe Thr Ser Asp Arg Ala Phe Arg Gly Arg Asn Ala Ala Ala Lys Ala tet ggc ctg gtc ggt ctg ace gac aag agg caa gaa tgc tgt tet tat

Ser Gly Leu Val Gly Leu Thr Asp Lys Arg Gin Glu Cys Cys Ser Tyr cct gcc tgt aac eta gat cat cca gaa ctt tgt ggt tgaagacgct Pro Ala Cys Asn Leu Asp His Pro Glu Leu Cys Gly gatgctccag gaccctctga accacgacgt TABLE 78

DNA Sequence (SEQ ID NO:291) and Protein Sequence (SEQ ID NO:292) ofAfl.2 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace act gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser tec act tea ggt cgt cgt gca ttt cgt ggc agg aat gcc gca gcc aaa

Ser Thr Ser Gly Arg Arg Ala Phe Arg Gly Arg Asn Ala Ala Ala Lys gcg tet gga ctg gtc 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 teg 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 tgatgctcca ggaccctctg aaccacgacg t

TABLE 79

DNA Sequence (SEQ ID NO:293) and Protein Sequence (SEQ ID NO:294) of Arl.2 tet gat ggc agg aat gcc gca gcc aac gcg ttt gac ctg ate gat ctg Ser Asp Gly Arg Asn Ala Ala Ala Asn Ala Phe Asp Leu He Asp Leu ace gcc agg eta aat tgc tgt atg att ccc ccc tgt tgg aag aaa tat Thr Ala Arg Leu Asn Cys Cys Met He Pro Pro Cys Trp Lys Lys Tyr gga gac aga tgt agt gaa gta cgc tgatgctcca ggaccctctg aaccacgacg Gly Asp Arg Cys Ser Glu Val Arg t

TABLE 80

DNA Sequence (SEQ ID NO:295) and Protein Sequence (SEQ ID NO:296) ofArl.3 tet gat ggc agg aat gcc gca cgc aaa gcg 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

He Pro Cys Leu Glu Arg Tyr Gly Asn Arg Cys Asn Glu Val His tgatgctcca ggaccctctg aaccacgcga cgt

TABLE 81

DNA Sequence (SEQ ID NO:297) and Protein Sequence (SEQ ID NO:298) ofArl.4 tet gat ggc age aat gcc gca gcc aac gag ttt gac ctg ate get ctg

Ser Asp Gly Ser Asn Ala Ala Ala Asn Glu Phe Asp Leu He Ala Leu ace gcc agg eta ggt tgc tgt aac 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 gac aaa tgt aat gaa gta cgc tgatgcttca ggaccctctg aaccacgacg Gly Asp Lys Cys Asn Glu Val Arg TABLE 82

DNA Sequence (SEQ ID NO:299) and Protein Sequence (SEQ ID NO:300) ofArl.5 tet gat ggc agg aat gtc gca gca aaa gcg ttt cac egg ate ggc egg Ser Asp Gly Arg Asn Val Ala Ala Lys Ala Phe His Arg He Gly Arg ace ate agg gat gaa tgc tgt tec aat cct gcc tgt agg gtg aat aat

Thr He Arg Asp Glu Cys Cys Ser Asn Pro Ala Cys Arg Val Asn Asn cca cac gtt tgt aga cga cgc tgatgctcca ggaccctctg aaccacgacg t Pro His Val Cys Arg Arg Arg

TABLE 83 DNA Sequence (SEQ ID NO:301) and Protein Sequence (SEQ ID NO:302) ofArl.6 tet gat ggc agg aat gcc 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 ace gcc agg eta aat tgc tgt age att ccc ggc tgt tgg aac gaa tat Thr Ala Arg Leu Asn Cys Cys Ser He Pro Gly Cys Trp Asn Glu Tyr aaa gac aga tgt agt aaa gta cgc tgatgctcca ggaccctctg aaccacgacg

Lys Asp Arg Cys Ser Lys Val Arg

TABLE 84 DNA Sequence (SEQ ID NO:303) and Protein Sequence (SEQ ID NO:304) ofAyl.2 tctgatggca ggaatgccgc agccgacgac aaagcgtctg acctggtcgc t ctg gtc

Leu Val gtc agg gga gga tgc tgt tec cac cct gtc tgt tac ttt aat aat cca Val Arg Gly Gly Cys Cys Ser His Pro Val Cys Tyr Phe Asn Asn Pro caa atg tgt cgt gga aga cgc tgatgctcca ggaccctctg aaccacgacg t Gin Met Cys Arg Gly Arg Arg

TABLE 85

DNA Sequence (SEQ ID NO:305) and Protein Sequence (SEQ ID NO:306) ofAyl.3 tctgatggca ggaatgccgc agccgacgac aaagcgtctg acctggtcgc t ctg gcc

Leu Ala gtc agg gga gga tgc tgt tec cac cct gtc tgt aac ttg aat aat cca

Val Arg Gly Gly Cys Cys Ser His Pro Val Cys Asn Leu Asn Asn Pro caa atg tgt cgt gga aga cgc tgatgctcca ggaccctctg aaccacgacg t Gin Met Cys Arg Gly Arg Arg

TABLE 86 DNA Sequence (SEQ ID NO:307) and Protein Sequence (SEQ ID NO:308) ofBtl.8 ttt cgt ggc agg aat ccc gca gcc aac gac aaa agg tet gac ctg gcc

Phe Arg Gly Arg Asn Pro Ala Ala Asn Asp Lys Arg Ser Asp Leu Ala get ctg age gtc agg gga gga tgc tgt tec cat cct gcc tgt age 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:310) ofBtl.9 tet gat ggc ggg aat gcc gca gcc aaa gcg tet gac ctg ate get cag

Ser Asp Gly Gly Asn Ala Ala Ala Lys Ala Ser Asp Leu He Ala Gin ace ate agg gga gga tgc tgt tec tat cct gcc tgt age gtg gaa cat Thr He Arg Gly Gly Cys Cys Ser Tyr Pro Ala Cys Ser Val Glu His caa gac ctt tgt gat gga aga cgc tgatgctcca ggaccctctg aaccacgacg Gin Asp Leu Cys Asp Gly Arg Arg

TABLE 88

DNA Sequence (SEQ ID NO-311) and Protein Sequence (SEQ ID NO:312) of Cal .3 tet 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 Glu 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 He Arg Tyr Gin Glu Glu Cys Leu Glu Ala gat ccc agg ace etc tga Asp Pro Arg Thr Leu

TABLE 89

DNA Sequence (SEQ ID NO:313) and Protein Sequence (SEQ ID NO:314) ofCal.4 tet gat ggc agg aat gcc gca gcc aac gcc ctt gac ctg ate act ctg Ser Asp Gly Arg Asn Ala Ala Ala Asn Ala Leu Asp Leu He Thr Leu ate gcc agg caa aat tgc tgt age att ccc ggc tgt tgg gag aaa tat He Ala Arg Gin Asn Cys Cys Ser He Pro Gly Cys Trp Glu Lys Tyr gga gac aaa tgt agt gaa gta cgc tga Gly Asp Lys Cys Ser Glu Val Arg

TABLE 90

DNA Sequence (SEQ ID NO:315) and Protein Sequence (SEQ ID NO:316) ofC1.2 tet gat ggc agg aat gaa gca gcc aac gac gaa gcg tet gac gtg ate

Ser Asp Gly Arg Asn Glu Ala Ala Asn Asp Glu Ala Ser Asp Val He gag ctg gcc etc aag gga tgc tgt tec 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 get tgt ggt aga aga cgc tgatgctcca ggaccctctg His Pro Asn Ala Cys Gly Arg Arg Arg aaccacgacg t

TABLE 91 DNA Sequence (SEQ ID NO:317) and Protein Sequence (SEQ ID NO:318) ofC1.3 tet gat ggc agg aat gcc gca gcc aac gac aaa gcg tet gac ctg gtc Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala Ser Asp Leu Val get ctg gcc gtc agg gga tgc tgt tec aac cct ate tgt tac ttt aat

Ala Leu Ala Val Arg Gly Cys Cys Ser Asn Pro He Cys Tyr Phe Asn aat cca cga att tgt cgt gga aga cgc tgatgctcca ggaccctctg Asn Pro Arg He Cys Arg Gly Arg Arg aaccacgacg t

TABLE 92

DNA Sequence (SEQ ID NO:319) and Protein Sequence (SEQ ID NO:320) ofEpl.2 tet cat ggc agg aat gcc gca cgc aaa gcg tet gac ctg ate get ctg Ser His Gly Arg Asn Ala Ala Arg Lys Ala Ser Asp Leu He Ala Leu ace gtc agg gaa tgc tgt tet cag cct ccc tgt cgc tgg aaa cat cca Thr Val Arg Glu Cys Cys Ser Gin Pro Pro Cys Arg Trp Lys His Pro gaa ctt tgt agt tga Glu Leu Cys Ser

TABLE 93

DNA Sequence (SEQ ID NO:321) and Protein Sequence (SEQ ID NO:322) of GIJ tet gat ggc agg aat gac gca gcc aaa gcg ttt gac ctg ata tet teg

Ser Asp Gly Arg Asn Asp Ala Ala Lys Ala Phe Asp Leu He Ser Ser ace gtc aag aaa gga tgc tgt tec cat cct gcc tgt gcg ggg aat aat Thr Val Lys Lys Gly Cys Cys Ser His Pro Ala Cys Ala Gly Asn Asn caa cat att tgt ggc cga aga cgc tgatgctcca ggaccctctg aaccacgacg Gin His He Cys Gly Arg Arg Arg

TABLE 94

DNA Sequence (SEQ ID NO:323) and Protein Sequence (SEQ ID NO:324) of G1.3 tet gat ggc agg aat gcc gca gcc aac gac caa gcg tet gac ctg atg Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Gin Ala Ser Asp Leu Met get gcg ace gtc agg gga tgc tgt gcc gtt cct tec tgt cgc etc 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 95

DNA Sequence (SEQ ID NO:325) and Protein Sequence (SEQ ID NO:326) ofIml.3 ctt gat gaa agg aat gcc gca gcc gac gac aaa gcg tet gac ctg ate Leu Asp Glu Arg Asn Ala Ala Ala Asp Asp Lys Ala Ser Asp Leu He get caa ate gtc agg aga gga tgc tgt tec cat cct gcc tgt aac gtg

Ala Gin He 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 He Cys Gly

TABLE 96 DNA Sequence (SEQ ID NO:327) and Protein Sequence (SEQ ID NO:328) ofLvl.2 tet gat ggc agg aat act gca gcc aaa gtc aaa tat tet aag acg ccg Ser Asp Gly Arg Asn Thr Ala Ala Lys Val Lys Tyr Ser Lys Thr Pro gag gaa tgc tgt ccc aat cct ccc tgt ttc gcg aca aat teg gat att Glu Glu Cys Cys Pro Asn Pro Pro Cys Phe Ala Thr Asn Ser Asp He 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 Lvl.3 tet 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 egg ace gtc agg gat get tgc tgt tea gac cct cgc tgt tec ggg Lys Arg Thr Val Arg Asp Ala Cys Cys Ser Asp Pro Arg Cys Ser Gly aaa cat caa gac ctg tgt ggc tgaagacgct gatgctccag gaccctctga Lys His Gin Asp Leu Cys Gly accacgacgt

TABLE 98

DNA Sequence (SEQ ID NO:331) and Protein Sequence (SEQ ID NO:332) ofLvl A tet 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 gag ctg ace gtc agg gaa gat tgc tgt tea gac cct cgc tgt tec gtg

Glu Leu Thr Val Arg Glu Asp Cys Cys Ser Asp Pro Arg Cys Ser Val 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) ofLvl.6 gca ttt gat ggc agg aat get gca gcc age gac aaa gcg tec gag ctg Ala Phe Asp Gly Arg Asn Ala Ala Ala Ser Asp Lys Ala Ser Glu Leu atg get ctg gcc gtc agg gga tgc tgt tec cat cct gcc tgt get ggg Met Ala Leu Ala Val Arg Gly Cys Cys Ser His Pro Ala Cys Ala Gly agt aat gca cat ate tgt ggc aga aga cgc tgatgctcca ggaccctctg

Ser Asn Ala His He Cys Gly Arg Arg Arg aaccacgacg t

TABLE 100 DNA Sequence (SEQ ID NO:335) and Protein Sequence (SEQ ID NO:336) ofLvl.7 tet 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 ace gtc agg gag gat tgc tgt tea gac cct cgc tgt tec 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) ofLvl.8 ttt gaa tgc agg aat get 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 get ctg act gtc agg gga tgc tgt tec cat cct gcc tgt get ggg aat Ala Leu Thr Val Arg Gly Cys Cys Ser His Pro Ala Cys Ala Gly Asn aat cca cat ate tgc ggc tgaagacgct gatgctccag gaccctctga Asn Pro His He Cys Gly accacgacgt

TABLE 102

DNA Sequence (SEQ ID NO:339) and Protein Sequence (SEQ ID NO:340) ofLvl.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 get ctg act gtc aga gga tgc tgt ggc aat cct tea tgt age ate cat

Ala Leu Thr Val Arg Gly Cys Cys Gly Asn Pro Ser Cys Ser He His att cct tac gtt tgt aat tagagacact gatgctccag gaccctctga He Pro Tyr Val Cys Asn accacgacgt

TABLE 103 DNA Sequence (SEQ ID NO:341) and Protein Sequence (SEQ ID NO:342) ofLvl JO tet 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 egg ace gac age gaa gaa tgc tgt tta gac tet cgc tgt gcc ggg Lys Arg Thr Asp Ser Glu 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 Gly Arg Arg aaccacgacg t

TABLE 104

DNA Sequence (SEQ ID NO:343) and Protein Sequence (SEQ ID NO:344) ofMr1.3 tet gat ggc agg aat gcc gca gcc aag gac aaa gcg tet gac ctg gtc

Ser Asp Gly Arg Asn Ala Ala Ala Lys Asp Lys Ala Ser Asp Leu Val get ctg ace gtc aag gga tgc tgt tet aat cct ccc tgt tac gcg aat Ala Leu Thr Val 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) ofMr1.4 tet gat ggc agg aat gcc gca gcc aag gac aaa gcg tet gac ctg gtc Ser Asp Gly Arg Asn Ala Ala Ala Lys Asp Lys Ala Ser Asp Leu Val get ctg ace gtc aag gga tgc tgt tet cat cct gcc tgt age gtg aat

Ala Leu Thr Val Lys Gly Cys Cys Ser His Pro Ala Cys Ser Val Asn aat cca gac att tgt ggt tga Asn Pro Asp He Cys Gly

TABLE 106 DNA Sequence (SEQ ID NO:347) and Protein Sequence (SEQ ID NO:348) ofMsl J tet gat ggc agg aat get gca gcc aac aac aaa gtg get ttg ace atg Ser Asp Gly Arg Asn Ala Ala Ala Asn Asn Lys Val Ala Leu Thr Met agg gga aaa tgc tgt ate aat gat gcg tgt cgc teg aaa cat cca cag Arg Gly Lys Cys Cys He Asn Asp Ala Cys Arg Ser Lys His Pro Gin tac tgt tet gga aga cgc tgatactcca ggaccctctg aaccacgacg t

Tyr Cys Ser Gly Arg Arg TABLE 107

DNA Sequence (SEQ ID NO:349) and Protein Sequence (SEQ ID NO:350) ofMsl.6 tet gat ggc agg aat get gca gcc aac gac aaa gtg tet gac cag atg Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Val Ser Asp Gin Met get 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 He Ala Cys Arg He Asn aat cca egg tac tgt cgt gga aaa cgc tgatgttcca ggaccctctg 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 O1J tctgaaggca ggaatgccgc agccaacgac aaagcgtctg acctgatggc t ctg aac

Leu Asn gtc agg gga tgc tgt tec 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) ofO1.2 tctgatggcg ggaatgccgc agcaaaagcg tttgatctaa tcact ctg gcc etc 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 110

DNA Sequence (SEQ ID NO:355) and Protein Sequence (SEQ ID NO:356) of O1.4 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace ace gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ccc act tea gat cgt gca tet 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 gac ctg aga tat teg ace gcc aag aga gga tgc tgt tec 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 TABLE 11 1

DNA Sequence (SEQ ID NO:357) and Protein Sequence (SEQ ID NO:358) ofO1.7 atg ttc ace gtg ttt ctg ttg gtt gtc ttg gca ace ace gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr Thr Val Val Ser ttc act tea gat cgt gca tet gat ggc ggg aat gtc gca gcg tet cac

Phe Thr Ser Asp Arg Ala Ser Asp Gly Gly Asn Val Ala Ala Ser His ctg ate get ctg ace ate aag gga tgc tgt tet cac cct ccc tgt gcc Leu He Ala Leu Thr He Lys Gly Cys 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 O1.8 atg ttc ace gtg ttt ctg ttg gtt gtc tta tea ace ace gtc gtt tec Met Phe Thr Val Phe Leu Leu Val Val Leu Ser Thr Thr Val Val Ser tec act tea gat cgt gca tet 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 tet gac ctg atg tat teg ace gtc aag aaa gga tgt tgt tec cat cct Ser Asp Leu Met Tyr Ser Thr Val Lys Lys Gly Cys Cys Ser His Pro gcc tgt teg ggg aat aat cga gaa tat tgt cgt gaa agt ggc

Ala Cys Ser Gly Asn Asn Arg Glu Tyr Cys Arg Glu Ser Gly taatgctcca ggaccctctg aaccacgacg t

TABLE 113

DNA Sequence (SEQ ID NO:361) and Protein Sequence (SEQ ID NO:362) ofOml.2 tttgatggca ggaatgcctc agccgacagc aaagtggctg cccggatcgc t cag ate

Gin He gac agg gat cca tgc tgt tec tat cct gac tgt ggc gcg aat cat 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 aaccacgacg t Glu He Cys Gly Gly Lys Arg

TABLE 114

DNA Sequence (SEQ ID NO:363) and Protein Sequence (SEQ ID NO:364) ofOml.3 tctcatggca ggaatgccgc acgct ctg ace gtc agg gaa tgc tgt tet cag

Leu Thr Val Arg Glu Cys Cys Ser Gin cct cct tgt cgc tgg aaa cat cca gaa ctt tgt agt tgaagacgct

Pro Pro Cys Arg Trp Lys His Pro Glu Leu Cys Ser gatgctccag gaccctctga accacgacgt

TABLE 115

DNA Sequence (SEQ ID NO:365) and Protein Sequence (SEQ ID NO:366) ofOml.4 tttgatggca ggaatgctgc agccagcgac aaagcgtctg agctgatggc t ctg gcc Leu Ala gtc agg gga tgc tgt tec cat cct gcc tgt get ggg aat aat cca cat Val Arg Gly Cys Cys Ser His Pro Ala Cys Ala Gly Asn Asn Pro His ate tgt ggc aga aga cgc tgatgctcca ggaccctctg aaccacgacg t He Cys Gly Arg Arg Arg

TABLE 116

DNA Sequence (SEQ ID NO:367) and Protein Sequence (SEQ ID NO:368) of Oml .5 tctggtgtca ggaaagacgc agcgcctggc ctgatcgct ctg ace ate aag gga

Leu Thr He Lys Gly tgc tgt tet gat cct age 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) ofOml.6 tctaatggca ggaatgccgc agccaaattc aaagcgcctg ccctgatgga g ctg ace 57 Leu Thr gtc agg gaa gaa tgc tgt tea gac cct cgc tgt tec gtg gga cat caa 105 Val Arg Glu Glu Cys Cys Ser Asp Pro Arg Cys Ser Val Gly His Gin gat atg tgt egg tgaagcacgt gatgctccag gaccctctga accacgacgt 157 Asp Met Cys Arg

TABLE 118

DNA Sequence (SEQ ID NO:371) and Protein Sequence (SEQ ID NO:372) ofP1.4 act gat ggc agg aat get gca gcc ata gcg ctt gac ctg ate get ccg Thr Asp Gly Arg Asn Ala Ala Ala He Ala Leu Asp Leu He Ala Pro gcc gtc agg gga gga tgc tgt tec aat cct gcc tgt tta gtg aat cat Ala Val Arg Gly Gly Cys Cys Ser Asn Pro Ala Cys Leu Val Asn His eta gaa atg tgt ggt aaa aga cgc tgatgcccca ggaccctctg aaccacgacg Leu Glu Met Cys Gly Lys Arg Arg TABLE 119

DNA Sequence (SEQ ID NO:373) and Protein Sequence (SEQ ID NO:374) ofP1.5 tet gat ggc agg gat gcc gca gcc aac gac aaa gcg tet gac ctg ate Ser Asp Gly Arg Asp Ala Ala Ala Asn Asp Lys Ala Ser Asp Leu He get ctg ace gcc agg aga gat cca tgc 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 cca cag att tgt ggt tgaagacgct gatgctccag gaccctctga Val Asn Asn Pro Gin He Cys Gly accacgacgt

TABLE 120

DNA Sequence (SEQ IDNO:375) and Protein Sequence (SEQ ID NO:376) ofP1.6 tet gat ggc agg gat get gag aaa aca ggc ttt gac acg ace att gtg Ser Asp Gly Arg Asp Ala Glu Lys Thr Gly Phe Asp Thr Thr He Val ccg gaa gac tgc tgt teg gat cct tec tgt tgg agg ctg cat agt tta Pro Glu Asp Cys Cys Ser Asp Pro Ser Cys Trp Arg Leu His Ser Leu get tgt act gga att gta aac cgc tgatgctcca ggaccctctg aaccacgacg Ala Cys Thr Gly He Val Asn Arg

TABLE 121 DNA Sequence (SEQ IDNO:377) and Protein Sequence (SEQ IDNO:378) ofP1.8 act gat ggc agg agt get gca gcc ata gcg ttt gcc ctg ate get ccg Thr Asp Gly Arg Ser Ala Ala Ala He Ala Phe Ala Leu He Ala Pro ace gtc tgc tgt act aat cct gcc tgt etc gtg aat aat ata cgc ttt Thr Val Cys Cys Thr Asn Pro Ala Cys Leu Val Asn Asn He Arg Phe tgt ggt gga aga cgc tgatgcccca ggaccctctg aaccacgacg t

Cys Gly Gly Arg Arg

TABLE 122 DNA Sequence (SEQ ID NO:379) and Protein Sequence (SEQ ID NO:380) ofRgl J tet gat gga aga aat gcc gca age gac gcc aaa gcg ttt ccc egg ate Ser Asp Gly Arg Asn Ala Ala Ser Asp Ala Lys Ala Phe Pro Arg He get cca ate gtc agg gac gaa tgc tgt age gat cct agg tgt cac ggg Ala Pro He Val Arg Asp Glu Cys Cys Ser Asp Pro Arg Cys His Gly aat aat egg gac cac tgt get tgaagacgct gctgctccag gaccctctga Asn Asn Arg Asp His Cys Ala accacgacgt TABLE 123

DNA Sequence (SEQ ID NO:381) and Protein Sequence (SEQ ID NO:382) ofRgl.3 tet gat ggc agg aat ace gcg gcc gac gaa aaa gcg tec gac ctg ate Ser Asp Gly Arg Asn Thr Ala Ala Asp Glu Lys Ala Ser Asp Leu He tet caa act gtc aag aga gat tgc tgt tec cat cct etc 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 gctgctccag gaccctctga Phe Val Pro Gly Leu Cys He accacgact TABLE 124

DNA Sequence (SEQ ID NO:383) and Protein Sequence (SEQ ID NO:384) ofRgl.4 tet gat ggc agg aat gcc gca gcc gac aac aaa gcg tet gac eta ate Ser Asp Gly Arg Asn Ala Ala Ala Asp Asn Lys Ala Ser Asp Leu He get caa ate gtc agg aga gga tgc tgt tec cat cct gtc tgt aaa gtg Ala Gin He Val Arg Arg Gly Cys Cys Ser His Pro Val Cys Lys Val agg tat cca gac ctg tgt cgt tgaagacgct gctgctccag gaccctctga Arg Tyr Pro Asp Leu Cys Arg accacgacgt

TABLE 125 DNA Sequence (SEQ ID NO:385) and Protein Sequence (SEQ ID NO:386) ofRgl.5 tet gat ggc agg aat gcc gca gcc gac aac aga gcg tet gac eta ate Ser Asp Gly Arg Asn Ala Ala Ala Asp Asn Arg Ala Ser Asp Leu He get caa ate gtc agg aga gga tgc tgt tec cat cct gcc tgt aat gtg Ala Gin He Val Arg Arg Gly Cys Cys Ser His Pro Ala Cys Asn Val aat aat cca cac att tgt ggt tgaagacgct gctgctccag gaccctctga

Asn Asn Pro His He Cys Gly accacgacgt

TABLE 126

DNA Sequence (SEQ ID NO:387) and Protein Sequence (SEQ ID NO:388) ofRgl .8 tet gat ggc agg aat gcc gca gcc gac aac aaa ccg tet gac eta ate

Ser Asp Gly Arg Asn Ala Ala Ala Asp Asn Lys Pro Ser Asp Leu He get caa ate gtc agg aga gga tgc tgt teg cat cct gtc tgt aaa gtg Ala Gin He Val Arg Arg Gly Cys Cys Ser His Pro Val Cys Lys Val agg tat tea gac atg tgt ggt tgaagacgct gctgctccag gaccctctga Arg Tyr Ser Asp Met Cys Gly accacgacgt TABLE 127 DNA Sequence (SEQ ID NO:389) and Protein Sequence (SEQ ID NO:390) ofSml A tet gat ggc agg aat gca gag cga cga caa age gtc tgt cct ggt cgc Ser Asp Gly Arg Asn Ala Glu Arg Arg Gin Ser Val Cys Pro Gly Arg tet ggc ccc agg gga gga tgt tgt tec cac cct gcc tgt aag gtg cat

Ser Gly Pro Arg Gly Gly Cys Cys Ser His Pro Ala Cys Lys Val His ttt cca cac agt tgt ggt tgacgacgct gatgctccag gaccctctga Phe Pro His Ser Cys Gly accacgacgt

TABLE 128

DNA Sequence (SEQ ID NO:391) and Protein Sequence (SEQ ID NO:392) ofSml.5 tet gat ggc agg aat gcc gca gcc age gac aga gcg tet gac gcg gcc Ser Asp Gly Arg Asn Ala Ala Ala Ser Asp Arg Ala Ser Asp Ala Ala cac cag gta tgc tgt tec aac cct gtc tgt cac gtg gat cat cca gaa His Gin Val Cys Cys Ser Asn Pro Val Cys His Val Asp His Pro Glu ctt tgt cgt aga aga cgc tgatgctcca ggaccctctg aaccacgacg t Leu Cys Arg Arg Arg Arg

TABLE 129 DNA Sequence (SEQ ID NO:393) and Protein Sequence (SEQ ID NO:394) ofSI.5 tet gat ggc agg aat gcc gcg gcc aac gac aaa gcg tet gac ctg gtc

Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala Ser Asp Leu Val get ccg gcc ate agg gga tgc tgt tec cac cct gtc tgt aac ttg agt Ala Pro Ala He 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 He Cys Arg Gly Arg Arg aaccacgacg t

TABLE 130 DNA Sequence (SEQ ID NO:395) and Protein Sequence (SEQ ID NO:396) of Txl .5 ttt cat ggc agg aat gcc gca gcc aaa gcg tet ggc ctg gtc ggt ctg Phe His Gly Arg Asn Ala Ala Ala Lys Ala Ser Gly Leu Val Gly Leu ace gac aag agg caa gaa tgc tgt tet 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 He Cys Arg TABLE 131 DNA Sequence (SEQ ID NO:397) and Protein Sequence (SEQ ID NO:398) ofTl.l act gat ggc agg agt get gca gcc ata gcg ttt gcc ctg ate get ccg Thr Asp Gly Arg Ser Ala Ala Ala He Ala Phe Ala Leu He Ala Pro ace gtc tgg gaa gga tgc tgt tet aat cct gcc tgt etc 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 He Arg Phe Cys Gly Gly Arg Arg

TABLE 132

DNA Sequence (SEQ ID NO:399) and Protein Sequence (SEQ ID NO:400) ofVrl.3 tet aat ggc atg aat gcc gca gcc ate agg aaa gcg tet gcc ctg gtg Ser Asn Gly Met Asn Ala Ala Ala He Arg Lys Ala Ser Ala Leu Val get cag ate gcc cat cga gac tgc tgt gac gat cct gcc tgc ace gtg Ala Gin He 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) ofG1.2 tet gat ggc ggg aat gcc gca gca aaa gag tet gac gtg ate get ctg Ser Asp Gly Gly Asn Ala Ala Ala Lys Glu Ser Asp Val He Ala Leu ace gtc tgg aaa tgc tgt ace att cct tec tgt tat gag aaa aaa aaa Thr Val Trp Lys Cys Cys Thr He Pro Ser Cys Tyr Glu Lys Lys Lys att aaa gca tgt gtc ttt tgacgacgct gatgctccag gaccctctga

He Lys Ala Cys Val Phe accacgacgt

TABLE 134

DNA Sequence (SEQ ID NO:403) and Protein Sequence (SEQ ID NO:404) ofRgl .12 tet gat ggc gca gtc gac gac aaa gcg ttg gat cga ate get gaa ate

Ser Asp Gly Ala Val Asp Asp Lys Ala Leu Asp Arg He Ala Glu He gtc agg aga gga tgc tgt ggc aat cct gcc tgt age ggc tec teg aaa Val Arg Arg Gly Cys Cys Gly Asn Pro Ala Cys Ser Gly Ser Ser Lys gat gca ccc tet tgt ggt tgaagacgct gctgctccag gaccctctga Asp Ala Pro Ser Cys Gly accacgacgt It will be appreciated that the methods and compositions of the instant invention can be incoφorated 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.

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Claims

WHAT TS CLAIMED IS:

1. A substantially pure α-conotoxin peptide having the generic formula I: Xaa,-Xaa₂-Xaa₃- Xaa₄-Xaa₅-Cys-Cys-Xaa₆-Xaa₇-Xaa₈-Xaa₉-Cys-Xaa,₀-Xaa, ,-Xaa,₂-Cys-Xaa,₃ (SEQ ID NOl :), wherein Xaa, is des-Xaa,, He, Leu or Val; Xaa, is des-Xaa₂, Ala or Gly; Xaa₃ is des- Xaa₃, Gly, Tφ (D or L), neo-Tφ, halo-Tφ or any unnatural aromatic amino acid; Xaa₄ is des-Xaa₄, Asp, Phe, Gly, Ala, Glu,γ-carboxy-Glu (Gla) or any unnatural aromatic amino acid; Xaa₅ is Glu, Gla, Asp, Ala, Thr, Ser, Gly, He, Tyr, nor-Tyr, mono-halo-Tyr, di-halo- Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa₆ 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; Xaa₇ 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; Xaa₈ is Ser, Thr, Asn, Ala, Gly, His, halo-His, Pro or hydroxy-Pro; Xaa, 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; Xaa,₀ is Gly, Ser, Thr, Ala, Asn, Arg, ornithine, homoarginine,

Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa,, is Gin, Leu, His, halo-His, Tφ (D or L), halo-Tφ, neo-Tφ, 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,₂ is Asn, His, halo-His, He, 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,₃ is des-Xaa₁₃, Val, He, Leu, Arg, ornithine, 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.

2. A substantially pure α-conotoxin peptide of generic formula I selected from the group consisting of:

Asp-Xaa,-Cys-Cys-Ser-Asp-Ser-Arg-Cys-Gly-Xaa₂-Asn-Cys-Leu (SEQ ID NO:4); Ala-Cys-Cys-Ser-Asp-Arg-Arg-Cys-Arg-Xaa₃-Arg-Cys (SEQ ID NO:5); Phe-Thr-Cys-Cys-Arg-Arg-Gly-Thr-Cys-Ser-Gln-His-Cys (SEQ ID NO:6); Asp-Xaa₄-Cys-Cys-Arg-Arg-His-Ala-Cys-Thr-Leu-Ile-Cys (SEQ ID NO:7);

Asp-Xaa₄-Cys-Cys-Arg-Xaa₅-Xaa₅-Cys-Thr-Leu-Ile-Cys (SEQ ID NO:8);

Gly-Cys-Cys-Ser-Asρ-Xaa₅-Arg-Cys-Arg-Xaa₄-Arg-Cys-Arg (SEQ ID NO:9);

Gly-Gly-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ala-Xaa₃-Arg-Cys (SEQ ID NO: 10); Ile-Ala-Xaa₃-Asp-Ile-Cys-Cys-Ser-Xaa,-Xaa₅-Asp-Cys-Asn-His-Xaa₂-Cys-Val(SEQ

ID NOJ 1); and

Gly-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Xaa₂-His-Gln-Cys (SEQ ID NO: 12), wherein Xaa, is Glu or γ-carboxy-Glu (Gla); Xaa₂ is Lys, N-methyl-Lys, N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa₃ is Tφ (D or L), halo-Tφ or neo-Tφ; Xaa₄ is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa₅ is Pro or hydroxy-Pro; and the C-terminus contains a carboxyl or amide group, or derivatives thereof.

3. The substanially pure α-conotoxin peptide of claim 2, wherein Xaa, is Glu.

4. The substantially pure α-conotoxin peptide of claim 2, wherein Xaa₂ is Lys.

5. The substantially pure α-conotoxin peptide of claim 2, wherein Xaa₄ is Tyr.

6. The substantially pure α-conotoxin peptide of claim 2, wherein Xaa₄ is mono-iodo-Tyr.

7. The substantially pure α-conotoxin peptide of claim 2, wherein Xaa₄ is di-iodo-Tyr.

8. The substantially pure α-conotoxin peptide of claim 1 , which is modified to contain an O- glycan, an S-glycan or an N-glycan.

9 The substantially pure α-conotoxin peptide of claim 2 which is modified to contain an O- glycan, an S-glycan or an N-glycan.

0 A substantially pure α-conotoxin peptide having the generic formula II: Xaa,-Xaa₂-Xaa₃- Xaa₄-Cys-Cys-Xaa₅-Xaa₆-Xaa₇-Xaa₈-Cys-Xaa₉-Xaa,₀-Xaa₁₁-Xaa,₂-Xaa₁₃-Xaa₁₄-Cys-Xaa,₅- Xaa,₆-Xaa,₇ (SEQ ID NO:2), wherein Xaa, is des-Xaa,, Asp, Glu or γ-carboxy-Glu (Gla); Xaa₂ is des-Xaa₂, Gin, Ala, Asp, Glu, Gla; Xaa₃ is des-Xaa₃, Gly, Ala, Asp, Glu, Gla, Pro or hydroxy-Pro; Xaa₄ is des-Xaa₄, Gly, Glu, Gla, Gin, Asp, Asn, Pro or hydroxy-Pro; Xaa₅ is Ser, Thr, Gly, Glu, Gla, Asn, Tφ (D or L), neo-Tφ, halo-Tφ, 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; Xaa₆ 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; Xaa₇ is Pro or hydroxy-Pro; Xaa₈ is Ala, Ser, Thr, Asp, Val, He, 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;

Xaag is Gly, He, Leu, Val, Ala, Thr, Ser, Pro, hydroxy-Pro, Phe, Tφ (D or L), neo-Tφ, halo- Tφ, 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,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; Xaa,, is Thr, Ser, His, halo-His, Leu, He, Val, Asn, Met, Pro, hydroxy-Pro, 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,₂ is Asn, Pro, hydroxy-Pro, Gin, 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-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, He, 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, O- phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; and Xaa,₅ is des- Xaa, ₅, Gly, Ala, Met, Ser, Thr, Tφ (D or L), neo-Tφ, halo-Tφ, 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,₆, Tφ (D or L), neo-Tφ, halo-Tφ, 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 ₁₇, Arg, ornithine, 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.

11. A substantially pure α-conotoxin peptide of generic formula II seleceted from the group consisting of:

Cys-Cys-Ser-Asp-Xaa₅-Ala-Cys-Xaa₂-Gln-Thr-Xaa₅-Gly-Cys-Arg(SEQIDNO:13); Cys-Cys-Xaa,-Asn-Xaa₅-Ala-Cys-Arg-His-Thr-Gln-Gly-Cys (SEQ ID NO:14); Gly-Cys-Cys-Xaa₃-His-Xaa₅-Ala-Cys-Gly-Arg-His-Xaa₄-Cys (SEQ ID NO:15); Ala-Xaa₅-Cys-Cys-Asn-Asn-Xaa₅-Ala-Cys-Val-Xaa₂-His-Arg-Cys(SEQIDNO:16);

Ala-Xaa₅-Gly-Cys-Cys-Asn-Asn-Xaa₅-Ala-Cys-Val-Xaa₂-His-Arg-Cys (SEQ ID NO:17);

Xaa₅-Xaa₅-Cys-Cys-Asn-Asn-Xaa₅-Ala-Cys-Val-Xaa₂-His-Arg-Cys (SEQ ID NO:18); Asp-Xaa,-Asn-Cys-Cys-Xaa₃-Asn-Xaa₅-Ser-Cys-Xaa₅-Arg-Xaa₅-Arg-Cys-Thr(SEQ

ID NO:19);

Gly-Cys-Cys-Ser-Thr-Xaa₅-Xaa₅-Cys-Ala-Val-Leu-Xaa₄-Cys (SEQ ID NO:20); Gly-Cys-Cys-Gly-Asn-Xaa₅-Asp-Cys-Thr-Ser-His-Ser-Cys (SEQ ID NO:21); Gly-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ala-His-Asn-Asn-Xaa₅-Asp-Cys-Arg (SEQ ID NO:42);

Gly-Cys-Cys-Xaa₄-Asn-Xaa₅-Val-Cys-Xaa₂-Xaa₂-Xaa₄-Xaa₄-Cys-Xaa₃-Xaa₂(SEQ ID NO:154);

Xaa₆-Xaa,-Xaa₅-Gly-Cys-Cys-Arg-His-Xaa₅-Ala-Cys-Gly-Xaa₂-Asn-Arg-Cys(SEQ ID NOJ55); Cys-Cys-Ala-Asp-Xaa₅-Asp-Cys-Arg-Phe-Arg-Xaa₅-Gly-Cys (SEQ ID NOJ 56);

Gly-Cys-Cys-Xaa₄-Asn-Xaa₅-Ser-Cys-Xaa₃-Xaa₅-Xaa₂-Thr-Xaa₄-Cys-Ser-Xaa₃-Xaa₂ (SEQ ID NO:157);

Cys-Cys-Ser-Asn-Xaa₅-Thr-Cys-Xaa₂-Xaa,-Thr-Xaa₄-Gly-Cys (SEQ ID NO:158); Cys-Cys-Ala-Asn-Xaa₅-Ile-Cys-Xaa₂-Asn-Thr-Xaa₅-Gly-Cys (SEQ ID NO:159); Cys-Cys-Asn-Asn-Xaa₅-Thr-Cys-Xaa₂-Xaa,-Thr-Xaa₄-Gly-Cys (SEQ ID NO:160);

Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-Xaa₂-Xaa_rThr-Xaa₄-Gly-Cys (SEQ ID NOJ61); Gly-Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Xaa₅-Cys-Ile-Ala-Ser-Asn-Xaa₅-Xaa₂-Cys-Gly (SEQ ID NO:162);

Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Ser-Ala-Met-Ser-Xaa₅-He-Cys (SEQ ID NOJ63); Gly-Cys-Cys-Xaa₂-Asn-Xaa₅-Xaa₄-Cys-Gly-Ala-Ser-Xaa₂-Thr-Xaa₄-Cys (SEQ ID

NO:164);

Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Xaa₅-Cys-Phe-Ala-Thr-Asn-Xaa₅-Asp-Cys (SEQ ID NOJ65);

Gly-Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Xaa₅-Cys-Ile-Ala-Asn-Asn-Xaa₅-Leu-Cys-Ala (SEQ ID NO:166);

Gly-Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Xaa₅-Cys-Ile-Ala-Asn-Asn-Xaa₅-Phe-Cys-Ala (SEQ ID NO:167);

Asp-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ser-Gln-Asn-Asn-Xaa₅-Asp-Cys-Met (SEQ ID NO:168); and Asp-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ala-His-Asn-Asn-Xaa₅-Asp-Cys-Arg (SEQ

ID NO:169), wherein Xaa, is Glu or γ-carboxy-Glu (Gla); Xaa₂ is Lys, N-methyl-Lys, N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa₃ is Tφ (D or L), halo-Tφ or neo-Tφ; Xaa₄ is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaaj is Pro or hydroxy-Pro; and the C-terminus contains a carboxyl or amide group, or derivatives thereof.

12. The substantially pure α-conotoxin peptide of claim 11, wherein Xaa₂ is Lys.

13. The substantially pure α-conotoxin peptide of claim 1 1, wherein Xaa, is Glu.

14. The substantially pure α-conotoxin peptide of claim 11, wherein Xaa₃ is Tφ.

15. The substantially pure α-conotoxin peptide of claim 11, wherein Xaa₄ is Tyr.

16. The substantially pure α-conotoxin peptide of claim 11, wherein Xaa₄ is mono-iodo-Tyr.

17. The substantially pure α-conotoxin peptide of claim 11 , wherein Xaa₄ is di-iodo-Tyr.

18. The substantially pure α-conotoxin peptide of claim 10, which is modified to contain an O- glycan, an S-glycan or an N-glycan.

19 The substantially pure α-conotoxin peptide of claim 11 which is modified to contain an O- glycan, an S-glycan or an N-glycan.

20. A substantially pure α-conotoxin peptide having the generic formula III: Xaa,-Xaa₂-Xaa₃-

Xaa₄-Xaa₅-Cys-Cys-Xaa₆-Xaa₇-Xaa₈-Xaa₉-Cys-Xaa|₀-Xaa,₁-Xaa,₂-Xaa,₃-Xaa,₄-Xaa,₅-Xaa,₆- Cys-Xaa|₇-Xaa,₈-Xaa₁₉-Xaa₂₀-Xaa_2!-Xaa₂₂-Xaa₂₃-Xaa₂₄ (SEQ ID NO:3), wherein Xaa is des- Xaa,, Ser or Thr; Xaa₂ is des-Xaa₂, Asp, Glu, γ-carboxy-Glu (Gla), Asn, Ser or Thr; Xaa₃ is des-Xaa₃, Ala, Gly, Asn, Ser, Thr, 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;

Xaa₄ is des-Xaa₄, Ala, Val, Leu, He, Gly, Glu, Gla, Gin, Asp, Asn, Phe, Pro, hydroxy-Pro or any unnatural aromatic amino acid; Xaa₅ is des-Xaa₅, 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; Xaa₆ is Thr, Ser, Asp, Asn, Met, Val, Ala, Gly, Leu, He, Phe, any unnatural aromatic amino acid, 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; Xaa₇ is He, 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 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; Xaa₈ is Pro, hyroxy-Pro, Ser, Thr, He, 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; Xaac, is Val, Ala, Gly, He, 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 unnatural basic amino acid; Xaa_I0 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, Ser, Thr, Phe, He, Leu, Gly, Tφ (D or L), neo-Tφ, halo-Tφ, 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; Xaa,, is Leu, Gin, Val, He, 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, Tφ (D or L), neo-Tφ, halo-Tφ or any unnatural aromatic amino acid; Xaa,₂ 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,₃ is His, halo-His, Asn, Thr, Ser, He, 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-Try, mono-halo-Tyr, di-halo-Tyr,

O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa,₄ is Ser, Thr, Ala, Gin, Pro, hydroxy-Pro, Gly, He, Leu, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N-N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa,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; Xaa₁₆ is Met, He, Thr, Ser, Val, Leu, Pro, hydroxy-Pro, Phe, any unnatural aromatic amino acid, Tyr, nor-Tyr, mono-halo- Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, any unnatural hydroxy containing amino acid, Glu, Gla, Ala, His, halo-His, 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, Gly, Asp, Asn, Ala, He, Leu, Ser, Thr, His, halo-His, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N-N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa₁₈ is des-Xaa,_g, Gly, Glu, Gla, Gin, Tφ (D or L), neo, halo- Tφ, 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 des- Xaa_I9, Ser, Thr, Val, He, Ala, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N-N- dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa₂₀ is des-Xaa₂₀, Val, Asp, His, halo-His, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N-N-dimethyl- Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa₂, is des-Xaa₂,, Asn, Pro or hydroxy-Pro; Xaa₂₂ is des-Xaa₂₂, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N- dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa₂₃ is des-Xaa₂₃, Ser or Thr; Xaa₂₄ is des-Xaa₂₄, Leu, He or Val; and the C-terminus contains a free carboxyl group or an amide group, with the proviso that (a) Xaa₅ is not Gly, when Xaa, is des-Xaa,, Xaa₂ is des-Xaa₂, Xaa₃ is des-Xaa₃, Xaa₄ is des-Xaa₄, Xaa₆ is Ser, Xaa₇ is His, Xaa₈ is Pro, Xaa, is Ala, Xaa,₀ is Ser, Xaa,, is Val, Xaa,₂ is Asn, Xaa,₃ is Asn, Xaa₁₄ is Pro, Xaa,₅ is Asp, Xaa,₆ is He, Xaa,₇ is des-Xaa,₇, Xaa,₈ is des-Xaa,_g, Xaa,₉ is des-Xaa,₉, Xaa₂₀ is des-Xaa₂₀,

Xaa₂, is des-Xaa₂₁, Xaa₂₂ is des-Xaa₂₂, Xaa ₃ is des-Xaa₂₃, and Xaa₂₄ is des-Xaa₂₄.

21. A substantially pure α-conotoxin peptide of generic forumula III selected from the group consisting of:

Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Leu-Xaa,-His-Ser-Asn-Met-Cys (SEQ ID NO.22);

Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-Arg-Gln-Asn-Asn-Ala-Xaa,-Xaa₄-Cys-Arg (SEQ ID NO:23);

Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa,-Ile-Cys-Arg (SEQ ID NO:24); Xaas-Xaaj-Cys-Cys-Ser-His-Xaas-Ala-Cys-Asn-Val-Asp-His-Xaas-Xaaj-Ile-Cys-Arg

(SEQ ID NO:25);

Xaa₅-Arg-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa,-Ile-Cys-Arg (SEQ ID NO:27);

Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Gly-Ile-Cys-Arg (SEQ ID NO:28);

Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa,-Thr-Cys-Arg (SEQ ID NO:29); Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa,-Val-Cys-Arg

(SEQ ID NO:30);

Xaa₅-Gln-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa,-Ile-Cys-Arg- Arg-Arg-Arg (SEQ ID NO:32); Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Val-Asn-His-Xaa₅-Xaa,-Leu-Cys (SEQ ID NO:33);

Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Val-Asn-His-Xaa₅-Xaa,-Leu-Cys (SEQ ID NO:34); Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa,-He-Cys (SEQ ID

NO:35);

Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Gly-Xaa₂-Thr-Gln-Xaa,-Xaa₅-Cys-Arg- Xaa,-Ser (SEQ ID NO:36);

Xaa₅-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Gly-Asn-Asn-Xaa₅-Xaa,-Phe-Cys-Arg-Gln (SEQ ID NO:37);

Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Gly-Asn-Asn-Xaa₅-Xaa,-Phe-Cys-Arg-Gln (SEQ ID NO:38);

Gly-Cys-Cys-Ser-His-Xaa₅-Xaa₅-Cys-Ala-Met-Asn-Asn-Xaa₅-Asp-Xaa₄-Cys (SEQ ID NO:39); Gly-Cys-Cys-Ser-His-Xaa₅-Xaa₅-Cys-Phe-Leu-Asn-Asn-Xaa₅-Asp-Xaa₄-Cys (SEQ

ID NO:40);

Gly-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ile-Ala-Xaa₂-Asn-Xaa₅-His-Met-Cys-Gly (SEQ ID NO:41);

Gly-Cys-Cys-Ser-Asn-Xaa₅-Ala-Cys-Ala-Gly-Asn-Asn-Xaa₅-His-Val-Cys-Arg-Gln (SEQ ID NO:43);

Gly-Cys-Cys-Ser-Arg-Xaa₅-Ala-Cys-Ile-Ala-Asn-Asn-Xaa₅-Asp-Leu-Cys (SEQ ID NO:44);

Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Val-Xaa,-His-Xaa₅-Xaa,-Leu-Cys-Arg- Arg-Arg-Arg (SEQ ID NO:45); Gly-Gly-Cys-Cys-Ser-Phe-Xaa₅-Ala-Cys-Arg-Xaa₂-Xaa₅-Arg-Xaa₅-Xaa,-Met-Cys-

Gly (SEQ ID NO:46);

Xaa₅-Xaa,-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Asn-Ser-Ser-His-Xaa₅-Xaa,-Leu-Cys- Gly (SEQ ID NO:47);

Xaa₅-Gln-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Asn-Val-Gly-His-Xaa₅-Xaa,-Leu-Cys- Gly (SEQ ID NO:48);

Xaae-Val-Cys-Cys-Ser-Asp-Xaas-Arg-Cys-Asn-Val-Gly-His-Xaas-Xaa lle-Cys-Gly (SEQ ID NO:49); Gly-Cys-Cys-Ser-Arg-Xaa₅-Xaa₅-Cys-Ile-Ala-Asn-Asn-Xaa₅-Asp-Leu-Cys (SEQ ID NO:50);

Xaa₅-Gln-Cys-Cys-Ser-His-Leu-Ala-Cys-Asn-Val-Asp-His-Xaa₅-Xaa,-Ile-Cys-Arg (SEQ ID NO:51); Gly-Cys-Cys-Ser-Xaa₄-Phe-Asp-Cys-Arg-Met-Met-Phe-Xaa₅-Xaa,-Met-Cys-Gly-

Xaa₃-Arg (SEQ ID NO:52);

Gly-Gly-Cys-Cys-Ser-Phe-Ala-Ala-Cys-Arg-Xaa₂-Xaa₄-Arg-Xaa₅-Xaa,-Met-Cys- Gly (SEQ ID NO:53);

Gly-Gly-Cys-Cys-Phe-His-Xaa₅-Val-Cys-Xaa₄-Ile-Asn-Leu-Leu-Xaa,-Met-Cys-Arg- Gin- Arg (SEQ ID NO:54);

Ser-Ala-Thr-Cys-Cys-Asn-Xaa₄-Xaa₅-Xaa₅-Cys-Xaa₄-Xaa,-Thr-Xaa₄-Xaa₅-Xaa₁-Ser- Cys-Leu (SEQ ID NO:55);

Ala-Cys-Cys-Ala-Xaa₄-Xaa₅-Xaa₅-Cys-Phe-Xaa,-Ala-Xaa₄-Xaa₅-Xaa₁-Arg-Cys-Leu (SEQ ID NO:56); Asn-Ala-Xaa₁-Cys-Cys-Xaa₄-Xaa₄-Xaa₅-Xaa₅-Cys-Xaa₄-Xaa,-Ala-Xaa₄-Xaa₅-Xaa₁-

Ile-Cys-Leu (SEQ ID NO:57);

Xaa|-Cys-Cys-Thr-Asn-Xaa₅-Val-Cys-His-Ala-Xaa,-His-Gln-Xaa,-Leu-Cys-Ala- Arg-Arg-Arg (SEQ ID NO: 170);

Gly-Cys-Cys-Ser-Asn-Xaa_r Val-Cys-His-Leu-Xaa, -His-Ser- Asn-Leu-Cys (SEQ ID NOJ71);

Xaa, -Cys-Cys-Thr-Asn-Xaa₅-Val-Cys-His-Val-Xaa, -His-Gln-Xaa, -Leu-Cys-Ala- Arg-Arg-Arg (SEQ ID NO: 172);

Xaa₆-Xaa,-Cys-Cys-Ser-Xaa₄-Xaa₅-Ala-Cys-Asn-Leu-Asp-His-Xaa₅-Xaa,-Leu-Cys (SEQ ID NO: 173); Xaa₅-Xaa|-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Asn-Ser-Thr-His-Xaa₅-Xaa,-Leu-Cys-

Gly (SEQ ID NO: 174);

Leu-Asn-Cys-Cys-Met-Ile-Xaa₅-Xaa₅-Cys-Xaa₃-Xaa₂-Xaa₂-Xaa₄-Gly-Asp-Arg-Cys- Ser-Xaa,-Val-Arg (SEQ ID NO: 175);

Ala-Phe-Gly-Cys-Cys-Asp-Leu-Ile-Xaa₅-Cys-Leu-Xaa,-Arg-Xaa₄-Gly-Asn-Arg- Cys-Asn-Xaa,-Val-His (SEQ ID NO: 176);

Leu-Gly-Cys-Cys-Asn-Val-Thr-Xaa₅-Cys-Xaa₃-Xaa,-Xaa₂-Xaa₄-Gly-Asp-Xaa₂-Cys- Asn-Xaa,-Val-Arg (SEQ ID NO: 177); Asp-Xaa,-Cys-Cys-Ser-Asn-Xaa₅-Ala-Cys-Arg-Val-Asn-Asn-Xaa₅-His-Val-Cys- Arg-Arg-Arg (SEQ ID NO: 178);

Leu-Asn-Cys-Cys-Ser-Ile-Xaa₅-Gly-Cys-Xaa₃-Asn-Xaa,-Xaa₄-Xaa₂-Asp-Arg-Cys- Ser-Xaa₂-Val-Arg (SEQ ID NO: 179); Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Xaa₄-Phe-Asn-Asn-Xaa₅-Gln-Met-Cys-Arg

(SEQ ID NO: 180);

Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Asn-Leu-Asn-Asn-Xaa₅-Gln-Met-Cys-Arg (SEQ ID NO: 181);

Gly-Cys-Cys-Ser-His-Xaa₅-Xaa₅-Cys-Xaa₄-Ala-Asn-Asn-Gln-Ala-Xaa₄-Cys-Asn (SEQ ID NO: 182);

Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Val-Thr-His-Xaa₅-Xaa,-Leu-Cys(SEQ ID NO: 183);

Gly-Gly-Cys-Cys-Ser-Xaa₄-Xaa₅-Ala-Cys-Ser-Val-Xaa,-His-Gln-Asp-Leu-Cys-Asp (SEQ ID NO: 184); Val-Ser-Cys-Cys-Val-Val-Arg-Xaa₅-Cys-Xaa₃-Ile-Arg-Xaa₄-Gln-Xaa,-Xaa,-Cys-

Leu-Xaa,-Ala-Asp-Xaa₅-Arg-Thr-Leu (SEQ ID NO: 185);

Xaa₆-Asn-Cys-Cys-Ser-Ile-Xaa₅-Gly-Cys-Xaa₃-Xaa,-Xaa₂-Xaa₄-Gly-Asp-Xaa₂-Cys-

Ser-Xaa,-Val-Arg (SEQ ID NOJ 86);

Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Leu-Xaa,-His-Xaa₅-Asn-Ala-Cys (SEQ ID NO: 187);

Gly-Cys-Cys-Ser-Asn-Xaa₅-Ile-Cys-Xaa₄-Phe-Asn-Asn-Xaa₅-Arg-Ile-Cys-Arg(SEQ ID NOJ88);

Xaa,-Cys-Cys-Ser-Gln-Xaa₅-Xaa₅-Cys-Arg-Xaa₃-Xaa₂-His-Xaa₅-Xaa,-Leu-Cys-Ser (SEQ ID NO: 189); Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Gly-Asn-Asn-Gln-His-Ile-Cys (SEQ ID

NO: 190);

Gly-Cys-Cys-Ala-Val-Xaa₅-Ser-Cys-Arg-Leu-Arg-Asn-Xaa₅-Asp-Leu-Cys-Gly-Gly (SEQ ID NOJ91);

Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asn-Asn-Xaa₅-His-Ile-Cys (SEQ ID NOJ92);

Thr-Xaa₅-Xaa_|-Xaa,-Cys-Cys-Xaa₅-Asn-Xaa₅-Xaa₅-Cys-Phe-Ala-Thr-Asn-Ser-Asp- Ile-Cys-Gly (SEQ ID NO: 193); Asp-Ala-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ser-Gly-Xaa₂-His-Gln-Asp-Leu-Cys(SEQ ID NO: 194);

Xaa,-Asp-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Leu-Cys(SEQ ID NO: 195); Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Gly-Ser-Asn-Ala-His-Ile-Cys (SEQ ID

NO: 196);

Xaa,-Asp-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Met-Cys (SEQ ID NO: 197);

Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Gly-Asn-Asn-Xaa₅-His-Ile-Cys (SEQ ID NOJ98);

Gly-Cys-Cys-Gly-Asn-Xaa₅-Ser-Cys-Ser-He-His-He-Xaa₅-Xaa₄-Val-Cys-Asn (SEQ ID NOJ 99);

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-Xaa₅-Xaa₅-Cys-Xaa₄-Ala-Asn-Asn-Gln-Ala-Xaa₄-Cys-Asn

(SEQ ID NO:201);

Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Val-Asn-Asn-Xaa₅-Asp-Ile-Cys (SEQ ID NO:202);

Gly-Xaa₂-Cys-Cys-Ile-Asn-Asp-Ala-Cys-Arg-Ser-Xaa₂-His-Xaa₅-Gln-Xaa₄-Cys-Ser (SEQ ID NO:203);

Gly-Cys-Cys-Xaa₄-Asn-Ile-Ala-Cys-Arg-Ile-Asn-Asn-Xaa₅-Arg-Xaa₄-Cys-Arg(SEQ ID NO:204);

Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Arg-Phe-Asn-Xaa₄-Xaa₅-Xaa₂-Xaa₄-Cys-Gly (SEQ ID NO:205); Asp-Xaa,-Cys-Cys-Ala-Ser-Xaa₅-Xaa₅-Cys-Arg-Leu-Asn-Asn-Xaa₅-Xaa₄-Val-Cys-

His (SEQ ID NO:206);

Gly-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-Xaa₃-Gln-Asn-Asn-Ala-Xaa,-Xaa₄-Cys-Arg- Xaa,-Ser (SEQ ID NO:207);

Gly-Cys-Cys-Ser-His-Xaa₅-Xaa₅-Cys-Ala-Gln-Asn-Asn-Gln-Asp-Xaa₄-Cys (SEQ ID NO:208);

Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ser-Gly-Asn-Asn-Arg-Xaa,-Xaa₄-Cys-Arg- Xaa,-Ser (SEQ ID NO:209); Asp-Xaa₅-Cys-Cys-Ser-Xaa₄-Xaa₅-Asp-Cys-Gly-Ala-Asn-His-Xaa₅-Xaa,-Ile-Cys- Gly (SEQ ID NO:210);

Xaa,-Cys-Cys-Ser-Gln-Xaa₅-Xaa₅-Cys-Arg-Xaa₃-Xaa₂-His-Xaa₅-Xaa,-Leu-Cys-Ser (SEQ ID NO:211); Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Ala-Gly-Asn-Asn-Xaa₅-His-Ile-Cys (SEQ ID

NO:212);

Gly-Cys-Cys-Ser-Asp-Xaa₅-Ser-Cys-Asn-Val-Asn-Asn-Xaa₅-Asp-Xaa₄-Cys (SEQ ID NO.213);

Xaa,-Xaa,-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Met-Cys-Arg (SEQ ID NO:214);

Gly-Gly-Cys-Cys-Ser-Asn-Xaa₅-Ala-Cys-Leu-Val-Asn-His-Leu-Xaa,-Met-Cys (SEQ ID NO.215);

Arg-Asp-Xaa₅-Cys-Cys-Phe-Asn-Xaa₅-Ala-Cys-Asn-Val-Asn-Asn-Xaa₅-Gln-Ile-Cys (SEQ ID NO:216); Cys-Cys-Ser-Asp-Xaa₅-Ser-Cys-Xaa₃-Arg-Leu-His-Ser-Leu-Ala-Cys-Thr-Gly-Ile-

Val-Asn-Arg (SEQ ID NO:217);

Cys-Cys-Thr-Asn-Xaa₅-Ala-Cys-Leu-Val-Asn-Asn-Ile-Arg-Phe-Cys-Gly (SEQ ID NO.218);

Asp-Xaa,-Cys-Cys-Ser-Asp-Xaa₅-Arg-Cys-His-Gly-Asn-Asn-Arg-Asp-His-Cys-Ala (SEQ ID NO:219);

Asp-Cys-Cys-Ser-His-Xaa₅-Leu-Cys-Arg-Leu-Phe-Val-Xaa₅-Gly-Leu-Cys-Ile(SEQ ID NO:220);

Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Xaa₂-Val-Arg-Xaa₄-Xaa₅-Asp-Leu-Cys-Arg (SEQ ID NO:221); Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asn-Asn-Xaa₅-His-Ile-Cys (SEQ ID

NO:222);

Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Xaa₂-Val-Arg-Xaa₄-Ser-Asp-Met-Cys(SEQID NO:223);

Gly-Gly-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Xaa₂-Val-His-Phe-Xaa₅-His-Ser-Cys(SEQ ID NO:224);

Val-Cys-Cys-Ser-Asn-Xaa₅-Val-Cys-His-Val-Asp-His-Xaa₅-Xaa,-Leu-Cys-Arg-Arg- Arg-Arg (SEQ ID NO:225); Gly-Cys-Cys-Ser-His-Xaa₅-Val-Cys-Asn-Leu-Ser-Asn-Xaa₅-Gln-Ile-Cys-Arg(SEQ ID NO:226);

Xaa₆-Xaa,-Cys-Cys-Ser-His-Xaa₅-Ala-Cys-Asn-Val-Asp-His-Xaa₃-Xaaι-Ile-Cys-Arg (SEQ ID NO:227); Gly-Cys-Cys-Ser-Asn-Xaa₅-Ala-Cys-Leu-Val-Asn-His-He-Arg-Phe-Cys-Gly (SEQ

ID NO:228);

Asp-Cys-Cys-Asp-Asp-Xaa₅-Ala-Cys-Thr-Val-Asn-Asn-Xaa₅-Gly-Leu-Cys-Thr (SEQ ID NO:229); and

Gly-Cys-Cys-Ser-Asn-Xaa₅-Xaa₅-Cys-Ile-Ala-Xaa₂-Asn-Xaa₅-His-Met-Cys-Gly- Gly-Arg-Arg (SEQ ID NO:230), wherein Xaa, is Glu or γ-carboxy-Glu (Gla); Xaa₂ is Lys, N-methyl-Lys, N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa₃ is Tφ (D or L), halo-Tφ or neo-Tφ; Xaa₄ is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa₅ is Pro or hydroxy-Pro; Xaa^ is Gin or pyro-Glu; and the C-terminus contains a carboxyl or amide group, or derivatives thereof.

22. The substantially pure α-conotoxin peptide of claim 21, wherein Xaa₂ is Lys.

23. The substantially pure α-conotoxin peptide of claim 21, wherein Xaa, is Glu.

24. The substantially pure α-conotoxin peptide of claim 21, wherein Xaa₃ is Tφ.

25. The substantially pure α-conotoxin peptide of claim 21 , wherein Xaa₄ is Tyr.

26. The substantially pure α-conotoxin peptide of claim 21 , wherein Xaa₄ is mono-iodo-Tyr.

27. The substantially pure α-conotoxin peptide of claim 21 , wherein Xaa₄ is di-iodo-Tyr.

28. The substantially pure α-conotoxin peptide of claim 20, which is modified to contain an O- glycan, an S-glycan or an N-glycan. 29 The substantially pure α-conotoxin peptide of claim 21 which is modified to contain an O- glycan, an S-glycan or an N-glycan.

30. A substantially pure α-conotoxin peptide seleceted from the group consisting of:

Cys-Cys-Thr-Ile-Xaa₅-Ser-Cys-Xaa₄-Xaa,-Xaa₂-Xaa₂-Xaa₂-Ile-Xaa₂-Ala-Cys-Val- Phe (SEQ ID NO:231) and

Gly-Cys-Cys-Gly-Asn-Xaa₅-Ala-Cys-Ser-Gly-Ser-Ser-Xaa₂-Asp-Ala-Xaa₅-Ser-Cys (SEQ ID NO:232), wherein Xaa, is Glu or γ-carboxy-Glu (Gla); Xaa₂ is Lys, N-methyl-Lys, N-N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa₄ is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa₅ is Pro or hydroxy-Pro; and the C-terminus contains a carboxyl or amide group, or derivatives thereof.

31. The substantially pure α-conotoxin peptide of claim 30, wherein Xaa₂ is Lys.

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

33. The substantially pure α-conotoxin peptide of claim 30, wherein Xaa₄ is Tyr.

34. The substantially pure α-conotoxin peptide of claim 30, wherein Xaa₄ is mono-iodo-Tyr.

35. The substantially pure α-conotoxin peptide of claim 30, wherein Xaa₄ is di-iodo-Tyr.

36. The substantially pure α-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 α-conotoxin precursor comprising an amino acid sequence selected from the group of amino acid sequences set forth in Tables 1-134.

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 α-conotoxin protein precursor comprising an amino acid sequence selected from the group of amino acid sequences set forth in Tables 1-134.