# Patent

## Title
Apha-conotoxin peptides

## 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.

## Background
CROSS-REFERENCE TO RELATED APPLICATION
The present application is a division of U.S. patent application Ser. No. 09/493,795 filed 28 Jan. 2000, now U.S. Pat. No. 6,797,808. U.S. patent application Ser. No. 09/493,795 is related to and claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent application Ser. No. 60/118,381, filed 29 Jan. 1999. Each application is incorporated herein by reference.


This invention was made with Government support under Grant No. PO1 GM48677 awarded by the National Institute of General Medical Sciences, National Institutes of Health, Bethesda, Md. 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 Ser. No. 09/488,799, filed 21 Jan. 2000, incorporated by reference herein. Additional α-conotoxins and uses for them have been described in U.S. Pat. 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. Ser. No. 09/219,446, filed 22 Dec. 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-Xaa10-Xaa11-Xaa12-Cys-Xaa13 (SEQ ID NO:1), wherein Xaa1 is des-Xaa1, Ile, 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, Ile, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; 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, Arg, Lys, ornithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, His, halo-His, Pro or hydroxy-Pro; Xaa9 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; Xaa11 is Gln, 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; Xaa12 is Asn, His, halo-His, Ile, Leu, Val, Gln, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa13 is des-Xaa13, Val, Ile, 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-Xaa6-Xaa7-Xaa8-Cys-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Cys-Xaa15-Xaa16-Xaa17 (SEQ ID NO:2), wherein Xaa1 is des-Xaa1, Asp, Glu or γ-carboxy-Glu (Gla); Xaa2 is des-Xaa2, Gln, Ala, Asp, Glu, Gla; Xaa3 is des-Xaa3, Gly, Ala, Asp, Glu, Gla, Pro or hydroxy-Pro; Xaa4 is des-Xaa4, Gly, Glu, Gla, Gln, 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; Xaa8 is Ala, Ser, Thr, Asp, Val, Ile, 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; Xaa9 is Gly, Ile, 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, Gln, 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; Xaa11 is Thr, Ser, His, halo-His, Leu, Ile, Val, Asn, Met, Pro, hydroxy-Pro, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-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; Xaa12 is Asn, Pro, hydroxy-Pro, Gln, Ser, Thr, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa13 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, Ile, Val, Asp, Leu, Phe, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; and Xaa15 is des-Xaa15, 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; Xaa16 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; Xaa17 is des-Xaa17, 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-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-Cys-Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24 (SEQ ID NO:3), wherein Xaa1 is des-Xaa1, 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, Ile, Gly, Glu, Gla, Gln, Asp, Asn, Phe, Pro, hydroxy-Pro or any unnatural aromatic amino acid; Xaa5 is des-Xaa5, Thr, Ser, Asp, Glu, Gla, Gln, 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, Ile, 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 Ile, Leu, Val, Ser, Thr, Gln, 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, hydroxy-Pro, Ser, Thr, Ile, Asp, Leu, Val, Gly, Ala, Phe, any unnatural aromatic amino acid, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa9 is Val, Ala, Gly, Ile, Leu, Asp, Ser, Thr, Pro, hydroxy-Pro, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa10 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, Ile, 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; Xaa11 is Leu, Gln, Val, Ile, Gly, Met, Ala, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, Ser, Thr, Arg, homoarginine, ornithine, any unnatural basic amino acid, Asn, Glu, Gla, Gln, Phe, Trp (D or L), neo-Trp, halo-Trp or any unnatural aromatic amino acid; Xaa12 is Glu, Gla, Gln, Asn, Asp, Pro, hydroxy-Pro, Ser, Gly, Thr, Lys, N-methyl-Lys, 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; Xaa13 is His, halo-His, Asn, Thr, Ser, Ile, Val, Leu, Phe, any unnatural aromatic amino acid, Arg, homoarginine, ornithine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Try, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa4 is Ser, Thr, Ala, Gln, Pro, hydroxy-Pro, Gly, Ile, Leu, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa15 is Asn, Glu, Gla, Asp, Gly, His, halo-His, Ala, Leu, Gln, 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, Ile, 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; Xaa17 is des-Xaa17, Gly, Asp, Asn, Ala, Ile, 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-Xaa18, Gly, Glu, Gla, Gln, 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; Xaa19 is des-Xaa19, Ser, Thr, Val, Ile, 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; Xaa21 is des-Xaa21, 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, Ile or Val; with the proviso that (a) Xaa5 is not Gly, when Xaa1 is des-Xaa1, Xaa2 is des-Xaa2, Xaa3 is des-Xaa3, Xaa4 is des-Xaa4, Xaa6 is Ser, Xaa7 is His, Xaa8 is Pro, Xaa9 is Ala, Xaa10 is Ser, Xaa11 is Val, Xaa12 is Asn, Xaa13 is Asn, Xaa14 is Pro, Xaa15 is Asp, Xaa16 is Ile, Xaa17 is des-Xaa17, Xaa18 is des-Xaa8, Xaa19 is des-Xaa19, Xaa20 is des-Xaa20, Xaa21 is des-Xaa21, 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-Xaa1-Cys-Cys-Ser-Asp-Ser-Arg-
(SEQ ID NO:4)


 


Cys-Gly-Xaa2-Asn-Cys-Leu;


 


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


 


Xaa3-Arg-Cys;


 


Phe-Thr-Cys-Cys-Arg-Arg-Gly-Thr-Cys-
(SEQ ID NO:6)


 


Ser-Gln-His-Cys;


 


Asp-Xaa4-Cys-Cys-Arg-Arg-His-Ala-
(SEQ ID NO:7)


 


Cys-Thr-Leu-Ile-Cys;


 


Asp-Xaa4-Cys-Cys-Arg-Xaa5-Xaa5-Cys-
(SEQ ID NO:8)


 


Thr-Leu-Ile-Cys;


 


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


 


Arg-Xaa4-Arg-Cys-Arg;


 


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


 


Cys-Ala-Xaa3-Arg-Cys;


 


Ile-Ala-Xaa3-Asp-Ile-Cys-Cys-Ser-
(SEQ ID NO:11)


 


Xaa1-Xaa5-Asp-Cys-Asn-His-Xaa2-


 


Cys-Val; and


 


Gly-Cys-Cys-Ser-Asp-Xaa5-Arg-Cys-
(SEQ ID NO:12)


 


Xaa2-His-Gln-Cys,






wherein Xaa1 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, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Lys residues may be substituted by Arg, ornithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Tyr residues may be substituted with any unnatural hydroxy containing amino acid; the Ser residues may be substituted with Thr; the Thr residues may be substituted with Ser; and the Phe and Trp residues may be substituted with any unnatural aromatic amino acid. The Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or 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:













Im1.1:
SEQ ID NO: 4, wherein Xaa1 is Glu and Xaa2 is Lys;


Im1.2:
SEQ ID NO: 5, wherein Xaa3 is Trp;


Rg1.2:
SEQ ID NO: 6;


Rg1.6:
SEQ ID NO: 7, wherein Xaa4 is Tyr;


Rg1.6A:
SEQ ID NO: 8, wherein Xaa4 is Tyr and Xaa5 is Pro;


Rg1.7:
SEQ ID NO: 9, wherein Xaa4 is Tyr and Xaa5 is Pro;


Rg1.9:
SEQ ID NO: 10, wherein Xaa3 is Trp and Xaa5 is Pro;


Rg1.10:
SEQ ID NO: 11, wherein Xaa1 is Glu, Xaa2 is Lys, Xaa3 is



Trp and Xaa5 is Pro; and


Rg1.11:
SEQ ID NO: 12, wherein Xaa2 is Lys and Xaa5 is Pro.









The C-terminus of Im1.1, Rg1.7 an Rg1.10 preferably contains a free carboxyl group. The C-terminus of Im1.2, Rg1.2, Rg1.6, Rg1.6A, Rg1.9 and Rg1.11 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-
(SEQ ID NO:13)


 


Gln-Thr-Xaa5-Gly-Cys-Arg;


 


Cys-Cys-Xaa1-Asn-Xaa5-Ala-Cys-Arg-
(SEQ ID NO:14)


 


His-Thr-Gln-Gly-Cys;


 


Gly-Cys-Cys-Xaa3-His-Xaa5-Ala-Cys-
(SEQ ID NO:15)


 


Gly-Arg-His-Xaa4-Cys;


 


Ala-Xaa5-Cys-Cys-Asn-Asn-Xaa5-Ala-
(SEQ ID NO:16)


 


Cys-Val-Xaa2-His-Arg-Cys;


 


Ala-Xaa5-Gly-Cys-Cys-Asn-Asn-Xaa5-
(SEQ ID NO:17)


 


Ala-Cys-Val-Xaa2-His-Arg-Cys;


 


Xaa5-Xaa5-Cys-Cys-Asn-Asn-Xaa5-Ala-
(SEQ ID NO:18)


 


Cys-Val-Xaa2-His-Arg-Cys;


 


Asp-Xaa1-Asn-Cys-Cys-Xaa3-Asn-Xaa5-
(SEQ ID NO:19)


 


Ser-Cys-Xaa5-Arg-Xaa5-Arg-Cys-Thr;


 


Gly-Cys-Cys-Ser-Thr-Xaa5-Xaa5-Cys-
(SEQ ID NO:20)


 


Ala-Val-Leu-Xaa4-Cys;


 


Gly-Cys-Cys-Gly-Asn-Xaa5-Asp-Cys-
(SEQ ID NO:21)


 


Thr-Ser-His-Ser-Cys;


 


Gly-Cys-Cys-Ser-Asn-Xaa5-Xaa5-Cys-
(SEQ ID NO:42)


 


Ala-His-Asn-Asn-Xaa5-Asp-Cys-Arg;


 


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


 


Xaa2-Xaa2-Xaa4-Xaa4-Cys-Xaa3-Xaa2;


 


Xaa6-Xaa1-Xaa5-Gly-Cys-Cys-Arg-His-
(SEQ ID NO:155)


 


Xaa5-Ala-Cys-Gly-Xaa2-Asn-Arg-Cys;


 


Cys-Cys-Ala-Asp-Xaa5-Asp-Cys-Arg-
(SEQ ID NO:156)


 


Phe-Arg-Xaa5-Gly-Cys;


 


Gly-Cys-Cys-Xaa4-Asn-Xaa5-Ser-Cys-
(SEQ ID NO:157)


 


Xaa3-Xaa5-Xaa2-Thr-Xaa4-Cys-Ser-


 


Xaa3-Xaa2;


 


Cys-Cys-Ser-Asn-Xaa5-Thr-Cys-Xaa2-
(SEQ ID NO:158)


 


Xaa1-Thr-Xaa4-Gly-Cys;


 


Cys-Cys-Ala-Asn-Xaa5-Ile-Cys-Xaa2-
(SEQ ID NO:159)


 


Asn-Thr-Xaa5-Gly-Cys;


 


Cys-Cys-Asn-Asn-Xaa5-Thr-Cys-Xaa2-
(SEQ ID NO:160)


 


Xaa1-Thr-Xaa4-Gly-Cys;


 


Cys-Cys-Ser-Asn-Xaa5-Val-Cys-Xaa2-
(SEQ ID NO:161)


 


Xaa1-Thr-Xaa4-Gly-Cys;


 


Gly-Gly-Cys-Cys-Ser-Xaa4-Xaa5-Xaa5-
(SEQ ID NO:162)


 


Cys-Ile-Ala-Ser-Asn-Xaa5-Xaa2-Cys-


 


Gly;


 


Gly-Cys-Cys-Ser-His-Xaa5-Val-Cys-
(SEQ ID NO:163)


 


Ser-Ala-Met-Ser-Xaa5-Ile-Cys;


 


Gly-Cys-Cys-Xaa2-Asn-Xaa5-Xaa4-Cys-
(SEQ ID NO:164)


 


Gly-Ala-Ser-Xaa2-Thr-Xaa4-Cys;


 


Gly-Cys-Cys-Ser-Xaa4-Xaa5-Xaa5-Cys-
(SEQ ID NO:165)


 


Phe-Ala-Thr-Asn-Xaa5-Asp-Cys;


 


Gly-Gly-Cys-Cys-Ser-Xaa4-Xaa5-Xaa5-
(SEQ ID NO:166)


 


Cys-Ile-Ala-Asn-Asn-Xaa5-Leu-Cys-


 


Ala;


 


Gly-Gly-Cys-Cys-Ser-Xaa4-Xaa5-Xaa5-
(SEQ ID NO:167)


 


Cys-Ile-Ala-Asn-Asn-Xaa5-Phe-Cys-


 


Ala;


 


Asp-Cys-Cys-Ser-Asn-Xaa5-Xaa5-Cys-
(SEQ ID NO:168)


 


Ser-Gln-Asn-Asn-Xaa5-Asp-Cys-Met;


and


 


Asp-Cys-Cys-Ser-Asn-Xaa5-Xaa5-Cys-
(SEQ ID NO:169)


 


Ala-His-Asn-Asn-Xaa5-Asp-Cys-Arg,






wherein Xaa1 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-tenninus contains a carboxyl or amide group. The halo is preferably bromine, chlorine or iodine, more preferably iodine for Tyr and bromine for Trp. In addition, the His residues may be substituted with halo-His; the Arg residues may be substituted by Lys, ornithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Lys residues may be substituted by Arg, ornithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Tyr residues may be substituted with any unnatural hydroxy containing amino acid; the Ser residues may be substituted with Thr; the Thr residues may be substituted with Ser; and the Phe and Trp residues may be substituted with any unnatural aromatic amino acid. The Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or 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:













Sn1.1:
SEQ ID NO: 13, wherein Xaa2 is Lys and Xaa5 is Pro;


Sn1.2:
SEQ ID NO: 14, wherein Xaa1 is Glu and Xaa5 is Pro;


Sl1.3:
SEQ ID NO: 15, wherein Xaa3 is Trp, Xaa4 is Tyr and Xaa5 is



Pro;


A1.2:
SEQ ID NO: 16, wherein Xaa2 is Lys and Xaa5 is Pro;


Bu1.1:
SEQ ID NO: 17, wherein Xaa2 is Lys and Xaa5 is Pro;


Bu1.2:
SEQ ID NO: 18, wherein Xaa2 is Lys and Xaa5 is Pro;


Bu1.3:
SEQ ID NO: 19, wherein Xaa1 is Glu, Xaa3 is Trp and Xaa5 is



Pro;


Bu1.4:
SEQ ID NO: 20, wherein Xaa4 is Tyr and Xaa5 is Pro;


Cr1.3:
SEQ ID NO: 21, wherein Xaa5 is Pro;


Di1.1:
SEQ ID NO: 42 wherein Xaa5 is Pro;


Ms1.7:
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 Xaa1 is Glu, Xaa2 is Lys, Xaa5 is Pro



and Xaa6 is Gln;


Ms1.2:
SEQ ID NO: 156, wherein Xaa5 is Pro;


Ms1.3:
SEQ ID NO: 157, wherein Xaa2 is Lys, Xaa3 is Trp, Xaa4 is Tyr



and Xaa5 is Pro;


Ms1.4:
SEQ ID NO: 158, wherein Xaa1 is Glu, Xaa2 is Lys, Xaa4 is Tyr



and Xaa5 is Pro;


Ms1.5:
SEQ ID NO: 159, wherein Xaa2 is Lys and Xaa5 is Pro;


Ms1.8:
SEQ ID NO: 160, wherein Xaa1 is Glu, Xaa2 is Lys, Xaa4 is Tyr



and Xaa5 is Pro;


Ms1.9:
SEQ ID NO: 161, wherein Xaa1 is Glu, Xaa2 is Lys, Xaa4 is Tyr



and Xaa5 is Pro;


Bt1.7:
SEQ ID NO: 162, wherein Xaa2 is Lys, Xaa4 is Tyr and



Xaa5 is Pro;


Lv1.5:
SEQ ID NO: 163, wherein Xaa5 is Pro;


Ms1.10:
SEQ ID NO: 164, wherein Xaa2 is Lys, Xaa4 is Tyr and



Xaa5 is Pro;


Om1.1:
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;


Vr1.1:
SEQ ID NO: 168, wherein Xaa5 is Pro; and


Vr1.2:
SEQ ID NO: 169, wherein Xaa5 is Pro.









The C-terminus preferably contains a carboxyl group for the peptides Sn1.1, Sn1.2, Cr1.3, Di1.1, Ms1.2, Ms1.4, Ms1.5, Ms1.8, Ms1.9, Vr1.1 and Vr1.2. 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-
(SEQ ID NO:22)


 


His-Leu-Xaa1-His-Ser-Asn-Met-Cys;


 


Gly-Cys-Cys-Ser-Asn-Xaa5-Val-Cys-
(SEQ ID NO:23)


 


Arg-Gln-Asn-Asn-Ala-Xaa1-Xaa4-Cys-


 


Arg;


 


Xaa5-Gln-Cys-Cys-Ser-His-Xaa5-Ala-
(SEQ ID NO:24)


 


Cys-Asn-Val-Asp-His-Xaa5-Xaa1-Ile-


 


Cys-Arg;


 


Xaa5-Xaa1-Cys-Cys-Ser-His-Xaa5-
(SEQ ID NO:25)


 


Ala-Cys-Asn-Val-Asp-His-Xaa5-Xaa1-


 


Ile-Cys-Arg;


 


Xaa5-Gln-Cys-Cys-Ser-His-Xaa5-Ala-
(SEQ ID NO:26)


 


Cys-Asn-Val-Asp-His-Xaa5-Xaa1-Ile-


 


Cys-Asp;


 


Xaa5-Arg-Cys-Cys-Ser-His-Xaa5-Ala-
(SEQ ID NO:27)


 


Cys-Asn-Val-Asp-His-Xaa5-Xaa1-Ile-


 


Cys-Arg;


 


Xaa5-Gln-Cys-Cys-Ser-His-Xaa5-Ala-
(SEQ ID NO:28)


 


Cys-Asn-Val-Asp-His-Xaa5-Gly-Ile-


 


Cys-Arg;


 


Xaa5-Gln-Cys-Cys-Ser-His-Xaa5-Ala-
(SEQ ID NO:29)


 


Cys-Asn-Val-Asp-His-Xaa5-Xaa1-Thr-


 


Cys-Arg;


 


Xaa5-Gln-Cys-Cys-Ser-His-Xaa5-Ala-
(SEQ ID NO:30)


 


Cys-Asn-Val-Asp-His-Xaa5-Xaa1-Val-


 


Cys-Arg;


 


Xaa5-Gln-Cys-Cys-Ser-His-Xaa5-Ala-
(SEQ ID NO:31)


 


Cys-Asn-Ile-Asp-His-Xaa5-Xaa1-Ile-


 


Cys-Arg;


 


Xaa5-Gln-Cys-Cys-Ser-His-Xaa5-Ala-
(SEQ ID NO:32)


 


Cys-Asn-Val-Asp-His-Xaa5-Xaa1-Ile-


 


Cys-Arg-Arg-Arg-Arg;


 


Gly-Gly-Cys-Cys-Ser-His-Xaa5-Ala-
(SEQ ID NO:33)


 


Cys-Ala-Val-Asn-His-Xaa5-Xaa1-Leu-


 


Cys;


 


Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-
(SEQ ID NO:34)


 


Ser-Val-Asn-His-Xaa5-Xaa1-Leu-Cys;


 


Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-
(SEQ ID NO:35)


 


Asn-Val-Asp-His-Xaa5-Xaa1-Ile-Cys;


 


Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-
(SEQ ID NO:36)


 


Ser-Gly-Xaa2-Thr-Gln-Xaa1-Xaa5-


 


Cys-Arg-Xaa1-Ser;


 


Xaa5-Cys-Cys-Ser-His-Xaa5-Ala-Cys-
(SEQ ID NO:37)


 


Ser-Gly-Asn-Asn-Xaa5-Xaa1-Phe-Cys-


 


Arg-Gln;


 


Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-
(SEQ ID NO:38)


 


Ser-Gly-Asn-Asn-Xaa5-Xaa1-Phe-Cys-


 


Arg-Gln;


 


Gly-Cys-Cys-Ser-His-Xaa5-Xaa5-Cys-
(SEQ ID NO:39)


 


Ala-Met-Asn-Asn-Xaa5-Asp-Xaa4-Cys;


 


Gly-Cys-Cys-Ser-His-Xaa5-Xaa5-Cys-
(SEQ ID NO:40)


 


Phe-Leu-Asn-Asn-Xaa5-Asp-Xaa4-Cys;


 


Gly-Cys-Cys-Ser-Asn-Xaa5-Xaa5-Cys-
(SEQ ID NO:41)


 


Ile-Ala-Xaa2-Asn-Xaa5-His-Met-Cys-


 


Gly;


 


Gly-Cys-Cys-Ser-Asn-Xaa5-Ala-Cys-
(SEQ ID NO:43)


 


Ala-Gly-Asn-Asn-Xaa5-His-Val-Cys-


 


Arg-Gln;


 


Gly-Cys-Cys-Ser-Arg-Xaa5-Ala-Cys-
(SEQ ID NO:44)


 


Ile-Ala-Asn-Asn-Xaa5-Asp-Leu-Cys;


 


Gly-Cys-Cys-Ser-Asn-Xaa5-Val-Cys-
(SEQ ID NO:45)


 


His-Val-Xaa1-His-Xaa5-Xaa1-Leu-


 


Cys-Arg-Arg-Arg-Arg;


 


Gly-Gly-Cys-Cys-Ser-Phe-Xaa5-Ala-
(SEQ ID NO:46)


 


Cys-Arg-Xaa2-Xaa5-Arg-Xaa5-Xaa1-


 


Met-Cys-Gly;


 


Xaa5-Xaa1-Cys-Cys-Ser-Asp-Xaa5-
(SEQ ID NO:47)


 


Arg-Cys-Asn-Ser-Ser-His-Xaa5-Xaa1-


 


Leu-Cys-Gly;


 


Xaa5-Gln-Cys-Cys-Ser-Asp-Xaa5-Arg-
(SEQ ID NO:48)


 


Cys-Asn-Val-Gly-His-Xaa5-Xaa1-Leu-


 


Cys-Gly;


 


Xaa6-Val-Cys-Cys-Ser-Asp-Xaa5-Arg-
(SEQ ID NO:49);


 


Cys-Asn-Val-Gly-His-Xaa5-Xaa1-Ile-


 


Cys-Gly;


 


Gly-Cys-Cys-Ser-Arg-Xaa5-Xaa5-Cys-
(SEQ ID NO:50)


 


Ile-Ala-Asn-Asn-Xaa5-Asp-Leu-Cys;


 


Xaa5-Gln-Cys-Cys-Ser-His-Leu-Ala-
(SEQ ID NO:51)


 


Cys-Asn-Val-Asp-His-Xaa5-Xaa1-Ile-


 


Cys-Arg;


 


Gly-Cys-Cys-Ser-Xaa4-Phe-Asp-Cys-
(SEQ ID NO:52)


 


Arg-Met-Met-Phe-Xaa5-Xaa1-Met-Cys-


 


Gly-Xaa3-Arg;


 


Gly-Gly-Cys-Cys-Ser-Phe-Ala-Ala-
(SEQ ID NO:53)


 


Cys-Arg-Xaa2-Xaa4-Arg-Xaa5-Xaa1-


 


Met-Cys-Gly;


 


Gly-Gly-Cys-Cys-Phe-His-Xaa5-Val-
(SEQ ID NO:54)


 


Cys-Xaa4-Ile-Asn-Leu-Leu-Xaa1-Met-


 


Cys-Arg-Gln-Arg;


 


Ser-Ala-Thr-Cys-Cys-Asn-Xaa4-Xaa5-
(SEQ ID NO:55)


 


Xaa5-Cys-Xaa4-Xaa1-Thr-Xaa4-Xaa5-


 


Xaa1-Ser-Cys-Leu;


 


Ala-Cys-Cys-Ala-Xaa4-Xaa5-Xaa5-
(SEQ ID NO:56)


 


Cys-Phe-Xaa1-Ala-Xaa4-Xaa5-Xaa1-


 


Arg-Cys-Leu;


 


Asn-Ala-Xaa1-Cys-Cys-Xaa4-Xaa4-
(SEQ ID NO:57)


 


Xaa5-Xaa5-Cys-Xaa4-Xaa1-Ala-Xaa4-


 


Xaa5-Xaa1-Ile-Cys-Leu;


 


Xaa1-Cys-Cys-Thr-Asn-Xaa5-Val-Cys-
(SEQ ID NO:170)


 


His-Ala-Xaa1-His-Gln-Xaa1-Leu-Cys-


 


Ala-Arg-Arg-Arg;


 


Gly-Cys-Cys-Ser-Asn-Xaa5-Val-Cys-
(SEQ ID NO:171)


 


His-Leu-Xaa1-His-Ser-Asn-Leu-Cys;


 


Xaa1-Cys-Cys-Thr-Asn-Xaa5-Val-Cys-
(SEQ ID NO:172)


 


His-Val-Xaa1-His-Gln-Xaa1-Leu-Cys-


 


Ala-Arg-Arg-Arg;


 


Xaa6-Xaa1-Cys-Cys-Ser-Xaa4-Xaa5-
(SEQ ID NO:173)


 


Ala-Cys-Asn-Leu-Asp-His-Xaa5-Xaa1-


 


Leu-Cys;


 


Xaa5-Xaa1-Cys-Cys-Ser-Asp-Xaa5-
(SEQ ID NO:174)


 


Arg-Cys-Asn-Ser-Thr-His-Xaa5-Xaa1-


 


Leu-Cys-Gly;


 


Leu-Asn-Cys-Cys-Met-Ile-Xaa5-Xaa5-
(SEQ ID NO:175)


 


Cys-Xaa3-Xaa2-Xaa2-Xaa4-Gly-Asp-


 


Arg-Cys-Ser-Xaa1-Val-Arg;


 


Ala-Phe-Gly-Cys-Cys-Asp-Leu-Ile-
(SEQ ID NO:176)


 


Xaa5-Cys-Leu-Xaa1-Arg-Xaa4-Gly-


 


Asn-Arg-Cys-Asn-Xaa1-Val-His;


 


Leu-Gly-Cys-Cys-Asn-Val-Thr-Xaa5-
(SEQ ID NO:177)


 


Cys-Xaa3-Xaa1-Xaa2-Xaa4-Gly-Asp-


 


Xaa2-Cys-Asn-Xaa1-Val-Arg;


 


Asp-Xaa1-Cys-Cys-Ser-Asn-Xaa5-Ala-
(SEQ ID NO:178)


 


Cys-Arg-Val-Asn-Asn-Xaa5-His-Val-


 


Cys-Arg-Arg-Arg;


 


Leu-Asn-Cys-Cys-Ser-Ile-Xaa5-Gly-
(SEQ ID NO:179)


 


Cys-Xaa3-Asn-Xaa1-Xaa4-Xaa2-Asp-


 


Arg-Cys-Ser-Xaa2-Val-Arg;


 


Gly-Gly-Cys-Cys-Ser-His-Xaa5-Val-
(SEQ ID NO:180)


 


Cys-Xaa4-Phe-Asn-Asn-Xaa5-Gln-Met-


 


Cys-Arg;


 


Gly-Gly-Cys-Cys-Ser-His-Xaa5-Val-
(SEQ ID NO:181)


 


Cys-Asn-Leu-Asn-Asn-Xaa5-Gln-Met-


 


Cys-Arg;


 


Gly-Cys-Cys-Ser-His-Xaa5-Xaa5-Cys-
(SEQ ID NO:182)


 


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


 


Asn;


 


Gly-Gly-Cys-Cys-Ser-His-Xaa5-Ala-
(SEQ ID NO:183)


 


Cys-Ser-Val-Thr-His-Xaa5-Xaa1-Leu-


 


Cys;


 


Gly-Gly-Cys-Cys-Ser-Xaa4-Xaa5-Ala-
(SEQ ID NO:184)


 


Cys-Ser-Val-Xaa1-His-Gln-Asp-Leu-


 


Cys-Asp;


 


Val-Ser-Cys-Cys-Val-Val-Arg-Xaa5-
(SEQ ID NO:185)


 


Cys-Xaa3-Ile-Arg-Xaa4-Gln-Xaa1-


 


Xaa1-Cys-Leu-Xaa1-Ala-Asp-Xaa5-


 


Arg-Thr-Leu;


 


Xaa6-Asn-Cys-Cys-Ser-Ile-Xaa5-Gly-
(SEQ ID NO:186)


 


Cys-Xaa3-Xaa1-Xaa2-Xaa4-Gly-Asp-


 


Xaa2-Cys-Ser-Xaa1-Val-Arg;


 


Gly-Cys-Cys-Ser-Asn-Xaa5-Val-Cys-
(SEQ ID NO:187)


 


His-Leu-Xaa1-His-Xaa5-Asn-Ala-Cys;


 


Gly-Cys-Cys-Ser-Asn-Xaa5-Ile-Cys-
(SEQ ID NO:188)


 


Xaa4-Phe-Asn-Asn-Xaa5-Arg-Ile-Cys-


 


Arg;


 


Xaa1-Cys-Cys-Ser-Gln-Xaa5-Xaa5-
(SEQ ID NO:189)


 


Cys-Arg-Xaa3-Xaa2-His-Xaa5-Xaa1-


 


Leu-Cys-Ser;


 


Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-
(SEQ ID NO:190)


 


Ala-Gly-Asn-Asn-Gln-His-Ile-Cys;


 


Gly-Cys-Cys-Ala-Val-Xaa5-Ser-Cys-
(SEQ ID NO:191)


 


Arg-Leu-Arg-Asn-Xaa5-Asp-Leu-Cys-


 


Gly-Gly;


 


Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-
(SEQ ID NO:192)


 


Asn-Val-Asn-Asn-Xaa5-His-Ile-Cys;


 


Thr-Xaa5-Xaa1-Xaa1-Cys-Cys-Xaa5-
(SEQ ID NO:193)


 


Asn-Xaa5-Xaa5-Cys-Phe-Ala-Thr-Asn-


 


Ser-Asp-Ile-Cys-Gly;


 


Asp-Ala-Cys-Cys-Ser-Asp-Xaa5-Arg-
(SEQ ID NO:194)


 


Cys-Ser-Gly-Xaa2-His-Gln-Asp-Leu-


 


Cys;


 


Xaa1-Asp-Cys-Cys-Ser-Asp-Xaa5-Arg-
(SEQ ID NO:195)


 


Cys-Ser-Val-Gly-His-Gln-Asp-Leu-


 


Cys;


 


Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-
(SEQ ID NO:196)


 


Ala-Gly-Ser-Asn-Ala-His-Ile-Cys;


 


Xaa1-Asp-Cys-Cys-Ser-Asp-Xaa5-Arg-
(SEQ ID NO:197)


 


Cys-Ser-Val-Gly-His-Gln-Asp-Met-


 


Cys;


 


Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-
(SEQ ID NO:198)


 


Ala-Gly-Asn-Asn-Xaa5-His-Ile-Cys;


 


Gly-Cys-Cys-Gly-Asn-Xaa5-Ser-Cys-
(SEQ ID NO:199)


 


Ser-Ile-His-Ile-Xaa5-Xaa4-Val-Cys-


 


Asn;


 


Thr-Asp-Ser-Xaa1-Xaa1-Cys-Cys-Leu-
(SEQ ID NO:200)


 


Asp-Ser-Arg-Cys-Ala-Gly-Gln-His-


 


Gln-Asp-Leu-Cys-Gly;


 


Gly-Cys-Cys-Ser-Asn-Xaa5-Xaa5-Cys-
(SEQ ID NO:201)


 


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


 


Asn;


 


Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-
(SEQ ID NO:202)


 


Ser-Val-Asn-Asn-Xaa5-Asp-Ile-Cys;


 


Gly-Xaa2-Cys-Cys-Ile-Asn-Asp-Ala-
(SEQ ID NO:203)


 


Cys-Arg-Ser-Xaa2-His-Xaa5-Gln-


 


Xaa4-Cys-Ser;


 


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


 


Arg-Ile-Asn-Asn-Xaa5-Arg-Xaa4-Cys-


 


Arg;


 


Gly-Cys-Cys-Ser-His-Xaa5-Val-Cys-
(SEQ ID NO:205)


 


Arg-Phe-Asn-Xaa4-Xaa5-Xaa2-Xaa4-


 


Cys-Gly;


 


Asp-Xaa1-Cys-Cys-Ala-Ser-Xaa5-
(SEQ ID NO:206)


 


Xaa5-Cys-Arg-Leu-Asn-Asn-Xaa5-


 


Xaa4-Val-Cys-His;


 


Gly-Cys-Cys-Ser-Asn-Xaa5-Val-Cys-
(SEQ ID NO:207)


 


Xaa3-Gln-Asn-Asn-Ala-Xaa1-Xaa4-


 


Cys-Arg-Xaa1-Ser;


 


Gly-Cys-Cys-Ser-His-Xaa5-Xaa5-Cys-
(SEQ ID NO:208)


 


Ala-Gln-Asn-Asn-Gln-Asp-Xaa4-Cys;


 


Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-
(SEQ ID NO:209)


 


Ser-Gly-Asn-Asn-Arg-Xaa1-Xaa4-Cys-


 


Arg-Xaa1-Ser;


 


Asp-Xaa5-Cys-Cys-Ser-Xaa4-Xaa5-
(SEQ ID NO:210)


 


Asp-Cys-Gly-Ala-Asn-His-Xaa5-Xaa1-


 


Ile-Cys-Gly;


 


Xaa1-Cys-Cys-Ser-Gln-Xaa5-Xaa5-
(SEQ ID NO:211)


 


Cys-Arg-Xaa3-Xaa2-His-Xaa5-Xaa1-


 


Leu-Cys-Ser;


 


Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-
(SEQ ID NO:212)


 


Ala-Gly-Asn-Asn-Xaa5-His-Ile-Cys;


 


Gly-Cys-Cys-Ser-Asp-Xaa5-Ser-Cys-
(SEQ ID NO:213)


 


Asn-Val-Asn-Asn-Xaa5-Asp-Xaa4-Cys;


 


Xaa1-Xaa1-Cys-Cys-Ser-Asp-Xaa5-
(SEQ ID NO:214)


 


Arg-Cys-Ser-Val-Gly-His-Gln-Asp-


 


Met-Cys-Arg;


 


Gly-Gly-Cys-Cys-Ser-Asn-Xaa5-Ala-
(SEQ ID NO:215)


 


Cys-Leu-Val-Asn-His-Leu-Xaa1-Met-


 


Cys;


 


Arg-Asp-Xaa5-Cys-Cys-Phe-Asn-Xaa5-
(SEQ ID NO:216)


 


Ala-Cys-Asn-Val-Asn-Asn-Xaa5-Gln-


 


Ile-Cys;


 


Cys-Cys-Ser-Asp-Xaa5-Ser-Cys-Xaa3-
(SEQ ID NO:217)


 


Arg-Leu-His-Ser-Leu-Ala-Cys-Thr-


 


Gly-Ile-Val-Asn-Arg;


 


Cys-Cys-Thr-Asn-Xaa5-Ala-Cys-Leu-
(SEQ ID NO:218)


 


Val-Asn-Asn-Ile-Arg-Phe-Cys-Gly;


 


Asp-Xaa1-Cys-Cys-Ser-Asp-Xaa5-Arg-
(SEQ ID NO:219)


 


Cys-His-Gly-Asn-Asn-Arg-Asp-His-


 


Cys-Ala;


 


Asp-Cys-Cys-Ser-His-Xaa5-Leu-Cys-
(SEQ ID NO:220)


 


Arg-Leu-Phe-Val-Xaa5-Gly-Leu-Cys-


 


Ile;


 


Gly-Cys-Cys-Ser-His-Xaa5-Val-Cys-
(SEQ ID NO:221)


 


Xaa2-Val-Arg-Xaa4-Xaa5-Asp-Leu-


 


Cys-Arg;


 


Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-
(SEQ ID NO:222)


 


Asn-Val-Asn-Asn-Xaa5-His-Ile-Cys;


 


Gly-Cys-Cys-Ser-His-Xaa5-Val-Cys-
(SEQ ID NO:223)


 


Xaa2-Val-Arg-Xaa4-Ser-Asp-Met-Cys;


 


Gly-Gly-Cys-Cys-Ser-His-Xaa5-Ala-
(SEQ ID NO:224)


 


Cys-Xaa2-Val-His-Phe-Xaa5-His-Ser-


 


Cys;


 


Val-Cys-Cys-Ser-Asn-Xaa5-Val-Cys-
(SEQ ID NO:225)


 


His-Val-Asp-His-Xaa5-Xaa1-Leu-Cys-


 


Arg-Arg-Arg-Arg;


 


Gly-Cys-Cys-Ser-His-Xaa5-Val-Cys-
(SEQ ID NO:226)


 


Asn-Leu-Ser-Asn-Xaa5-Gln-Ile-Cys-


 


Arg;


 


Xaa6-Xaa1-Cys-Cys-Ser-His-Xaa5-
(SEQ ID NO:227)


 


Ala-Cys-Asn-Val-Asp-His-Xaa5-Xaa1-


 


Ile-Cys-Arg;


 


Gly-Cys-Cys-Ser-Asn-Xaa5-Ala-Cys-
(SEQ ID NO:228)


 


Leu-Val-Asn-His-Ile-Arg-Phe-Cys-


 


Gly;


 


Asp-Cys-Cys-Asp-Asp-Xaa5-Ala-Cys-
(SEQ ID NO:229)


 


Thr-Val-Asn-Asn-Xaa5-Gly-Leu-Cys-


 


Thr; and


 


Gly-Cys-Cys-Ser-Asn-Xaa5-Xaa5-Cys-
(SEQ ID NO:230)


 


Ile-Ala-Xaa2-Asn-Xaa5-His-Met-Cys-


 


Gly-Gly-Arg-Arg,






wherein Xaa1 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 Gln or pyro-Glu; and the C-terminus contains a carboxyl or amide group. The halo is preferably bromine, chlorine or iodine, more preferably iodine for Tyr and bromine for Trp. In addition, the His residues may be substituted with halo-His; the Arg residues may be substituted by Lys, ornithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Lys residues may be substituted by Arg, ornithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Tyr residues may be substituted with any unnatural hydroxy containing amino acid; the Ser residues may be substituted with Thr; the Thr residues may be substituted with Ser; and the Phe and Trp residues may be substituted with any unnatural aromatic amino acid. The Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or 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:













SmI:
SEQ ID NO: 22, wherein Xaa1 is Glu and Xaa5 is Pro;


OB-29:
SEQ ID NO: 23, wherein Xaa1 is Glu, Xaa3 is Tyr and



Xaa5 is Pro;


Tx1.1:
SEQ ID NO: 24, wherein Xaa1 is Glu and Xaa5 is Pro;


R1.1A:
SEQ ID NO: 25, wherein Xaa1 is Glu and Xaa5 is Pro;


R1.1B:
SEQ ID NO: 26, wherein Xaa1 is Glu and Xaa5 is Pro;


Om-9:
SEQ ID NO: 27, wherein Xaa1 is Glu and Xaa5 is Pro;


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


Om-21:
SEQ ID NO: 29, wherein Xaa1 is Glu and Xaa5 is Pro;


Om-25:
SEQ ID NO: 30, wherein Xaa1 is Glu and Xaa5 is Pro;


Om-27:
SEQ ID NO: 31, wherein Xaa1 is Glu and Xaa5 is Pro;


Om-28:
SEQ ID NO: 32, wherein Xaa1 is Glu and Xaa5 is Pro;


Bt1.2:
SEQ ID NO: 33, wherein Xaa1 is Glu and Xaa5 is Pro;


Bt1.4:
SEQ ID NO: 34, wherein Xaa1 is Glu and Xaa5 is Pro;


Da1.1:
SEQ ID NO: 35, wherein Xaa1 is Glu and Xaa5 is Pro;


OB-20:
SEQ ID NO: 36, wherein Xaa1 is Glu, Xaa2 is Lys and



Xaa5 is Pro;


TI:
SEQ ID NO: 37, wherein Xaa1 is Glu and Xaa5 is Pro;


TIB:
SEQ ID NO: 38, wherein Xaa1 is Glu and Xaa5 is Pro;


Pn1.1:
SEQ ID NO: 39, wherein Xaa5 is Pro;


Pn1.2:
SEQ ID NO: 40, wherein Xaa1 is Glu and Xaa5 is Pro;


T1:
SEQ ID NO: 41, wherein Xaa2 is Lys and Xaa5 is Pro;


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


Da1.2:
SEQ ID NO: 44, wherein Xaa5 is Pro;


Cr1.2:
SEQ ID NO: 45, wherein Xaa1 is Glu and Xaa5 is Pro;


Sl1.2:
SEQ ID NO: 46, wherein Xaa1 is Glu, Xaa2 is Lys and



Xaa5 is Pro;


Tx1.3:
SEQ ID NO: 47, wherein Xaa1 is Glu and Xaa5 is Pro;


Da1.3:
SEQ ID NO: 48, wherein Xaa1 is Glu and Xaa5 is Pro;


Da1.4:
SEQ ID NO: 49, wherein Xaa1 is Glu, Xaa5 is Pro and



Xaa6 is Gln;


Tx1.2:
SEQ ID NO: 50, wherein Xaa5 is Pro;


Om-35:
SEQ ID NO: 51, wherein Xaa1 is Glu and Xaa5 is Pro;


Sl1.1:
SEQ ID NO: 52, wherein Xaa1 is Glu, Xaa3 is Trp, Xaa4 is Tyr



and Xaa5 is Pro;


Sl1.6:
SEQ ID NO: 53, wherein Xaa1 is Glu, Xaa2 is Lys, Xaa4 is Tyr



and Xaa5 is Pro;


Sl1.7:
SEQ ID NO: 54, wherein Xaa1 is Glu Xaa4 is Tyr and



Xaa5 is Pro;


Bt1.1:
SEQ ID NO: 55, wherein Xaa1 is Glu Xaa4 is Tyr and



Xaa5 is Pro;


Bt: 1.3:
SEQ ID NO: 56, wherein Xaa1 is Glu Xaa4 is Tyr and



Xaa5 is Pro;


Bt1.5:
SEQ ID NO: 57, wherein Xaa1 is Glu Xaa4 is Tyr and



Xaa5 is Pro;


A1.4:
SEQ ID NO: 170, wherein Xaa1 is Glu and Xaa5 is Pro;


A1.5:
SEQ ID NO: 171, wherein Xaa1 is Glu and Xaa5 is Pro;


A1.6:
SEQ ID NO: 172, wherein Xaa1 is Glu and Xaa5 is Pro;


Af1.1:
SEQ ID NO: 173, wherein Xaa1 is Glu Xaa4 is Tyr, Xaa5 is Pro



and Xaa6 is Gln;


Af1.2:
SEQ ID NO: 174, wherein Xaa1 is Glu and Xaa5 is Pro;


Ar1.2:
SEQ ID NO: 175, wherein Xaa1 is Glu, Xaa2 is Lys, Xaa3 is Trp,



Xaa4 is Try and Xaa5 is Pro;


Ar1.3:
SEQ ID NO: 176, wherein Xaa1 is Glu, Xaa4 is Tyr



and Xaa5 is Pro;


Ar1.4:
SEQ ID NO: 177, wherein Xaa1 is Glu, Xaa2 is Lys, Xaa3 is Trp,



Xaa4 is Try and Xaa5 is Pro;


Ar1.5:
SEQ ID NO: 178, wherein Xaa1 is Glu and Xaa5 is Pro;


Ar1.6:
SEQ ID NO: 179, wherein Xaa1 is Glu, Xaa2 is Lys, Xaa3 is



Trp, Xaa4 is Try and Xaa5 is Pro;


Ay1.2:
SEQ ID NO: 180, wherein Xaa4 is Tyr and Xaa5 is Pro;


Ay1.3:
SEQ ID NO: 181, wherein Xaa5 is Pro;


Bn1.4:
SEQ ID NO: 182, wherein Xaa4 is Tyr and Xaa5 is Pro;


Bt1.8:
SEQ ID NO: 183, wherein Xaa1 is Glu and Xaa5 is Pro;


Bt1.9:
SEQ ID NO: 184, wherein Xaa1 is Glu, Xaa4 is Tyr and



Xaa5 is Pro;


Ca1.3:
SEQ ID NO: 185, wherein Xaa1 is Glu, Xaa3 is Trp, Xaa4 is



Try and Xaa5 is Pro;


Ca1.4:
SEQ ID NO: 186, wherein Xaa1 is Glu, Xaa2 is Lys, Xaa3 is Trp,



Xaa4 is Try, Xaa5 is Pro and Xaa6 is Gln;


C1.2:
SEQ ID NO: 187, wherein Xaa1 is Glu and Xaa5 is Pro;


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


Ep1.2:
SEQ ID NO: 189, wherein Xaa1 is Glu, Xaa2 is Lys, Xaa3 is



Trp and Xaa5 is Pro;


G1.1:
SEQ ID NO: 190, wherein Xaa5 is Pro;


G1.3:
SEQ ID NO: 191, wherein Xaa5 is Pro;


Im1.3:
SEQ ID NO: 192, wherein Xaa5 is Pro;


Lv1.2:
SEQ ID NO: 193, wherein Xaa1 is Glu and Xaa5 is Pro;


Lv1.3:
SEQ ID NO: 194, wherein Xaa2 is Lys and Xaa5 is Pro;


Lv1.4:
SEQ ID NO: 195, wherein Xaa1 is Glu and Xaa5 is Pro;


Lv1.6:
SEQ ID NO: 196, wherein Xaa5 is Pro;


Lv1.7:
SEQ ID NO: 197, wherein Xaa1 is Glu and Xaa5 is Pro;


Lv1.8:
SEQ ID NO: 198, wherein Xaa5 is Pro;


Lv1.9:
SEQ ID NO: 199, wherein Xaa4 is Tyr and Xaa5 is Pro;


Lv1.10:
SEQ ID NO: 200, wherein Xaa1 is Glu;


Mr1.3:
SEQ ID NO: 201, wherein Xaa4 is Tyr and Xaa5 is Pro;


Mr1.4:
SEQ ID NO: 202, wherein Xaa5 is Pro;


Ms1.1:
SEQ ID NO: 203, wherein Xaa2 is Lys, Xaa4 is Tyr and



Xaa5 is Pro;


Ms1.6:
SEQ ID NO: 204, wherein Xaa4 is Tyr and Xaa5 is Pro;


O1.1:
SEQ ID NO: 205, wherein Xaa2 is Lys, Xaa4 is Tyr and



Xaa5 is Pro;


O1.2:
SEQ ID NO: 206, wherein Xaa1 is Glu, Xaa4 is Tyr and



Xaa5 is Pro;


O1.4:
SEQ ID NO: 207, wherein Xaa1 is Glu, Xaa3 is Trp, 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 Xaa1 is Glu, Xaa4 is Tyr and



Xaa5 is Pro;


Om1.2:
SEQ ID NO: 210, wherein Xaa1 is Glu, Xaa4 is Tyr



and Xaa5 is Pro;


Om1.3:
SEQ ID NO: 211, wherein Xaa1 is Glu, Xaa2 is Lys,



Xaa3 is Trp and Xaa5 is Pro;


Om1.4:
SEQ ID NO: 212, wherein Xaa5 is Pro;


Om1.5:
SEQ ID NO: 213, wherein Xaa4 is Tyr and Xaa5 is Pro;


Om1.6:
SEQ ID NO: 214, wherein Xaa1 is Glu and Xaa5 is Pro;


P1.4:
SEQ ID NO: 215, wherein Xaa1 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 Trp and Xaa5 is Pro;


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


Rg1.1:
SEQ ID NO: 219, wherein Xaa1 is Glu and Xaa5 is Pro;


Rg1.3:
SEQ ID NO: 220, wherein Xaa5 is Pro;


Rg1.4:
SEQ ID NO: 221, wherein Xaa2 is Lys, Xaa4 is Tyr and



Xaa5 is Pro;


Rg1.5:
SEQ ID NO: 222, wherein Xaa5 is Pro;


Rg1.8:
SEQ ID NO: 223, wherein Xaa2 is Lys, Xaa4 is Tyr and



Xaa5 is Pro;


Sm1.4:
SEQ ID NO: 224, wherein Xaa2 is Lys and Xaa5 is Pro;


Sm1.5:
SEQ ID NO: 225, wherein Xaa1 is Glu and Xaa5 is Pro;


S1.5:
SEQ ID NO: 226, wherein Xaa5 is Pro;


Tx1.5:
SEQ ID NO: 227, wherein Xaa1 is Glu, Xaa5 is Pro



and Xaa6 is Gln;


T1.1:
SEQ ID NO: 228, wherein Xaa5 is Pro;


Vr1.3:
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, Tx1.1, R1.1A, R1.1B, Om-9, Om-10, Om-21, Om-25, Om-27, Om-28, Cr1.2, Om-35, Bt1.1, Bt1.3, Bt1.5, A1.4, A1.6, Ar1.2, Ar1.3, Ar1.4, Ar1.5, Ar1.6, Ca1.3, Ca1.4, Ep1.2, Lv1.9, O1.2, Om1.3, Om1.6, P1.6, Rg1.1, Rg1.3, Rg1.4, Sm1.5, Tx1.5 and Vr1.3. The C-terminus of the other peptides preferably contains an amide group.

The present invention is also directed to the novel specific α-conotoxin peptides having the formulas:








Cys-Cys-Thr-Ile-Xaa5-Ser-Cys-Xaa4-
(SEQ ID NO:231)


 


Xaa1-Xaa2-Xaa2-Xaa2-Ile-Xaa2-Ala-


 


Cys-Val-Phe and


 


Gly-Cys-Cys-Gly-Asn-Xaa5-Ala-Cys-
(SEQ ID NO:232)


 


Ser-Gly-Ser-Ser-Xaa2-Asp-Ala-Xaa5-


 


Ser-Cys,






wherein Xaa1 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, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Lys residues may be substituted by Arg, ornithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; the Tyr residues may be substituted with any unnatural hydroxy containing amino acid; the Ser residues may be substituted with Thr; the Thr residues may be substituted with Ser; and the Phe 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:

    
    
        G1.2: SEQ ID NO:231, wherein Xaa1 is Glu, Xaa2 is Lys, Xaa4 is Tyr and Xaa5 is Pro; and
        Rg1.12: 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 Rg1.12 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 C1-C3 alkyl, carboxyl, hydroxymethyl, 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 website “amino-acids.com”), incorporated herein by reference, by and available from RSP Amino Acid Analogues, Inc., Worcester, Mass.
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 glycan may also include similar polyhydroxy groups, such as D-penicillamine 2,5 and halogenated derivatives thereof or polypropylene glycol derivatives. The glycosidic linkage is beta and 1-4 or 1-3, preferably 1-3. The linkage between the glycan and the amino acid may be alpha or beta, preferably alpha and is 1-.
Core O-glycans have been described by Van de Steen et al. (1998), incorporated herein by reference. Mucin type O-linked oligosaccharides are attached to Ser or Thr (or other hydroxylated residues of the present peptides) by a GalNAc residue. The 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. Ser. No. 09/420,797, filed 19 Oct. 1999 (now U.S. Pat. No. 6,369,193) and in PCT Application No. PCT/US99/24380, filed 19 Oct. 1999, both incorporated herein by reference. A preferred glycan is Gal(β1-3)GalNAc(α1→).
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 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 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 Ser. No. 09/488,799, filed 21 Jan. 2000, incorporated by reference herein. In a second aspect, additional α-conotoxins and uses for them have been described in U.S. Pat. Nos. 4,447,356 (Olivera et al., 1984); 5,432,155; 5,514,774, each incorporated herein by reference.
In a third aspect additional uses for α-conotoxins are described in U.S. Ser. No. 09/219,446, filed 22 Dec. 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. Pat. 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. Pat. No. 4,105,603 (Vale et al., 1978). The fragment condensation method of synthesis is exemplified in U.S. Pat. No. 3,972,859 (1976). Other available syntheses are exemplified by U.S. Pat. Nos. 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 paramethylbenzhydrylamine (MBHA) resin. Preparation of the hydroxymethyl resin is described by Bodansky et al. (1966). Chloromethylated resins are commercially available from Bio Rad Laboratories (Richmond, Calif.) 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. Pat. No. 4,569,967 (Kornreich et al., 1986) can be used, or should still other groups than the free acid be desired at the C-terminus, it may be preferable to synthesize the peptide using classical methods as set forth in the Houben-Weyl text (1974).
The C-terminal amino acid, protected by Boc or Fmoc and by a side-chain protecting group, if appropriate, can be first coupled to a chloromethylated resin according to the procedure set forth in K. Horiki et al. (1978), using KF in DMF at about 60° 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):CH2Cl2 (1:1) or in DMF or CH2Cl2 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-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and diethylisopropylethylamine (DIEA). The FMOC protecting group is removed by treatment with a 20% solution of piperidine in dimethylformamide(DMF). Resins are subsequently washed with DMF (twice), followed by methanol and NMP.
Pharmaceutical compositions containing a compound of the present invention or its pharmaceutically acceptable salts as the active ingredient can be prepared according to conventional pharmaceutical compounding techniques. See, for example, Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa.). Typically, an antagonistic amount of the active ingredient will be admixed with a pharmaceutically acceptable carrier. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, 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 specialists, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of techniques and protocols can be found in Remington's Pharmaceutical Sciences. Typically the conopeptides of the present invention exhibit their effect at a dosage range from about 0.001 mg/kg to about 250 mg/kg, preferably from about 0.05 mg/kg to about 100 mg/kg of the active ingredient, more preferably from a bout 0.1 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 0.1 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. Pat. 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 C18 semi-preparative column (10×250 mm) and elution with a linear gradient of acetonitrile in 0.1% TFA. Further purification of bioactive peaks was done on a Vydac C18 analytical column (4.6×220 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 MII, AuIA, AuIB, AuIC, MAR-1, MAR-2, TI, OB-29, EpI, S1.1, Bn1.1, Bn1.2, Ca1.1, Ca1.2, Cn1.1, Cn1.2 and Sm1.3 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-(1H-benzotriol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborated coupling using an ABI model 430A peptide synthesizer with amino acid derivatives purchased from Bachem (Torrance Calif.). 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 C18 preparative column (22×250 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 C18 preparative column (22×250 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 preparative column (22×250 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 M13 universal priming site and the M13 reverse universal priming site. Clones having a size of approximately 300 nucleotides were sequenced and screened for similarity in sequence to known 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 MII

















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc



Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



act gtc gtt tcc ttc cct tca gat cgt gca tct gat



Thr Val Val Ser Phe Pro Ser Asp Arg Ala Ser Asp



 



ggc agg aat gcc gca gcc aac gac aaa gcg tct gac



Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala Ser Asp



 



gtg atc acg ctg gcc ctc aag gga tgc tgt tcc aac



Val Ile Thr Leu Ala Leu Lys Gly Cys Cys Ser Asn



 



cct gtc tgt cac ttg gag cat tca aac ctt tgt ggt



Pro Val Cys His Leu Glu His Ser Asn Leu Cys Gly



 



aga aga cgc tgatgctcca ggaccctctg aaccacgacg



Arg Arg Arg



 



ttcgagca

















TABLE 2





DNA Sequence (SEQ ID NO:60) and


Protein Sequence (SEQ ID NO:61) of AuIA

















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc



Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



acc gtc gtt tcc ttc act tca gat cgt gca tct gat



Thr Val Val Ser Phe Thr Ser Asp Arg Ala Ser Asp



 



ggc agg aag gac gca gcg tct ggc ctg atc gct ctg



Gly Arg Lys Asp Ala Ala Ser Gly Leu Ile Ala Leu



 



acc atc aag gga tgc tgt tct tat cct ccc tgt ttc



Thr Ile Lys Gly Cys Cys Ser Tyr Pro Pro Cys Phe



 



gcg act aat tca gac tat tgt ggt tgacgacgct



Ala Thr Asn Ser Asp Tyr Cys Gly



 



gatgctccag gaccctctga accacgacgt

















TABLE 3





DNA Sequence (SEQ ID NO:62) and


Protein Sequence (SEQ ID NO:63) of AuIB















atg ttc acc gtg ttt ctg ttg gtc gtc ttg gca acc


Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr


 


acc gtc gtt tcc ttc act tca gat cgt gca tct gat


Thr Val Val Ser Phe Thr Ser Asp Arg Ala Ser Asp


 


ggc agg aag gac gca gcg tct ggc ctg att gct ctg


Gly Arg Lys Asp Ala Ala Ser Gly Leu Ile Ala Leu


 


acc atg aag gga tgc tgt tct tat cct ccc tgt ttc


Thr Met Lys Gly Cys Cys Ser Tyr Pro Pro Cys Phe


 


gcg act aat cca gac tgt ggt cga cga cgc tgatgctcca


Ala Thr Asn Pro Asp Cys Gly Arg Arg Arg


 


ggaccctctg aaccacgacg t

















TABLE 4





DNA Sequence (SEQ ID NO: 64) and



Protein Sequence (SEQ ID NO: 65) of Tx1.3
















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc



Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr


 


acc gtc gtt tcc ttc tct tca ggt cgt agt aca ttt


Thr Val Val Ser Phe Ser Ser Gly Arg Ser Thr Phe


 


cgt ggc agg aat gcc gca gcc aaa gcg tct ggc ctg


Arg Gly Arg Asn Ala Ala Ala Lys Ala Ser Gly Leu


 


gtc agt ctg act gac agg aga cca gaa tgc tgt agt


Val Ser Leu Thr Asp Arg Arg Pro Glu Cys Cys Ser


 


gat cct cgc tgt aac tcg agt cat cca gaa ctt tgt


Asp Pro Arg Cys Asn Ser Ser His Pro Glu Leu Cys


 


ggt gga aga cgc tgatgctcca ggaccctctg aaccacgacg t


Gly Gly Arg Arg

















TABLE 5





DNA Sequence (SEQ ID NO: 66) and



Protein Sequence (SEQ ID NO: 67) of Tx1.2


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



gcc gtc gtt tcc ttc act tca gat cgt gca tct gat



Ala Val Val Ser Phe Thr Ser Asp Arg Ala Ser Asp



 



gac ggg aaa gcc gct gcg tct gac ctg atc act ctg



Asp Gly Lys Ala Ala Ala Ser Asp Leu Ile Thr Leu



 



acc atc aag gga tgc tgt tct cgt cct ccc tgt atc



Thr Ile Lys Gly Cys Cys Ser Arg Pro Pro Cys Ile



 



gcg aat aat cca gac ttg tgt ggt tgacgacgct



Ala Asn Asn Pro Asp Leu Cys Gly



 



gatgctccag aacggtctga accacgacgt tcgagcaatg



 



ttcaccgtgt ttctgttggt tgtctt


















TABLE 6





DNA Sequence (SEQ ID NO: 68) and



Protein Sequence (SEQ ID NO: 69) of Tx1.1


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



acc gtc gtt tcc ttc act tca ggt cgt agt aca ttt



Thr Val Val Ser Phe Thr Ser Gly Arg Ser Thr Phe



 



cgt ggc agg aat gcc gca gcc aaa gcg tct ggc ctg



Arg Gly Arg Asn Ala Ala Ala Lys Ala Ser Gly Leu



 



gtc agt ctg act gac agg aga cca caa tgc tgt tct



Val Ser Leu Thr Asp Arg Arg Pro Gln Cys Cys Ser



 



cat cct gcc tgt aac gta gat cat cca gaa att tgt



His Pro Ala Cys Asn Val Asp His Pro Glu Ile Cys



 



cgt tgaagacgct gatgctccag gaccctctga accacgacgt



Arg


















TABLE 7





DNA Sequence (SEQ ID NO: 70) and



Protein Sequence (SEQ ID NO: 71) of R1.1A


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



acc gtc gtt tcc ttc act tca ggt cgt cgt aca ttt



Thr Val Val Ser Phe Thr Ser Gly Arg Arg Thr Phe



 



cat ggc agg aat gcc gca gcc aaa gcg tct ggc ctg



His Gly Arg Asn Ala Ala Ala Lys Ala Ser Gly Leu



 



gtc agt ctg act gac agg aga cca gaa tgc tgt tct



Val Ser Leu Thr Asp Arg Arg Pro Glu Cys Cys Ser



 



cat cct gcc tgt aac gta gat cat cca gaa att tgt



His Pro Ala Cys Asn Val Asp His Pro Glu Ile Cys



 



cgt tgaagacgct gatgctccag gaccctctga accacgacgt



Arg


















TABLE 8





DNA Sequence (SEQ ID NO: 72) and



Protein Sequence (SEQ ID NO: 73) of R1.1B


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



acc gtc gtt tcc ttc act tca ggt cgt agt aca ttt



Thr Val Val Ser Phe Thr Ser Gly Arg Ser Thr Phe



 



cgt ggc agg aat gcc gca gcc aaa gcg tct ggc ctg



Arg Gly Arg Asn Ala Ala Ala Lys Ala Ser Gly Leu



 



gtc agt ctg act gac agg aga cca caa tgc tgt tct



Val Ser Leu Thr Asp Arg Arg Pro Gln Cys Cys Ser



 



cat cct gcc tgt aac gta gat cat cca gaa att tgc



His Pro Ala Cys Asn Val Asp His Pro Glu Ile Cys



 



gat tgaagacgct gatgctccag gaccctctga accacgacgt



Asp


















TABLE 9





DNA Sequence (SEQ ID NO: 74) and



Protein Sequence (SEQ ID NO: 75) of S1.1


















atg ttc act gtg ttt ctg ttg gtt gtc ttg gca atc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Ile



 



act gtc gtt tcc ttc cct tta gat cgt gaa tct gat



Thr Val Val Ser Phe Pro Leu Asp Arg Glu Ser Asp



 



ggc gcg aat gcc gaa gcc cgc acc cac gat cat gag



Gly Ala Asn Ala Glu Ala Arg Thr His Asp His Glu



 



aag cac gca ctg gac cgg aat gga tgc tgt agg aat



Lys His Ala Leu Asp Arg Asn Gly Cys Cys Arg Asn



 



cct gcc tgt gag agc cac aga tgt ggt tgacgacgct



Pro Ala Cys Glu Ser His Arg Cys Gly



 



gatgctccag gaccctctga accacgacgt tcgagca


















TABLE 10





DNA Sequence (SEQ ID NO: 76) and



Protein Sequence (SEQ ID NO: 77) of Bn1.1


















atg ttc acc atg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Met Phe Leu Leu Val Val Leu Ala Thr



 



act gtc gtt tcc ttc gct tca gat cgt gca tct gat



Thr Val Val Ser Phe Ala Ser Asp Arg Ala Ser Asp



 



ggc agg aat gcc gca gcc aag gac aaa gcg tct gac



Gly Arg Asn Ala Ala Ala Lys Asp Lys Ala Ser Asp



 



ctg gtc gct ctg acc gtc aag gga tgc tgt tct cat



Leu Val Ala Leu Thr Val Lys Gly Cys Cys Ser His



 



cct gcc tgt agc gtg aat aat cca gac att tgt ggt



Pro Ala Cys Ser Val Asn Asn Pro Asp Ile Cys Gly



 



tgaagacgct gatgctccag gaccctctga accacgacgt



 



tcgagca


















TABLE 11





DNA Sequence (SEQ ID NO: 78) and



Protein Sequence (SEQ ID NO: 79) of Bn1.2


















aaa gaa tgc tgt act cat cct gcc tgt cac gtg agt




Lys Glu Cys Cys Thr His Pro Ala Cys His Val Ser



 



cat cca gaa ctc tgt ggt tgaaaagcga cgtgacgctc



His Pro Glu Leu Cys Gly



 



caggaccctc tgaaccacga cgttcgagca


















TABLE 12





DNA Sequence (SEQ ID NO: 80) and



Protein Sequence (SEQ ID NO: 81) of Bn1.3


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca act




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



gct gtt ctt cca gtc act tta gat cgt gca tct gat



Ala Val Leu Pro Val Thr Leu Asp Arg Ala Ser Asp



 



gga agg aat gca gca gcc aac gcc aaa acg cct cgc



Gly Arg Asn Ala Ala Ala Asn Ala Lys Thr Pro Arg



 



ctg atc gcg cca ttc atc agg gat tat tgc tgt cat



Leu Ile Ala Pro Phe Ile Arg Asp Tyr Cys Cys His



 



aga ggt ccc tgt atg gta tgg tgt ggt tgaagccgct



Arg Gly Pro Cys Met Val Trp Cys Gly



 



gctgctccag gaccctctga accac


















TABLE 13





DNA Sequence (SEQ ID NO: 82) and



Protein Sequence (SEQ ID NO: 83) of Ca1.1


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



act gtg gtt tcc ttc act tca gat cgt gct tct gat



Thr Val Val Ser Phe Thr Ser Asp Arg Ala Ser Asp



 



ggc agg aat gcc gca gcc aac gcg ttt gac ctg atc



Gly Arg Asn Ala Ala Ala Asn Ala Phe Asp Leu Ile



 



gct ctg atc gcc agg caa aat tgc tgt agc att ccc



Ala Leu Ile Ala Arg Gln Asn Cys Cys Ser Ile Pro



 



agc 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) of Ca1.2


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



act gtg gtt tcc ttc act tca gat cgt gcg tct gaa



Thr Val Val Ser Phe Thr Ser Asp Arg Ala Ser Glu



 



ggc agg aat gct gca gcc aag gac aaa gcg tct gac



Gly Arg Asn Ala Ala Ala Lys Asp Lys Ala Ser Asp



 



ctg gtg gct ctg aca gtc agg gga tgc tgt gcc att



Leu Val Ala Leu Thr Val Arg Gly Cys Cys Ala Ile



 



cgt gaa tgt cgc ttg cag aat gca gcg tat tgt ggt



Arg Glu Cys Arg Leu Gln Asn Ala Ala Tyr Cys Gly



 



gga ata tac tgatgctcca ggaccctctg aaccacgacg



Gly Ile Tyr


















TABLE 15





DNA Sequence (SEQ ID NO: 86) and



Protein Sequence (SEQ ID NO: 87) of TIB


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



act gtc gtt tcc ttc cct tca gat att gca act gag



Thr Val Val Ser Phe Pro Ser Asp Ile Ala Thr Glu



 



ggc agg aat gcc gca gcc aaa gcg ttt gac ctg ata



Gly Arg Asn Ala Ala Ala Lys Ala Phe Asp Leu Ile



 



tct tcg atc gtc aag aaa gga tgc tgt tcc cat cct



Ser Ser Ile Val Lys Lys Gly Cys Cys Ser His Pro



 



gcc tgt tcg ggg aat aat cca gaa ttt tgt cgt caa



Ala Cys Ser Gly Asn Asn Pro Glu Phe Cys Arg Gln



 



ggt cgc tgatgctcca ggaccctctg aaccacgacg t



Gly Arg


















TABLE 16





DNA Sequence (SEQ ID NO: 88) and



Protein Sequence (SEQ ID NO: 89) of TIA


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



act gtc gtt tcc ttc cct tca gat ata gca act gag



Thr Val Val Ser Phe Pro Ser Asp Ile Ala Thr Glu



 



ggc agg aat gcc gca gcc aaa gcg ttt gac ctg ata



Gly Arg Asn Ala Ala Ala Lys Ala Phe Asp Leu Ile



 



tct tcg atc gtc agg aaa gga tgc tgt tcc aat ccc



Ser Ser Ile Val Arg Lys Gly Cys Cys Ser Asn Pro



 



gcc tgt gcg ggg aat aat cca cat gtt tgt cgt caa



Ala Cys Ala Gly Asn Asn Pro His Val Cys Arg Gln



 



ggt cgc tgatgctcca ggaccctctg aaccacgacg t



Gly Arg


















TABLE 17





DNA Sequence (SEQ ID NO: 90) and



Protein Sequence (SEQ ID NO: 91) of Sl1.1


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



acc gtc gtt tcc ttc aat tca gat cgt gat cca gca



Thr Val Val Ser Phe Asn Ser Asp Arg Asp Pro Ala



 



tta ggt ggc agg aat gct gca gcc aaa gcg tct gac



Leu Gly Gly Arg Asn Ala Ala Ala Lys Ala Ser Asp



 



aag atc gct tcg acc ctc aag aga aga gga tgc tgt



Lys Ile Ala Ser Thr Leu Lys Arg Arg Gly Cys Cys



 



tcg tat ttt gac tgt aga atg atg ttt cca gaa atg



Ser Tyr Phe Asp Cys Arg Met Met Phe Pro Glu Met



 



tgt ggt tgg cga ggc tgatgctcca ggaccctctg



Cys Gly Trp Arg Gly



 



aaccacgacg t


















TABLE 18





DNA Sequence (SEQ ID NO: 92) and



Protein Sequence (SEQ ID NO: 93) of Sl1.2


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



acc gtc gtt tcc ttc aat tca gat cgt gat cca gca



Thr Val Val Ser Phe Asn Ser Asp Arg Asp Pro Ala



 



tta ggt ggc agg aat gct gca gcc ata gcg tct gac



Leu Gly Gly Arg Asn Ala Ala Ala Ile Ala Ser Asp



 



aag atc gct tcg acc ctc agg aga gga gga tgc tgt



Lys Ile Ala Ser Thr Leu Arg Arg Gly Gly Cys Cys



 



tct ttt cct gcc tgt aga aag tat cgt cca gaa atg



Ser Phe Pro Ala Cys Arg Lys Tyr Arg Pro Glu Met



 



tgt ggt gga cga cgc tgatgctcca ggaccctctg



Cys Gly Gly Arg Arg



 



aaccacgacg t


















TABLE 19





DNA Sequence (SEQ ID NO: 94) and



Protein Sequence (SEQ ID NO: 95) of Sl1.3


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



acc gtc gtt tcc ttc act tca gat cat gaa tct gat



Thr Val Val Ser Phe Thr Ser Asp His Glu Ser Asp



 



cgc ggt gat gcc caa acc atc caa gaa gtg ttt gag



Arg Gly Asp Ala Gln Thr Ile Gln Glu Val Phe Glu



 



atg ttc gct ctg gac agc gat gga tgc tgt tgg cat



Met Phe Ala Leu Asp Ser Asp Gly Cys Cys Trp His



 



cct gct tgt ggc aga cac tat tgt ggt cga aga cgc



Pro Ala Cys Gly Arg His Tyr Cys Gly Arg Arg Arg



 



tgatgctcca ggaccctctg aaccacgacg t


















TABLE 20





DNA Sequence (SEQ ID NO: 96) and



Protein Sequence (SEQ ID NO: 97) of Sl1.6


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



acc gtc gtt tcc ttc aat tca gat cgt gat cca gca



Thr Val Val Ser Phe Asn Ser Asp Arg Asp Pro Ala



 



tta ggt ggc agg aat gct gca gcc ata gcg tct gac



Leu Gly Gly Arg Asn Ala Ala Ala Ile Ala Ser Asp



 



aag atc gct tcg acc ctc agg aga gga gga tgc tgt



Lys Ile Ala Ser Thr Leu Arg Arg Gly Gly Cys Cys



 



tct ttt gct gcc tgt aga aag tat cgt cca gaa atg



Ser Phe Ala Ala Cys Arg Lys Tyr Arg Pro Glu Met



 



tgt ggt gga cga cgc tgatgct



Cys Gly Gly Arg Arg


















TABLE 21





DNA Sequence (SEQ ID NO: 98) and



Protein Sequence (SEQ ID NO: 99) of Sl1.7


















atg ttc acc gtg ttt ctg ttg gtt ctc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Leu Leu Ala Thr



 



acc gtc gtt tcc ttc aat tca gat cgt gca tta ggt



Thr Val Val Ser Phe Asn Ser Asp Arg Ala Leu Gly



 



ggc agg aat gct gca gcc aaa gcg tct gac aag atc



Gly Arg Asn Ala Ala Ala Lys Ala Ser Asp Lys Ile



 



ctt tcg aac ctc agg aga gga gga tgc tgt ttt cat



Leu Ser Asn Leu Arg Arg Gly Gly Cys Cys Phe His



 



cct gtc tgt tac atc aat ctt cta gaa atg tgt cgt



Pro Val Cys Tyr Ile Asn Leu Leu Glu Met Cys Arg



 



caa cga ggc tgatcgtcca ggaccctctg aaccacgacg t



Gln Arg Gly


















TABLE 22





DNA Sequence (SEQ ID NO: 100) and



Protein Sequence (SEQ ID NO: 101) of Cn1.1


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg aca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Thr Thr



 



act gtc gtt tcc ttc cct tca gat agt gca tct gat



Thr Val Val Ser Phe Pro Ser Asp Ser Ala Ser Asp



 



gtc agg gat gac gaa gcc aaa gac gaa agg tct gac



Val Arg Asp Asp Glu Ala Lys Asp Glu Arg Ser Asp



 



atg tac aaa tcg aaa cgg aat gga cgc tgt tgc cat



Met Tyr Lys Ser Lys Arg Asn Gly Arg Cys Cys His



 



cct gcc tgt ggc aaa cac ttt agt tgt gga cgc



Pro Ala Cys Gly Lys His Phe Ser Cys Gly Arg



 



tgatgctcca ggaccctctg aaccacgacg t


















TABLE 23





DNA Sequence (SEQ ID NO: 102) and



Protein Sequence (SEQ ID NO: 103) of SmI


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



act gtc gtt tcc tcc cct tca gat cgt gca tct gat



Thr Val Val Ser Ser Pro Ser Asp Arg Ala Ser Asp



 



ggc agg aat gcc gca gcc aac gag aaa gcg tct gac



Gly Arg Asn Ala Ala Ala Asn Glu Lys Ala Ser Asp



 



gtg atc gcg ctg gcc ctc aag gga tgc tgt tcc aac



Val Ile Ala Leu Ala Leu Lys Gly Cys Cys Ser Asn



 



cct gtc tgt cac ctg gag cat tca aac atg tgt ggt



Pro Val Cys His Leu Glu His Ser Asn Met Cys Gly



 



aga aga cgc tgatgctcca ggaccctctg aaccacgacg



Arg Arg Arg


















TABLE 24





DNA Sequence (SEQ ID NO: 104) and



Protein Sequence (SEQ ID NO: 105) of Bt1.1


















atg ttc tcc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Ser Val Phe Leu Leu Val Val Leu Ala Thr



 



act gtc gtt tcc tcc act tca ggt ggt gca tct ggt



Thr Val Val Ser Ser Thr Ser Gly Gly Ala Ser Gly



 



ggc agg aag gct gca gcc aaa gcg tct aac cgg atc



Gly Arg Lys Ala Ala Ala Lys Ala Ser Asn Arg Ile



 



gct ctg acc gtc agg agt gca aca tgc tgt aat tat



Ala Leu Thr Val Arg Ser Ala Thr Cys Cys Asn Tyr



 



cct ccc tgt tac gag act tat cca gaa agt tgt ctg



Pro Pro Cys Tyr Glu Thr Tyr Pro Glu Ser Cys Leu



 



taacgtgaat catccagagc tttgtggctg aagacactga



 



tgctccagga ccctctgaac cacgacgt


















TABLE 25





DNA Sequence (SEQ ID NO: 106) and



Protein Sequence (SEQ ID NO: 107) of Bt1.2


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



act gtg gtt tcc ttc act tca ggt cgt gca ttt cgt



Thr Val Val Ser Phe Thr Ser Gly Arg Ala Phe Arg



 



ggc agg aat cgc gca gcc gac gac aaa agg tct gac



Gly Arg Asn Arg Ala Ala Asp Asp Lys Arg Ser Asp



 



ctg gcc gct ctg agc gtc agg gga gga tgc tgt tcc



Leu Ala Ala Leu Ser Val Arg Gly Gly Cys Cys Ser



 



cat cct gcc tgt gcg gtg aat cat cca gag ctt tgt



His Pro Ala Cys Ala Val Asn His Pro Glu Leu Cys



 



ggc tgaagacgct gatgccccag gaccctctga accacgacgt



Gly


















TABLE 26





DNA Sequence (SEQ ID NO: 108) and



Protein Sequence (SEQ ID NO: 109) of Bt1.3


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



act gtc gtt tcc ttc act tca ggt cgt gca tct ggt



Thr Val Val Ser Phe Thr Ser Gly Arg Ala Ser Gly



 



ggc agg aat gct gca gcc aaa gcg tct aac cgg atc



Gly Arg Asn Ala Ala Ala Lys Ala Ser Asn Arg Ile



 



gct atg gcc atc agc agt gga gca tgc tgt gca tat



Ala Met Ala Ile Ser Ser Gly Ala Cys Cys Ala Tyr



 



cct ccc tgt ttc gag gct tat cca gaa aga tgt ctg



Pro Pro Cys Phe Glu Ala Tyr Pro Glu Arg Cys Leu



 



taacgtgaat catccagacc tttgtggctg aagacgctga



 



tgccccagga ccctctgaac cacgacgt

















TABLE 27





DNA Sequence (SEQ ID NO: 110) and


Protein Sequence (SEQ ID NO: 111) of Bt1.4
















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc



Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr


 


act gtc gtt tcc ttc act tca gat cgt gca ttt cgt


Thr Val Val Ser Phe Thr Ser Asp Arg Ala Phe Arg


 


ggc agg aat tcc gca gcc aac gac aaa agg tct gac


Gly Arg Asn Ser Ala Ala Asn Asp Lys Arg Ser Asp


 


ctg gcc gct ctg agc gtc agg aga gga tgc tgc tcc


Leu Ala Ala Leu Ser Val Arg Arg Gly Cys Cys Ser


 


cat ccc gcc tgt agc gtg aat cat cca gag ctt tgt


His Pro Ala Cys Ser Val Asn His Pro Glu Leu Cys


 


ggt aga aga cgc tgatgcccca ggaccctctg aaccacgacg t


Gly Arg Arg Arg

















TABLE 28





DNA Sequence (SEQ ID NO: 112) and



Protein Sequence (SEQ ID NO: 113) of Bt1.5


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



act gtc gtt tcc ttc act tca ggt cgt gca tct ggt



Thr Val Val Ser Phe Thr Ser Gly Arg Ala Ser Gly



 



ggc agg aat gct gca gcc aaa gcg tct aac cgg atc



Gly Arg Asn Ala Ala Ala Lys Ala Ser Asn Arg Ile



 



gct ctg atc gtc agg aat gca gaa tgc tgt tat tat



Ala Leu Ile Val Arg Asn Ala Glu Cys Cys Tyr Tyr



 



cct ccc tgt tac gag gct tat cca gaa att tgt ctg



Pro Pro Cys Tyr Glu Ala Tyr Pro Glu Ile Cys Leu



 



taacgtgaat catccagacc tttgtggctg aagaccctga



 



tgctccagga ccctctgaac cacgacgt


















TABLE 29





DNA Sequence (SEQ ID NO: 114) and



Protein Sequence (SEQ ID NO: 115) of Pn1.1


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



acc gtc att tcc ttc act tca gat cgt gca tct gat



Thr Val Ile Ser Phe Thr Ser Asp Arg Ala Ser Asp



 



ggc ggg aat gcc gca gcg tct gac ctg atc gct ctg



Gly Gly Asn Ala Ala Ala Ser Asp Leu Ile Ala Leu



 



acc atc aag gga tgc tgt tct cat cct ccc tgt gcc



Thr Ile Lys Gly Cys Cys Ser His Pro Pro Cys Ala



 



atg aat aat cca gac tat tgt ggt tgacgacgct



Met Asn Asn Pro Asp Tyr Cys Gly



 



gatgctccag gaccctctga accacgacg


















TABLE 30





DNA Sequence (SEQ ID NO: 116) and



Protein Sequence (SEQ ID NO: 117) of Pn1.2


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



acc gtc gtt tcc ttc act tca gat cgt gca tct gat



Thr Val Val Ser Phe Thr Ser Asp Arg Ala Ser Asp



 



ggc ggg aat gcc gca atg tct gac ctg atc gct ctg



Gly Gly Asn Ala Ala Met Ser Asp Leu Ile Ala Leu



 



acc atc aag gga tgc tgt tct cat cct ccc tgt ttc



Thr Ile Lys Gly Cys Cys Ser His Pro Pro Cys Phe



 



ctg aat aat cca gac tat tgt ggt tgacgacgct



Leu Asn Asn Pro Asp Tyr Cys Gly



 



gatgctccag gaccctctga accacgacg


















TABLE 31





DNA Sequence (SEQ ID NO: 118) and



Protein Sequence (SEQ ID NO: 119) of Sm1.3


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



act gtc gtt tcc ttc cct tca gat cgt gaa tct gat



Thr Val Val Ser Phe Pro Ser Asp Arg Glu Ser Asp



 



ggc gcg aat gac gaa gcc cgc acc gac gag cct gag



Gly Ala Asn Asp Glu Ala Arg Thr Asp Glu Pro Glu



 



gag cac gga ccg gac agg aat gga tgc tgt agg aat



Glu His Gly Pro Asp Arg Asn Gly Cys Cys Arg Asn



 



cct gcc tgt gag agc cac aga tgt ggt tgacgacgct



Pro Ala Cys Glu Ser His Arg Cys Gly



 



gatgctccag gaccctctga accacgacg


















TABLE 32





DNA Sequence (SEQ ID NO: 120) and



Protein Sequence (SEQ ID NO: 121) of Cr1.2


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



act gtc gtt tcc ttc cct tca gat cgt gca tct gat



Thr Val Val Ser Phe Pro Ser Asp Arg Ala Ser Asp



 



ggc agg aat gcc gca gcc agc gac aga gcg tct gac



Gly Arg Asn Ala Ala Ala Ser Asp Arg Ala Ser Asp



 



gcg gcc cac cag gga tgc tgt tcc aac cct gtc tgt



Ala Ala His Gln Gly Cys Cys Ser Asn Pro Val Cys



 



cac gtg gaa cat cca gaa ctt tgt cgt aga aga cgc



His Val Glu His Pro Glu Leu Cys Arg Arg Arg Arg



 



tgatgctcca ggaccctctg aaccacgacg


















TABLE 33





DNA Sequence (SEQ ID NO: 122) and



Protein Sequence (SEQ ID NO: 123) of Cr1.3
















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc



Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr


 


act gtc gtt tcc ttc cct tca aat cgt gaa tct gat


Thr Val Val Ser Phe Pro Ser Asn Arg Glu Ser Asp


 


ggc gcg aat gcc gaa gtc cgc acc gac gag cct gag


Gly Ala Asn Ala Glu Val Arg Thr Asp Glu Pro Glu


 


gag cac gac gaa ctg ggc ggg aat gga tgc tgt ggg


Glu His Asp Glu Leu Gly Gly Asn Gly Cys Cys Gly


 


aat cct gac tgt acg agc cac agt tgt gat tgacgacgct


Asn Pro Asp Cys Thr Ser His Ser Cys Asp


 


gatgctccag gaccctctga accacgacg

















TABLE 34





DNA Sequence (SEQ ID NO: 124) and



Protein Sequence (SEQ ID NO: 125) of EpI


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



acc gtc gtt tcc ttc act tca gat cgt gca tct gat



Thr Val Val Ser Phe Thr Ser Asp Arg Ala Ser Asp



 



agc agg aag gac gca gcg tct ggc ctg atc gct ctg



Ser Arg Lys Asp Ala Ala Ser Gly Leu Ile Ala Leu



 



acc atc aag gga tgc tgt tct gat cct cgc tgt aac



Thr Ile Lys Gly Cys Cys Ser Asp Pro Arg Cys Asn



 



atg aat aat cca gac tat tgt ggt tgacgacgct



Met Asn Asn Pro Asp Tyr Cys Gly



 



gatgctccag gaccctctga accacgacg


















TABLE 35





DNA Sequence (SEQ ID NO: 126) and



Protein Sequence (SEQ ID NO: 127) of Sn1.1
















atg tcc acc gtg ttt ctg ttg gtt gtc ctc gca acc



Met Ser Thr Val Phe Leu Leu Val Val Leu Ala Thr


 


acc gtc gtt tcc ttc act gta gat cgt gca tct gat


Thr Val Val Ser Phe Thr Val Asp Arg Ala Ser Asp


 


ggc agg gat gtc gca atc gac gac aga ttg gtg tct


Gly Arg Asp Val Ala Ile Asp Asp Arg Leu Val Ser


 


ctc cct cag atc gcc cat gct gac tgt tgt tcc gat


Leu Pro Gln Ile Ala His Ala Asp Cys Cys Ser Asp


 


cct gcc tgc aag cag acg ccc ggt tgt cgt taaagacgct


Pro Ala Cys Lys Gln Thr Pro Gly Cys Arg


 


gctgctccag gaccctctga accacgacg
















TABLE 36





DNA Sequence (SEQ ID NO: 128) and


Protein Sequence (SEQ ID NO: 129) of Sn1.2


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



acc gtc gct tcc ttc att atc gat gat cca tct gat



Thr Val Ala Ser Phe Ile Ile Asp Asp Pro Ser Asp



 



ggc agg aat att gca gtc gac gac aga ggg ctt ttc



Gly Arg Asn Ile Ala Val Asp Asp Arg Gly Leu Phe



 



tct acg ctc ttc cat gct gat tgc tgt gaa aat cct



Ser Thr Leu Phe His Ala Asp Cys Cys Glu Asn Pro



 



gcc tgt aga cac acg cag ggt tgt tgatctttgt



Ala Cys Arg His Thr Gln Gly Cys



 



tcttcaaaga cactgctggc ccaggaccct ctgaaccacg acg


















TABLE 37





DNA Sequence (SEQ ID NO: 130) and



Protein Sequence (SEQ ID NO: 131) of Da1.1


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



acc gtc gtt tcc ttc act tca gat cgt gca ttt cgt



Thr Val Val Ser Phe Thr Ser Asp Arg Ala Phe Arg



 



ggc agg aat gcc gca gcc aaa gag tct ggc ctg gtc



Gly Arg Asn Ala Ala Ala Lys Glu Ser Gly Leu Val



 



ggt ctg acc gac aag acg cga gga tgc tgt tct cat



Gly Leu Thr Asp Lys Thr Arg Gly Cys Cys Ser His



 



cct gcc tgt aac gta gat cat cca gaa att tgt ggt



Pro Ala Cys Asn Val Asp His Pro Glu Ile Cys Gly



 



tgaagacgct gatgctccag gaccctctga accacgacgt


















TABLE 38





DNA Sequence (SEQ ID NO: 132) and



Protein Sequence (SEQ ID NO: 133) of Da1.2


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



acc gtc gtt tcc ttc act tca gat ggt gca tct gat



Thr Val Val Ser Phe Thr Ser Asp Gly Ala Ser Asp



 



gac agg aaa gcc gct gcg tct gac ctg atc act ctg



Asp Arg Lys Ala Ala Ala Ser Asp Leu Ile Thr Leu



 



acc atc aag gga tgc tgt tct cgt cct ccc tgt atc



Thr Ile Lys Gly Cys Cys Ser Arg Pro Pro Cys Ile



 



gcg aat aat cca gac ttg tgt ggt cga cga cgc



Ala Asn Asn Pro Asp Leu Cys Gly Arg Arg Arg



 



tgatgctcca ggaccctctg


















TABLE 39





DNA Sequence (SEQ ID NO: 134) and



Protein Sequence (SEQ ID NO: 135) of Da1.3
















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc



Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr


 


act gtc gtt tcc tcc act tca ggt cgt cgt gca ttt


Thr Val Val Ser Ser Thr Ser Gly Arg Arg Ala Phe


 


cat ggc agg aat gcc gca gcc aaa gcg tct gga ctg


His Gly Arg Asn Ala Ala Ala Lys Ala Ser Gly Leu


 


gtc ggt ctg act gac agg aga cca caa tgc tgt agt


Val Gly Leu Thr Asp Arg Arg Pro Gln Cys Cys Ser


 


gat cct cgc tgt aac gta ggt cat cca gaa ctt tgt


Asp Pro Arg Cys Asn Val Gly His Pro Glu Leu Cys


 


ggt gga aga cgc tgatgctcca ggaccctctg aaccacaacg t


Gly Gly Arg Arg

















TABLE 40





DNA Sequence (SEQ ID NO: 136) and



Protein Sequence (SEQ ID NO: 137) of Da1.4


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



act gtc gtt tcc tcc act tca ggt cgt gca ttt cat



Thr Val Val Ser Ser Thr Ser Gly Arg Ala Phe His



 



ggc agg aat gcc gca gcc aaa gcg tct ggc ctg gtc



Gly Arg Asn Ala Ala Ala Lys Ala Ser Gly Leu Val



 



ggt ctg acc gac aag agg caa gta tgc tgt agt gat



Gly Leu Thr Asp Lys Arg Gln Val Cys Cys Ser Asp



 



cct cgc tgt aac gta ggt cat cca gaa att tgt ggt



Pro Arg Cys Asn Val Gly His Pro Glu Ile Cys Gly



 



gga aga cgc tgatgctcca ggaccctctg aaccacgacg t



Gly Arg Arg


















TABLE 41





DNA Sequence (SEQ ID NO: 138) and



Protein Sequence (SEQ ID NO: 139) of A1.2


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg aca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Thr Thr



 



act gtc gtt tcc ttc cct tca gat agt gca tct ggt



Thr Val Val Ser Phe Pro Ser Asp Ser Ala Ser Gly



 



ggc agg gat gac gag gcc aaa gac gaa agg tct gac



Gly Arg Asp Asp Glu Ala Lys Asp Glu Arg Ser Asp



 



atg tac gaa ttg aaa cgg aat gga cgc tgt tgc cat



Met Tyr Glu Leu Lys Arg Asn Gly Arg Cys Cys His



 



cct gcc tgt ggt ggc aaa tac gtt aaa tgt gga cgc



Pro Ala Cys Gly Gly Lys Tyr Val Lys Cys Gly Arg



 



tgatgctcca ggaccctctc gaaccacg


















TABLE 42





DNA Sequence (SEQ ID NO: 140) and



Protein Sequence (SEQ ID NO: 141) of Bu1.1
















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc



Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr


 


act gtc gtt tcc ttc tct aca gat gat gaa tct gat


Thr Val Val Ser Phe Ser Thr Asp Asp Glu Ser Asp


 


ggc tcg aat gaa gaa ccc agc gcc gac cag act gcc


Gly Ser Asn Glu Glu Pro Ser Ala Asp Gln Thr Ala


 


agg tcc tca atg aac agg gcg cct gga tgc tgt aac


Arg Ser Ser Met Asn Arg Ala Pro Gly Cys Cys Asn


 


aat cct gcc tgt gtg aag cac aga tgt gga tgacgctgat


Asn Pro Ala Cys Val Lys His Arg Cys Gly


 


gctccaggac cctctgaacc acgacgt

















TABLE 43





DNA Sequence (SEQ ID NO: 142) and



Protein Sequence (SEQ ID NO: 143) of Bu1.2


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



act gtc gtt tcc ttc tct aca gat gat gaa tct gat



Thr Val Val Ser Phe Ser Thr Asp Asp Glu Ser Asp



 



ggc tcg aat gaa gaa ccc agc gcc gac cag gct gcc



Gly Ser Asn Glu Glu Pro Ser Ala Asp Gln Ala Ala



 



agg tcc gca atg aac agg ccg cct gga tgc tgt aac



Arg Ser Ala Met Asn Arg Pro Pro Gly Cys Cys Asn



 



aat cct gcc tgt gtg aag cac aga tgt ggt gga



Asn Pro Ala Cys Val Lys His Arg Cys Gly Gly



 



tgacgctgat gctccaggac cctctgaacc acgacgt


















TABLE 44





DNA Sequence (SEQ ID NO: 144) and



Protein Sequence (SEQ ID NO: 145) of Bu1.3


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



act gtc gtt tcc ttc cct tca gat cgt gac tct gat



Thr Val Val Ser Phe Pro Ser Asp Arg Asp Ser Asp



 



ggc gcg gat gcc gaa gcc agt gac gag cct gtt gag



Gly Ala Asp Ala Glu Ala Ser Asp Glu Pro Val Glu



 



ttc gaa agg gac gag aat gga tgc tgt tgg aat cct



Phe Glu Arg Asp Glu Asn Gly Cys Cys Trp Asn Pro



 



tcc tgt ccg agg ccc aga tgt aca gga cga cgc



Ser Cys Pro Arg Pro Arg Cys Thr Gly Arg Arg



 



taatgctcca ggaccctctg aaccacgacg t


















TABLE 45





DNA Sequence (SEQ ID NO: 146) and



Protein Sequence (SEQ ID NO: 170) of Bu1.4


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg aca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Thr Thr



 



act gtc gtt tcc ttc cct tca gat cgt gca tct gat



Thr Val Val Ser Phe Pro Ser Asp Arg Ala Ser Asp



 



ggc agg aat gcc gca gcc aac gac aaa gcg tct gac



Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala Ser Asp



 



gtg gtc acg ctg gtc ctc aag gga tgc tgt tcc acc



Val Val Thr Leu Val Leu Lys Gly Cys Cys Ser Thr



 



cct ccc tgt gct gtg ctg tat tgt ggt aga aga cgc



Pro Pro Cys Ala Val Leu Tyr Cys Gly Arg Arg Arg



 



tgatgctcca ggaccctctg aaccacgacg t


















TABLE 46





DNA Sequence (SEQ ID NO: 148) and



Protein Sequence (SEQ ID NO: 149) of Di1.1


















atg ttc acc gtg ttt ctg ttg gtt gtc ttc gca tcc




Met Phe Thr Val Phe Leu Leu Val Val Phe Ala Ser



 



tct gtc acc tta gat cgt gca tct tat ggc agg tat



Ser Val Thr Leu Asp Arg Ala Ser Tyr Gly Arg Tyr



 



gcc tca ccc gtc gac aga gcg tct gcc ctg atc gct



Ala Ser Pro Val Asp Arg Ala Ser Ala Leu Ile Ala



 



cag gcc atc ctt cga gat tgc tgc tcc aat cct cct



Gln Ala Ile Leu Arg Asp Cys Cys Ser Asn Pro Pro



 



tgt gcc cat aat aat cca gac tgt cgt taaagacgct



Cys Ala His Asn Asn Pro Asp Cys Arg



 



gcttgctcca ggaccctctg aaccacgacg t


















TABLE 47





DNA Sequence (SEQ ID NO: 150) and



Protein Sequence (SEQ ID NO: 151) of T1


















gga tgc tgt tct aat cct ccc tgt atc gcg aag aat




Gly Cys Cys Ser Asn Pro Pro Cys Ile Ala Lys Asn



 



cca cac atg tgt ggt gga aga cgc tga



Pro His Met Cys Gly Gly Arg Arg


















TABLE 48





DNA Sequence (SEQ ID NO: 152) and



Protein Sequence (SEQ ID NO: 153) of Cn1.2


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



act gtc gtt tcc ttc cct tca gat cgt gca tct gat



Thr Val Val Ser Phe Pro Ser Asp Arg Ala Ser Asp



 



ggc agg aat gcc gca gcc aac gac aaa gcg tct gac



Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala Ser Asp



 



gtg atc acg ctg gcc ctc aag gga tgc tgt tcc aac



Val Ile Thr Leu Ala Leu Lys Gly Cys Cys Ser Asn



 



cct gtc tgt cac ttg gag cat tca aac ctt tgt ggt



Pro Val Cys His Leu Glu His Ser Asn Leu Cys Gly



 



aga aga cgc tgatgctcca ggaccctctg aaccacgacg t



Arg Arg Arg


















TABLE 49





DNA Sequence (SEQ ID NO: 233) and



Protein Sequence (SEQ ID NO: 234) of Im1.1


















tct gat gga aag agt gcc gcg gcc aaa gcc aaa ccg




Ser Asp Gly Lys Ser Ala Ala Ala Lys Ala Lys Pro



 



tct cac ctg acg gct cca ttc atc agg gac gaa tgc



Ser His Leu Thr Ala Pro Phe Ile Arg Asp Glu Cys



 



tgt tcc gat tct cgc tgt ggc aag aac tgt ctt tga



Cys Ser Asp Ser Arg Cys Gly Lys Asn Cys Leu


















TABLE 50





DNA Sequence (SEQ ID NO: 235) and



Protein Sequence (SEQ ID NO: 236) of Im1.2


















ttt gat gga agg aat gcc cca gcc gac gac aaa gcg




Phe Asp Gly Arg Asn Ala Pro Ala Asp Asp Lys Ala



 



tct gac ctg atc gct caa atc gtc agg aga gca tgc



Ser Asp Leu Ile Ala Gln Ile Val Arg Arg Ala Cys



 



tgt tcc gat cgt cgc tgt aga tgg agg tgt ggt tga



Cys Ser Asp Arg Arg Cys Arg Trp Arg Cys Gly


















TABLE 51





DNA Sequence (SEQ ID NO: 237) and



Protein Sequence (SEQ ID NO: 238) of Rg1.2


















tct gat gga agg aat gcc gca gcc gac gcc aga gcg




Ser Asp Gly Arg Asn Ala Ala Ala Asp Ala Arg Ala



 



tct ccc cgg atc gct ctt ttc ctc agg ttc aca tgc



Ser Pro Arg Ile Ala Leu Phe Leu Arg Phe Thr Cys



 



tgt agg aga ggt acc tgt tcc cag cac tgt ggt



Cys Arg Arg Gly Thr Cys Ser Gln His Cys Gly



 



tgaagacact gctgctccag gaccctctga accacgacgt


















TABLE 52





DNA Sequence (SEQ ID NO: 239) and



Protein Sequence (SEQ ID NO: 240) of Rg1.6


















tct aat gga agg aat gcc gca gcc gac gcc aaa gcg




Ser Asn Gly Arg Asn Ala Ala Ala Asp Ala Lys Ala



 



tct caa cgg atc gct cca ttc ctc agg gac tat tgc



Ser Gln Arg Ile Ala Pro Phe Leu Arg Asp Tyr Cys



 



tgt agg aga cat gcc tgt acg ttg att tgt ggt



Cys Arg Arg His Ala Cys Thr Leu Ile Cys Gly



 



tgaagacgct gctgctccag gaccctctga accacgacgt


















TABLE 53





DNA Sequence (SEQ ID NO: 241) and



Protein Sequence (SEQ ID NO: 242) of Rg1.6A


















tct aat gga agg aat gcc gca gcc gac gcc aaa gcg




Ser Asn Gly Arg Asn Ala Ala Ala Asp Ala Lys Ala



 



tct caa cgg atc gct cca ttc ctc agg gac tat tgc



Ser Gln Arg Ile Ala Pro Phe Leu Arg Asp Tyr Cys



 



tgt agg aga cct ccc tgt acg ttg att tgt ggt



Cys Arg Arg Pro Pro Cys Thr Leu Ile Cys Gly



 



tgaagacgct gctgctccag gaccctctga accacgacgt


















TABLE 54





DNA Sequence (SEQ ID NO: 243) and



Protein Sequence (SEQ ID NO: 244) of Rg1.7
















tct aat aaa agg aag aat gcc gca atg ctt gac atg



Ser Asn Lys Arg Lys Asn Ala Ala Met Leu Asp Met


 


atc gct caa cac gcc ata agg ggt tgc tgt tcc gat


Ile Ala Gln His Ala Ile Arg Gly Cys Cys Ser Asp


 


cct cgc tgt aga tat aga tgt cgt tgaagacgct


Pro Arg Cys Arg Tyr Arg Cys Arg


 


gctgctccag gaccctctga accacgacgt

















TABLE 55





DNA Sequence (SEQ ID NO: 245) and



Protein Sequence (SEQ ID NO: 246) of Rg1.9


















ttt aat gga agg agt gcc gca gcc gac caa aat gcg




Phe Asn Gly Arg Ser Ala Ala Ala Asp Gln Asn Ala



 



cct ggc ctg atc gct caa gtc gtc aga gga ggg tgc



Pro Gly Leu Ile Ala Gln Val Val Arg Gly Gly Cys



 



tgt tcc gat ccc cgc tgc gcc tgg aga tgt ggt



Cys Ser Asp Pro Arg Cys Ala Trp Arg Cys Gly



 



tgaagacgtt gctgctccag gaccctctga accacgacgt


















TABLE 56





DNA Sequence (SEQ ID NO: 247) and



Protein Sequence (SEQ ID NO: 248) of Rg1.10


















ttt gat gga agg aat gcc gca gcc gac gcc aaa gtg




Phe Asp Gly Arg Asn Ala Ala Ala Asp Ala Lys Val



 



att aac acg gtc gct cga atc gcc tgg gat ata tgc



Ile Asn Thr Val Ala Arg Ile Ala Trp Asp Ile Cys



 



tgt tcc gaa cct gac tgt aac cat aaa tgt gtt



Cys Ser Glu Pro Asp Cys Asn His Lys Cys Val



 



tgaagacgct tctgctccag gaccctctga accacgacgt


















TABLE 57





DNA Sequence (SEQ ID NO: 249) and



Protein Sequence (SEQ ID NO: 250) of Rg1.11


















tct aat aaa agg aag aat gcc gca atg ctt gac atg




Ser Asn Lys Arg Lys Asn Ala Ala Met Leu Asp Met



 



atc gct caa cac gcc ata agg ggt tgc tgt tcc gat



Ile Ala Gln His Ala Ile Arg Gly Cys Cys Ser Asp



 



cct cgc tgt aaa cat cag tgt ggt tgaagacgct



Pro Arg Cys Lys His Gln Cys Gly



 



gctgctccag gaccctctga accacgacgt


















TABLE 58





DNA Sequence (SEQ ID NO: 251) and



Protein Sequence (SEQ ID NO: 252) of Ms1.7


















atc aag aat aca gca gcc agc aac aaa gcg tct agc




Ile Lys Asn Thr Ala Ala Ser Asn Lys Ala Ser Ser



 



ctg gtg gct ctt gtt gtc agg gga tgc tgt tac aat



Leu Val Ala Leu Val Val Arg Gly Cys Cys Tyr Asn



 



cct gtc tgc aag aaa tat tat tgt tgg aaa ggc



Pro Val Cys Lys Lys Tyr Tyr Cys Trp Lys Gly



 



tgatgctcca ggaccctctg aaccacgacg t


















TABLE 59





DNA Sequence (SEQ ID NO: 253) and



Protein Sequence (SEQ ID NO: 254) of P1.7


















tct gaa ggc agg aat gct gaa gcc atc gac aac gcc




Ser Glu Gly Arg Asn Ala Glu Ala Ile Asp Asn Ala



 



tta gac cag agg gat cca aag cga cag gag ccg ggg



Leu Asp Gln Arg Asp Pro Lys Arg Gln Glu Pro Gly



 



tgc tgt agg cat cct gcc tgt ggg aag aac aga tgt



Cys Cys Arg His Pro Ala Cys Gly Lys Asn Arg Cys



 



gga aga cgc tgatgctcca ggaccctctg aaccacgacg t



Gly Arg Arg


















TABLE 60





DNA Sequence (SEQ ID NO: 255) and



Protein Sequence (SEQ ID NO: 256) of Ms1.2
















tct gat ggc agg aat att gca gtc gac gac aga tgg



Ser Asp Gly Arg Asn Ile Ala Val Asp Asp Arg Trp


 


tct ttc tat acg ctc ttc cat gct act tgc tgt gcc


Ser Phe Tyr Thr Leu Phe His Ala Thr Cys Cys Ala


 


gat cct gac tgt aga ttc cgg ccc ggt tgt tgatctttgt


Asp Pro Asp Cys Arg Phe Arg Pro Gly Cys


 


tcttcaaaga cgctgctggc ccaggaccct ctgaaccacg acgt

















TABLE 61





DNA Sequence (SEQ ID NO: 257) and



Protein Sequence (SEQ ID NO: 258) of Ms1.3
















atc aag aat act gca gcc agc aac aaa gcg cct agc



Ile Lys Asn Thr Ala Ala Ser Asn Lys Ala Pro Ser


 


ctg gtg gct att gcc gtc agg gga tgc tgt tac aat


Leu Val Ala Ile Ala Val Arg Gly Cys Cys Tyr Asn


 


cct tcc tgt tgg ccg aaa aca tat tgt agt tggaaaggct


Pro Ser Cys Trp Pro Lys Thr Tyr Cys Ser


 


gatgctccag gaccctctga accacgacgt

















TABLE 62





DNA Sequence (SEQ ID NO: 259) and



Protein Sequence (SEQ ID NO: 260) of Ms1.4


















tct gat agc agg aat gtc gca atc gag gac aga gtg




Ser Asp Ser Arg Asn Val Ala Ile Glu Asp Arg Val



 



tct gac ctg cac tct atg ttc ttc gat gtt tct tgc



Ser Asp Leu His Ser Met Phe Phe Asp Val Ser Cys



 



tgt agc aat cct acc tgt aaa gaa acg tat ggt tgt



Cys Ser Asn Pro Thr Cys Lys Glu Thr Tyr Gly Cys



 



tgatcgttgg ttttgaagac gctgatgctc caggaccctc


















TABLE 63







DNA Sequence (SEQ ID NO: 261) and



Protein Sequence (SEQ ID NO: 262) of Ms1.5











tct gtt ggc agg aat att gca gtc gac gac aga ggg



Ser Val Gly Arg Asn Ile Ala Val Asp Asp Arg Gly


 


att ttc tct acg ctc ttc cat gct cat tgc tgt gcc


Ile Phe Ser Thr Leu Phe His Ala His Cys Cys Ala


 


aat ccc atc tgt aaa aac acg ccc ggt tgt tgatctttgt


Asn Pro Ile Cys Lys Asn Thr Pro Gly Cys


 


tcttcaaaga cgctgctggc ccaggaccct ctgaaccacg acgt

















TABLE 64





DNA Sequence (SEQ ID NO: 263) and



Protein Sequence (SEQ ID NO: 264) of Ms1.8


















tcc gat ggc agg aat gtc gca atc gac gac aga gtg




Ser Asp Gly Arg Asn Val Ala Ile Asp Asp Arg Val



 



tct gac ctg cac tct atg ttc ttc gat att gct tgc



Ser Asp Leu His Ser Met Phe Phe Asp Ile Ala Cys



 



tgt aac aat cct acc tgt aaa gaa acg tat ggt tgt



Cys Asn Asn Pro Thr Cys Lys Glu Thr Tyr Gly Cys



 



tgatcgttgg ttttgaagac gctgatgctc caggaccctc



 



tgaaccacga cgt


















TABLE 65





DNA Sequence (SEQ ID NO: 265) and



Protein Sequence (SEQ ID NO: 266) of Ms1.9


















tct gat ggc agg aat gtc gca atc gag gac aga gtg




Ser Asp Gly Arg Asn Val Ala Ile Glu Asp Arg Val



 



tct gac ctg ctc tct atg ctc ttc gat gtt gct tgc



Ser Asp Leu Leu Ser Met Leu Phe Asp Val Ala Cys



 



tgt agc aat cct gtc tgt aaa gaa acg tat ggt tgt



Cys Ser Asn Pro Val Cys Lys Glu Thr Tyr Gly Cys



 



tgatcgttgg ttttgaagac gctgatgctc caggaccctc



 



tgaaccacga cgt


















TABLE 66





DNA Sequence (SEQ ID NO: 267) and



Protein Sequence (SEQ ID NO: 268) of Bt1.7


















tat gat ggc agg aat gct gcc gcc gac gac aaa gct




Tyr Asp Gly Arg Asn Ala Ala Ala Asp Asp Lys Ala



 



ttt gac ctg ctg gct atg acc ata agg gga gga tgc



Phe Asp Leu Leu Ala Met Thr Ile Arg Gly Gly Cys



 



tgt tcc tat cct ccc tgt atc gcg agt aat cct aaa



Cys Ser Tyr Pro Pro Cys Ile Ala Ser Asn Pro Lys



 



tgt ggt gga aga cgc tgatgctcca ggaccctctg



Cys Gly Gly Arg Arg



 



aaccacaacg t


















TABLE 67





DNA Sequence (SEQ ID NO: 269) and



Protein Sequence (SEQ ID NO: 270) of Lv1.5


















ttt gat ggc agg aat gct gca ggc aac gcc aaa atg




Phe Asp Gly Arg Asn Ala Ala Gly Asn Ala Lys Met



 



tcc gcc ctg atg gcc ctg acc atc agg gga tgc tgt



Ser Ala Leu Met Ala Leu Thr Ile Arg Gly Cys Cys



 



tcc cat cct gtc tgt agc gcg atg agt cca atc tgt



Ser His Pro Val Cys Ser Ala Met Ser Pro Ile Cys



 



ggc tgaagacgct gatgccccag gaccctctga accacgacgt



Gly


















TABLE 68





DNA Sequence (SEQ ID NO: 271) and



Protein Sequence (SEQ ID NO: 272) of Ms1.10
















atc aag aat gct gca gct gac gac aaa gca tct gac



Ile Lys Asn Ala Ala Ala Asp Asp Lys Ala Ser Asp


 


ctg ctc tct cag atc gtc agg aat gct gca tcc aat


Leu Leu Ser Gln Ile Val Arg Asn Ala Ala Ser Asn


 


gac aaa ggg tct gac ctg atg act ctt gcc ctc agg


Asp Lys Gly Ser Asp Leu Met Thr Leu Ala Leu Arg


 


gga tgc tgt aaa aat cct tac tgt ggt gcg tcg aaa


Gly Cys Cys Lys Asn Pro Tyr Cys Gly Ala Ser Lys


 


aca tat tgt ggt aga aga cgc tgatgctcca ggaccctctg


Thr Tyr Cys Gly Arg Arg Arg


 


aaccacgacg t

















TABLE 69





DNA Sequence (SEQ ID NO: 273) and



Protein Sequence (SEQ ID NO: 274) of Om1.1
















tctgatggca ggaatgccgc agcgtctgac ctgatggat ctg acc



                                           Leu Thr


 


atc aag gga tgc tgt tct tat cct ccc tgt ttc gcg


Ile Lys Gly Cys Cys Ser Tyr Pro Pro Cys Phe Ala


 


act aat cca gac tgt ggt cga cga cgc tgatgctcca


Thr Asn Pro Asp Cys Gly Arg Arg Arg


 


ggaccctctg aaccacgacg t

















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




Phe Asp Gly Arg Asn Ala Ala Ala Asp Tyr Lys Gly



 



tct gaa ttg ctc gct atg acc gtc agg gga gga tgc



Ser Glu Leu Leu Ala Met Thr Val Arg Gly Gly Cys



 



tgt tcc tat cct ccc tgt atc gca aat aat cct ctt



Cys Ser Tyr Pro Pro Cys Ile Ala Asn Asn Pro Leu



 



tgt gct gga aga cgc tga



Cys Ala Gly Arg Arg


















TABLE 71





DNA Sequence (SEQ ID NO: 277) and



Protein Sequence (SEQ ID NO: 278) of R1.7


















ttt gat ggc agg aat gcc gca gcc gac tac aaa ggg




Phe Asp Gly Arg Asn Ala Ala Ala Asp Tyr Lys Gly



 



tct gaa ttg ctc gct atg acc gtc agg gga gga tgc



Ser Glu Leu Leu Ala Met Thr Val Arg Gly Gly Cys



 



tgt tcc tat cct ccc tgt atc gca aat aat cct ttt



Cys Ser Tyr Pro Pro Cys Ile Ala Asn Asn Pro Phe



 



tgt gct gga aga cgc tga



Cys Ala Gly Arg Arg


















TABLE 72





DNA Sequence (SEQ ID NO: 279) and



Protein Sequence (SEQ ID NO: 280) of Vr1.1


















tct tat gac agg tat gcc tcg ccc gtc gac aga gcg




Ser Tyr Asp Arg Tyr Ala Ser Pro Val Asp Arg Ala



 



tct gcc ctg atc gct cag gcc atc ctt cga gat tgc



Ser Ala Leu Ile Ala Gln Ala Ile Leu Arg Asp Cys



 



tgt tcc aat cct cct tgt tcc caa aat aat cca gac



Cys Ser Asn Pro Pro Cys Ser Gln Asn Asn Pro Asp



 



tgt atg taaagacgct gcttgctcca ggaccctctg



Cys Met



 



aaccacgacg t


















TABLE 73





DNA Sequence (SEQ ID NO: 281) and



Protein Sequence (SEQ ID NO: 282) of Vr1.2


















tct tat ggc agg tat gcc tca ccc gtc gac aga gcg




Ser Tyr Gly Arg Tyr Ala Ser Pro Val Asp Arg Ala



 



tct gcc ctg atc gct cag gcc atc ctt cga gat tgc



Ser Ala Leu Ile Ala Gln Ala Ile Leu Arg Asp Cys



 



tgc tcc aat cct cct tgt gcc cat aat aat cca gac



Cys Ser Asn Pro Pro Cys Ala His Asn Asn Pro Asp



 



tgt cgt taaagacgct gcttgctcca ggaccctctg



Cys Arg



 



aaccacgacg t


















TABLE 74





DNA Sequence (SEQ ID NO: 283) and



Protein Sequence (SEQ ID NO: 284) of A1.4


















tct gat ggc agg aat gcc gca gcc aac gac aaa gcg




Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala



 



tct ggc atg agc gcg ctg gcc gtc aat gaa tgc tgt



Ser Gly Met Ser Ala Leu Ala Val Asn Glu Cys Cys



 



acc aac cct gtc tgt cac gcg gaa cat caa gaa ctt



Thr Asn Pro Val Cys His Ala Glu His Gln Glu Leu



 



tgt gct aga aga cgc tga



Cys Ala Arg Arg Arg


















TABLE 75





DNA Sequence (SEQ ID NO: 285) and



Protein Sequence (SEQ ID NO: 286) of A1.5


















tct gat ggc agg aat gcc gca gcc aac gac aaa gcg




Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala



 



tct gac gtg atc acg ctg gcc ctc aag gga tgc tgt



Ser Asp Val Ile Thr Leu Ala Leu Lys Gly Cys Cys



 



tcc aac cct gtc tgt cac ttg gag cat tca aac ctt



Ser Asn Pro Val Cys His Leu Glu His Ser Asn Leu



 



tgt ggt aga aga cgc tga



Cys Gly Arg Arg Arg


















TABLE 76





DNA Sequence (SEQ ID NO: 287) and



Protein Sequence (SEQ ID NO: 288) of A1.6


















tct gat ggc agg aat gcc gca gcc aac gac aaa gcg




Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala



 



tct ggc atg agc gcg ctg gcc gtc aat gaa tgc tgt



Ser Gly Met Ser Ala Leu Ala Val Asn Glu Cys Cys



 



acc aac cct gtc tgt cac gtg gaa cat caa gaa ctt



Thr Asn Pro Val Cys His Val Glu His Gln Glu Leu



 



tgt gct aga aga cgc tga



Cys Ala Arg Arg Arg


















TABLE 77





DNA Sequence (SEQ ID NO: 289) and



Protein Sequence (SEQ ID NO: 290) of Af1.1


















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc




Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr



 



acc gtc gtt tcc ttc act tca gat cgt gca ttt cgt



Thr Val Val Ser Phe Thr Ser Asp Arg Ala Phe Arg



 



ggc agg aat gcc gca gcc aaa gcg tct ggc ctg gtc



Gly Arg Asn Ala Ala Ala Lys Ala Ser Gly Leu Val



 



ggt ctg acc gac aag agg caa gaa tgc tgt tct tat



Gly Leu Thr Asp Lys Arg Gln Glu Cys Cys Ser Tyr



 



cct gcc tgt aac cta gat cat cca gaa ctt tgt ggt



Pro Ala Cys Asn Leu Asp His Pro Glu Leu Cys Gly



 



tgaagacgct gatgctccag gaccctctga accacgacgt

















TABLE 78





DNA Sequence (SEQ ID NO: 291) and


Protein Sequence (SEQ ID NO: 292) of Af1.2
















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc



Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr


 


act gtc gtt tcc tcc act tca ggt cgt cgt gca ttt


Thr Val Val Ser Ser Thr Ser Gly Arg Arg Ala Phe


 


cgt ggc agg aat gcc gca gcc aaa gcg tct gga ctg


Arg Gly Arg Asn Ala Ala Ala Lys Ala Ser Gly Leu


 


gtc ggt ctg act gac agg aga cca gaa tgc tgt agt


Val Gly Leu Thr Asp Arg Arg Pro Glu Cys Cys Ser


 


gat cct cgc tgt aac tcg act cat cca gaa ctt tgt


Asp Pro Arg Cys Asn Ser Thr His Pro Glu Leu Cys


 


ggt gga aga cgc tgatgctcca ggaccctctg aaccacgacg t


Gly Gly Arg Arg

















TABLE 79





DNA Sequence (SEQ ID NO: 293) and



Protein Sequence (SEQ ID NO: 294) of Ar1.2
















tct gat ggc agg aat gcc gca gcc aac gcg ttt gac



Ser Asp Gly Arg Asn Ala Ala Ala Asn Ala Phe Asp


 


ctg atc gat ctg acc gcc agg cta aat tgc tgt atg


Leu Ile Asp Leu Thr Ala Arg Leu Asn Cys Cys Met


 


att ccc ccc tgt tgg aag aaa tat gga gac aga tgt


Ile Pro Pro Cys Trp Lys Lys Tyr Gly Asp Arg Cys


 


agt gaa gta cgc tgatgctcca ggaccctctg aaccacgacg t


Ser Glu Val Arg

















TABLE 80





DNA Sequence (SEQ ID NO: 295) and



Protein Sequence (SEQ ID NO: 296) of Ar1.3
















tct gat ggc agg aat gcc gca cgc aaa gcg ttt ggc



Ser Asp Gly Arg Asn Ala Ala Arg Lys Ala Phe Gly


 


tgc tgc gac tta ata ccc tgt ttg gag aga tat ggt


Cys Cys Asp Leu Ile Pro Cys Leu Glu Arg Tyr Gly


 


aac aga tgt aat gaa gtg cac tgatgctcca ggaccctctg


Asn Arg Cys Asn Glu Val His


 


aaccacgcga cgt

















TABLE 81





DNA Sequence (SEQ ID NO: 297) and



Protein Sequence (SEQ ID NO: 298) of Ar1.4
















tct gat ggc agc aat gcc gca gcc aac gag ttt gac



Ser Asp Gly Ser Asn Ala Ala Ala Asn Glu Phe Asp


 


ctg atc gct ctg acc gcc agg cta ggt tgc tgt aac


Leu Ile Ala Leu Thr Ala Arg Leu Gly Cys Cys Asn


 


gtt aca ccc tgt tgg gag aaa tat gga gac aaa tgt


Val Thr Pro Cys Trp Glu Lys Tyr Gly Asp Lys Cys


 


aat gaa gta cgc tgatgcttca ggaccctctg aaccacgacg T


Asn Glu Val Arg

















TABLE 82





DNA Sequence (SEQ ID NO: 299) and



Protein Sequence (SEQ ID NO: 300) of Ar1.5


















tct gat ggc agg aat gtc gca gca aaa gcg ttt cac




Ser Asp Gly Arg Asn Val Ala Ala Lys Ala Phe His



 



cgg atc ggc cgg acc atc agg gat gaa tgc tgt tcc



Arg Ile Gly Arg Thr Ile Arg Asp Glu Cys Cys Ser



 



aat cct gcc tgt agg gtg aat aat cca cac gtt tgt



Asn Pro Ala Cys Arg Val Asn Asn Pro His Val Cys



 



aga cga cgc tgatgctcca ggaccctctg aaccacgacg t



Arg Arg Arg


















TABLE 83





DNA Sequence (SEQ ID NO: 301) and



Protein Sequence (SEQ ID NO: 302) of Ar1.6
















tct gat ggc agg aat gcc gca gcc aac gcg ttt gac



Ser Asp Gly Arg Asn Ala Ala Ala Asn Ala Phe Asp


 


ctg atg cct ctg acc gcc agg cta aat tgc tgt agc


Leu Met Pro Leu Thr Ala Arg Leu Asn Cys Cys Ser


 


att ccc ggc tgt tgg aac gaa tat aaa gac aga tgt


Ile Pro Gly Cys Trp Asn Glu Tyr Lys Asp Arg Cys


 


agt aaa gta cgc tgatgctcca ggaccctctg aaccacgacg T


Ser Lys Val Arg
















TABLE 84





DNA Sequence (SEQ ID NO:303) and Protein Sequence


(SEQ ID NO:304) of Ay1.2















tctgatggca ggaatgccgc agccgacgac aaagcgtctg


 


acctggtcgc t ctg gtc gtc agg gga gga tgc tgt tcc


             Leu Val Val Arg Gly Gly Cys Cys Ser


 


cac cct gtc tgt tac ttt aat aat cca caa atg tgt


His Pro Val Cys Tyr Phe Asn Asn Pro Gln Met Cys


 


cgt gga aga cgc tgatgctcca ggaccctctg aaccacgacg t


Arg Gly Arg Arg
















TABLE 85





DNA Sequence (SEQ ID NO:305) and Protein Sequence


(SEQ ID NO:306) of Ay1.3















tctgatggca ggaatgccgc agccgacgac aaagcgtctg


 


acctggtcgc t ctg gcc gtc agg gga gga tgc tgt tcc


             Leu Ala Val Arg Gly Gly Cys Cys Ser


 


cac cct gtc tgt aac ttg aat aat cca caa atg tgt


His Pro Val Cys Asn Leu Asn Asn Pro Gln Met Cys


 


cgt gga aga cgc tgatgctcca ggaccctctg aaccacgacg t


Arg Gly Arg Arg
















TABLE 86





DNA Sequence (SEQ ID NO:307) and Protein Sequence


(SEQ ID NO:308) of Bt1.8















ttt cgt ggc agg aat ccc gca gcc aac gac aaa agg


Phe Arg Gly Arg Asn Pro Ala Ala Asn Asp Lys Arg


 


tct gac ctg gcc gct ctg agc gtc agg gga gga tgc


Ser Asp Leu Ala Ala Leu Ser Val Arg Gly Gly Cys


 


tgt tcc cat cct gcc tgt agc gtg act cat cca gag


Cys Ser His Pro Ala Cys Ser Val Thr His Pro Glu


 


ctt tgt ggc tgaagacgct gatgccccag gaccctctga


Leu Cys Gly


 


accacgacgt
















TABLE 87





DNA Sequence (SEQ ID NO:309) and Protein Sequence


(SEQ ID NO:310) of Bt1.9















tct gat ggc ggg aat gcc gca gcc aaa gcg tct gac


Ser Asp Gly Gly Asn Ala Ala Ala Lys Ala Ser Asp


 


ctg atc gct cag acc atc agg gga gga tgc tgt tcc


Leu Ile Ala Gln Thr Ile Arg Gly Gly Cys Cys Ser


 


tat cct gcc tgt agc gtg gaa cat caa gac ctt tgt


Tyr Pro Ala Cys Ser Val Glu His Gln Asp Leu Cys


 


gat gga aga cgc tgatgctcca ggaccctctg aaccacgacg t


Asp Gly Arg Arg
















TABLE 88





DNA Sequence (SEQ ID NO:311) and Protein Sequence


(SEQ ID NO:312) of Ca1.3















tct tat ggc agg aat gcc gca gcc aaa gcg ttt gaa gtg agt tgc tgt


Ser Tyr Gly Arg Asn Ala Ala Ala Lys Ala Phe 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 Ile Arg Tyr Gln Glu Glu Cys Leu Glu Ala


 


gat ccc agg acc ctc tga


Asp Pro Arg Thr Leu
















TABLE 89





DNA Sequence (SEQ ID NO:313) and Protein Sequence


(SEQ ID NO:314) of Ca1.4















tct gat ggc agg aat gcc gca gcc aac gcc ctt gac


Ser Asp Gly Arg Asn Ala Ala Ala Asn Ala Leu Asp


 


ctg atc act ctg atc gcc agg caa aat tgc tgt agc


Leu Ile Thr Leu Ile Ala Arg Gln Asn Cys Cys Ser


 


att ccc ggc tgt tgg gag aaa tat gga gac aaa tgt


Ile Pro Gly Cys Trp Glu Lys Tyr Gly Asp Lys Cys


 


agt gaa gta cgc tga


Ser Glu Val Arg
















TABLE 90





DNA Sequence (SEQ ID NO:315) and Protein Sequence


(SEQ ID NO:316) of C1.2















tct gat ggc agg aat gaa gca gcc aac gac gaa gcg


Ser Asp Gly Arg Asn Glu Ala Ala Asn Asp Glu Ala


 


tct gac gtg atc gag ctg gcc ctc aag gga tgc tgt


Ser Asp Val Ile Glu Leu Ala Leu Lys Gly Cys Cys


 


tcc aac cct gtc tgt cac ttg gag cat cca aac gct


Ser Asn Pro Val Cys His Leu Glu His Pro Asn Ala


 


tgt ggt aga aga cgc tgatgctcca ggaccctctg


Cys Gly Arg Arg Arg


 


aaccacgacg t
















TABLE 91





DNA Sequence (SEQ ID NO:317) and Protein Sequence


(SEQ ID NO:318) of C1.3















tct gat ggc agg aat gcc gca gcc aac gac aaa gcg


Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala


 


tct gac ctg gtc gct ctg gcc gtc agg gga tgc tgt


Ser Asp Leu Val Ala Leu Ala Val Arg Gly Cys Cys


 


tcc aac cct atc tgt tac ttt aat aat cca cga att


Ser Asn Pro Ile Cys Tyr Phe Asn Asn Pro Arg Ile


 


tgt cgt gga aga cgc tgatgctcca ggaecctctg


Cys Arg Gly Arg Arg


 


aaccacgacg t
















TABLE 92





DNA Sequence (SEQ ID NO:319) and Protein Sequence


(SEQ ID NO:320) of Ep1.2















tct cat ggc agg aat gcc gca cgc aaa gcg tct gac


Ser His Gly Arg Asn Ala Ala Arg Lys Ala Ser Asp


 


ctg atc gct ctg acc gtc agg gaa tgc tgt tct cag


Leu Ile Ala Leu Thr Val Arg Glu Cys Cys Ser Gln


 


cct ccc tgt cgc tgg aaa cat cca gaa ctt tgt agt


Pro Pro Cys Arg Trp Lys His Pro Glu Leu Cys Ser


 


tga
















TABLE 93





DNA Sequence (SEQ ID NO:321) and Protein Sequence


(SEQ ID NO:322) of G1.1















tct gat ggc agg aat gac gca gcc aaa gcg ttt gac


Ser Asp Gly Arg Asn Asp Ala Ala Lys Ala Phe Asp


 


ctg ata tct tcg acc gtc aag aaa gga tgc tgt tcc


Leu Ile Ser Ser Thr Val Lys Lys Gly Cys Cys Ser


 


cat cct gcc tgt gcg ggg aat aat caa cat att tgt


His Pro Ala Cys Ala Gly Asn Asn Gln His Ile Cys


 


ggc cga aga cgc tgatgctcca ggaccctctg aaccacgacg t


Gly Arg Arg Arg
















TABLE 94





DNA Sequence (SEQ ID NO:323) and Protein Sequence


(SEQ ID NO:324) of G1.3















tct gat ggc agg aat gcc gca gcc aac gac caa gcg


Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Gln Ala


 


tct gac ctg atg gct gcg acc gtc agg gga tgc tgt


Ser Asp Leu Met Ala Ala Thr Val Arg Gly Cys Cys


 


gcc gtt cct tcc tgt cgc ctc cgt aat cca gac ctt


Ala Val Pro Ser Cys Arg Leu Arg Asn Pro Asp Leu


 


tgt ggt gga gga cgc tgatgctcca ggaccctctg


Cys Gly Gly Gly Arg


 


aaccacgacg t
















TABLE 95





DNA Sequence (SEQ ID NO:325) and Protein Sequence


(SEQ ID NO:326) of Im1.3















ctt gat gaa agg aat gcc gca gcc gac gac aaa gcg


Leu Asp Glu Arg Asn Ala Ala Ala Asp Asp Lys Ala


 


tct gac ctg atc gct caa atc gtc agg aga gga tgc


Ser Asp Leu Ile Ala Gln Ile Val Arg Arg Gly Cys


 


tgt tcc cat cct gcc tgt aac gtg aat aat cca cac


Cys Ser His Pro Ala Cys Asn Val Asn Asn Pro His


 


att tgt ggt tga


Ile Cys Gly
















TABLE 96





DNA Sequence (SEQ ID NO:327) and Protein Sequence


(SEQ ID NO:328) of Lv1.2















tct gat ggc agg aat act gca gcc aaa gtc aaa tat


Ser Asp Gly Arg Asn Thr Ala Ala Lys Val Lys Tyr


 


tct aag acg ccg gag gaa tgc tgt ccc aat cct ccc


Ser Lys Thr Pro Glu Glu Cys Cys Pro Asn Pro Pro


 


tgt ttc gcg aca aat tcg gat att tgt ggc gga aga


Cys Phe Ala Thr Asn Ser Asp Ile Cys Gly Gly Arg


 


cgc tgatgctcca ggaccctctg aaccacgacg t


Arg
















TABLE 97





DNA Sequence (SEQ ID NO:329) and Protein Sequence


(SEQ ID NO:330) of Lv1.3















tct aat ggc agg aat gcc gca gcc aaa ttc aaa gcg


Ser Asn Gly Arg Asn Ala Ala Ala Lys Phe Lys Ala


 


cct gcc ctg atg aag cgg acc gtc agg gat gct tgc


Pro Ala Leu Met Lys Arg Thr Val Arg Asp Ala Cys


 


tgt tca gac cct cgc tgt tcc ggg aaa cat caa gac


Cys Ser Asp Pro Arg Cys Ser Gly Lys His Gln Asp


 


ctg tgt ggc tgaagacgct gatgctccag gaccctctga


Leu Cys Gly


 


accacgacgt
















TABLE 98





DNA Sequence (SEQ ID NO:331) and Protein Sequence


(SEQ ID NO:332) of Lv1.4















tct aat ggc agg aat gcc gca gcc aaa ttc aaa gcg


Ser Asn Gly Arg Asn Ala Ala Ala Lys Phe Lys Ala


 


cct gcc ctg atg gag ctg acc gtc agg gaa gat tgc


Pro Ala Leu Met Glu Leu Thr Val Arg Glu Asp Cys


 


tgt tca gac cct cgc tgt tcc gtg gga cat caa gac


Cys Ser Asp Pro Arg Cys Ser Val Gly His Gln Asp


 


ctg tgt ggc tgaagacgct gatgctccag gaccctctga


Leu Cys Gly


 


Accacgacgt
















TABLE 99





DNA Sequence (SEQ ID NO:333) and Protein Sequence


(SEQ ID NO:334) of Lv1.6















gca ttt gat ggc agg aat gct gca gcc agc gac aaa


Ala Phe Asp Gly Arg Asn Ala Ala Ala Ser Asp Lys


 


gcg tcc gag ctg atg gct ctg gcc gtc agg gga tgc


Ala Ser Glu Leu Met Ala Leu Ala Val Arg Gly Cys


 


tgt tcc cat cct gcc tgt gct ggg agt aat gca cat


Cys Ser His Pro Ala Cys Ala Gly Ser Asn Ala His


 


atc tgt ggc aga aga cgc tgatgctcca ggaccctctg


Ile Cys Gly Arg Arg Arg


 


aaccacgacg t
















TABLE 100





DNA Sequence (SEQ ID NO:335) and Protein Sequence


(SEQ ID NO:336) of Lv1.7















tct aat ggc agg aat gcc gca gcc aaa ttc aaa gcg


Ser Asn Gly Arg Asn Ala Ala Ala Lys Phe Lys Ala


 


cct gcc ctg atg aag ctg acc gtc agg gag gat tgc


Pro Ala Leu Met Lys Leu Thr Val Arg Glu Asp Cys


 


tgt tca gac cct cgc tgt tcc gtg gga cat caa gac


Cys Ser Asp Pro Arg Cys Ser Val Gly His Gln Asp


 


atg tgt ggc tgaagacgct gatgctccag gaccctctga


Met Cys Gly


 


atcacgacgt
















TABLE 101





DNA Sequence (SEQ ID NO:337) and Protein Sequence


(SEQ ID NO:338) of Lv1.8















ttt gaa tgc agg aat gct gca ggc aac gac aaa gcg


Phe Glu Cys Arg Asn Ala Ala Gly Asn Asp Lys Ala


 


act gac ctg atg gct ctg act gtc agg gga tgc tgt


Thr Asp Leu Met Ala Leu Thr Val Arg Gly Cys Cys


 


tcc cat cct gcc tgt gct ggg aat aat cca cat atc


Ser His Pro Ala Cys Ala Gly Asn Asn Pro His Ile


 


tgc ggc tgaagacgct gatgctccag gaccctctga


Cys Gly


 


accacgacgt
















TABLE 102





DNA Sequence (SEQ ID NO:339) and


Protein Sequence (SEQ ID NO:340) of Lv1.9

















ttt gat ggc agg aac gcc gca gcc aac aac aaa gcg



Phe Asp Gly Arg Asn Ala Ala Ala Asn Asn Lys Ala



 



act gat ctg atg gct ctg act gtc aga gga tgc tgt



Thr Asp Leu Met Ala Leu Thr Val Arg Gly Cys Cys



 



ggc aat cct tca tgt agc atc cat att cct tac gtt



Gly Asn Pro Ser Cys Ser Ile His Ile Pro Tyr Val



 



tgt aat tagagacact gatgctccag gaccctctga



Cys Asn



 



accacgacgt

















TABLE 103





DNA Sequence (SEQ ID NO:341) and Protein Sequence


(SEQ ID NO:342) of Lv1.10















tct aat ggc agg aat gcc gca gcc aaa ttc aaa gcg


Ser Asn Gly Arg Asn Ala Ala Ala Lys Phe Lys Ala


 


cct gcc ctg atg aag cgg acc gac agc gaa gaa tgc


Pro Ala Leu Met Lys Arg Thr Asp Ser Glu Glu Cys


 


tgt tta gac tct cgc tgt gcc ggg caa cat caa gac


Cys Leu Asp Ser Arg Cys Ala Gly Gln His Gln Asp


 


ctg tgt ggc gga aga cgc tgatgctcca ggaccctctg


Leu Cys Gly Gly Arg Arg


 


aaccacgacg t
















TABLE 104





DNA Sequence (SEQ ID NO:343) and Protein Sequence


(SEQ ID NO:344) of Mr1.3















tct gat ggc agg aat gcc gca gcc aag gac aaa gcg


Ser Asp Gly Arg Asn Ala Ala Ala Lys Asp Lys Ala


 


tct gac ctg gtc gct ctg acc gtc aag gga tgc tgt


Ser Asp Leu Val Ala Leu Thr Val Lys Gly Cys Cys


 


tct aat cct ccc tgt tac gcg aat aat caa gcc tat


Ser Asn Pro Pro Cys Tyr Ala Asn Asn Gln Ala Tyr


 


tgt aat gga aga cgc tga


Cys Asn Gly Arg Arg
















TABLE 105





DNA Sequence (SEQ ID NO:345) and


Protein Sequence (SEQ ID NO:346) of Mr1.4

















tct gat ggc agg aat gcc gca gcc aag gac aaa gcg



Ser Asp Gly Arg Asn Ala Ala Ala Lys Asp Lys Ala



 



tct gac ctg gtc gct ctg acc gtc aag gga tgc tgt



Ser Asp Leu Val Ala Leu Thr Val Lys Gly Cys Cys



 



tct cat cct gcc tgt agc gtg aat aat cca gac att



Ser His Pro Ala Cys Ser Val Asn Asn Pro Asp Ile



 



tgt ggt tga



Cys Gly

















TABLE 106





DNA Sequence (SEQ ID NO:347) and


Protein Sequence (SEQ ID NO:348) ofMs1.1

















tct gat ggc agg aat gct gca gcc aac aac aaa gtg



Ser Asp Gly Arg Asn Ala Ala Ala Asn Asn Lys Val



 



gct ttg acc atg agg gga aaa tgc tgt atc aat gat



Ala Leu Thr Met Arg Gly Lys Cys Cys Ile Asn Asp



 



gcg tgt cgc tcg aaa cat cca cag tac tgt tct gga



Ala Cys Arg Ser Lys His Pro Gln Tyr Cys Ser Gly



 



aga cgc tgatactcca ggaccctctg aaccacgacg t



Arg Arg













TABLE 107





DNA Sequence (SEQ ID NO:349) and Protein Sequence


(SEQ ID NO:350) of Ms1.6















tct gat ggc agg aat gct gca gcc aac gac aaa gtg


Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Val


 


tct gac cag atg gct ctg gtt gtc agg gga tgc tgt


Ser Asp Gln Met Ala Leu Val Val Arg Gly Cys Cys


 


tac aat att gcc tgt aga att aat aat cca cgg tac


Tyr Asn Ile Ala Cys Arg Ile Asn Asn Pro Arg Tyr


 


tgt cgt gga aaa cgc tgatgttcca ggaccctctg


Cys Arg Gly Lys Arg


 


aaccacgacg t
















TABLE 108





DNA Sequence (SEQ ID NO:351) and Protein Sequence


(SEQ ID NO:352) of O1.1















tctgaaggca ggaatgccgc agccaacgac aaagcgtctg


 


acctgatggc t ctg aac gtc agg gga tgc tgt tcc cat


             Leu Asn Val Arg Gly Cys Cys Ser His


 


cct gtc tgt cgc ttc aat tat cca aaa tat tgt ggt


Pro Val Cys Arg Phe Asn Tyr Pro Lys Tyr Cys Gly


 


gga aga cgc tgatggtcca ggaccctctg aaccacgacg t


Gly Arg Arg
















TABLE 109





DNA Sequence (SEQ ID NO:353) and Protein Sequence


(SEQ ID NO:354) of O1.2















tctgatggcg ggaatgccgc agcaaaagcg tttgatctaa tcact


 


ctg gcc ctc agg gat gaa tgc tgt gcc agt cct ccc


Leu Ala Leu Arg Asp Glu Cys Cys Ala Ser Pro Pro


 


tgt cgt ttg aat aat cca tac gta tgt cat tgacgacgct


Cys Arg Leu Asn Asn Pro Tyr Val Cys His


 


gatgctccag gaccctctga accacgacgt
















TABLE 110





DNA Sequence (SEQ ID NO:355) and Protein Sequence


(SEQ ID NO:356) of O1.4















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc


Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr


 


acc gtc gtt tcc ccc act tca gat cgt gca tct gat


Thr Val Val Ser Pro Thr Ser Asp Arg Ala Ser Asp


 


agg agg aat gcc gca gcc aaa gcg ttt gac ctg aga


Arg Arg Asn Ala Ala Ala Lys Ala Phe Asp Leu Arg


 


tat tcg acc gcc aag aga gga tgc tgt tcc aat cct


Tyr Ser Thr Ala Lys Arg Gly Cys Cys Ser Asn Pro


 


gtc tgt tgg cag aat aat gca gaa tac tgt cgt gaa


Val Cys Trp Gln Asn Asn Ala Glu Tyr Cys Arg Glu


 


agt ggc taatgctcca ggaccctctg aaccacgacg t


Ser Gly
















TABLE 111





DNA Sequence (SEQ ID NO:357) and Protein Sequence


(SEQ ID NO:358) of O1.7















atg ttc acc gtg ttt ctg ttg gtt gtc ttg gca acc


Met Phe Thr Val Phe Leu Leu Val Val Leu Ala Thr


 


acc gtc gtt tcc ttc act tca gat cgt gca tct gat


Thr Val Val Ser Phe Thr Ser Asp Arg Ala Ser Asp


 


ggc ggg aat gtc gca gcg tct cac ctg atc gct ctg


Gly Gly Asn Val Ala Ala Ser His Leu Ile Ala Leu


 


acc atc aag gga tgc tgt tct cac cct ccc tgt gcc


Thr Ile Lys Gly Cys Cys Ser His Pro Pro Cys Ala


 


cag aat aat caa gac tat tgt ggt tgacgacgct


Gln Asn Asn Gln Asp Tyr Cys Gly


 


gatgctccag gaccctctga accacgacgt
















TABLE 112





DNA Sequence (SEQ ID NO:359) and Protein Sequence


(SEQ ID NO:360) of O1.8















atg ttc acc gtg ttt ctg ttg gtt gtc tta tca acc


Met Phe Thr Val Phe Leu Leu Val Val Leu Ser Thr


 


acc gtc gtt tcc tcc act tca gat cgt gca tct gat


Thr Val Val Ser Ser Thr Ser Asp Arg Ala Ser Asp


 


agg agg aat gcc gca gcc aaa gcg tct gac ctg atg


Arg Arg Asn Ala Ala Ala Lys Ala Ser Asp Leu Met


 


tat tcg acc gtc aag aaa gga tgt tgt tcc cat cct


Tyr Ser Thr Val Lys Lys Gly Cys Cys Ser His Pro


 


gcc tgt tcg ggg aat aat cga gaa tat tgt cgt gaa


Ala Cys Ser Gly Asn Asn Arg Glu Tyr Cys Arg Clu


 


agt ggc taatgctcca ggaccctctg aaccacgacg t


Ser Gly
















TABLE 113





DNA Sequence (SEQ ID NO:361) and Protein Sequence


(SEQ ID NO:362) of Om1.2















tttgatggca ggaatgcctc agccgacagc aaagtggctg


 


cccggatcgc t cag atc gac agg gat cca tgc tgt tcc


             Gln Ile Asp Arg Asp Pro Cys Cys Ser


 


tat cct gac tgt ggc gcg aat cat cca gag att tgt


Tyr Pro Asp Cys Gly Ala Asn His Pro Glu Ile Cys


 


ggt gga aaa cgc tgatgctcca ggaccctctg aaccacgacg t


Gly Gly Lys Arg
















TABLE 114





DNA Sequence (SEQ ID NO:363) and Protein Sequence


(SEQ ID NO:364) of Om1.3















tctcatggca ggaatgccgc acgct ctg acc gtc agg gaa


                            Leu Thr Val Arg Glu


 


tgc tgt tct cag cct cct tgt cgc tgg aaa cat cca


Cys Cys Ser Gln Pro Pro Cys Arg Trp Lys His Pro


 


gaa ctt tgt agt tgaagacgct gatgctccag gaccctctga


Glu Leu Cys Ser


 


accacgacgt
















TABLE 115





DNA Sequence (SEQ ID NO:365) and Protein Sequence


(SEQ ID NO:366) of Om1.4















tttgatggca ggaatgctgc agccagcgac aaagcgtctg


 


agctgatggc t ctg gcc gtc agg gga tgc tgt tcc cat


             Leu Ala Val Arg Gly Cys Cys Ser His


 


cct gcc tgt gct ggg aat aat cca cat atc tgt ggc


Pro Ala Cys Ala Gly Asn Asn Pro His Ile Cys Gly


 


aga aga cgc tgatgctcca ggaccctctg aaccacgacg t


Arg Arg Arg
















TABLE 116





DNA Sequence (SEQ ID NO:367) and Protein Sequence


(SEQ ID NO:368) of Om1.5















tctggtgtca ggaaagacgc agcgcctggc ctgatcgct ctg acc


                                           Leu Thr


 


atc aag gga tgc tgt tct gat cct agc tgt aac gtg


Ile Lys Gly Cys Cys Ser Asp Pro Ser Cys Asn Val


 


aat aat cca gac tat tgt ggt tgacgacgct gatgctccag


Asn Asn Pro Asp Tyr Cys Gly


 


gaccctctga accacgacgt
















TABLE 117





DNA Sequence (SEQ ID NO:369) and Protein Sequence


(SEQ ID NO:370) of Om1.6















tctaatggca ggaatgccgc agccaaattc aaagcgcctg


 


ccctgatgga g ctg acc gtc agg gaa gaa tgc tgt tca


             Leu Thr Val Arg Glu Glu Cys Cys Ser


 


gac cct cgc tgt tcc gtg gga cat caa gat atg tgt


Asp Pro Arg Cys Ser Val Gly His Gln Asp Met Cys


 


cgg tgaagcacgt gatgctccag gaccctctga accacgacgt


Arg
















TABLE 118





DNA Sequence (SEQ ID NO:371) and Protein Sequence


(SEQ ID NO:372) of P1.4















act gat ggc agg aat gct gca gcc ata gcg ctt gac


Thr Asp Gly Arg Asn Ala Ala Ala Ile Ala Leu Asp


 


ctg atc gct ccg gcc gtc agg gga gga tgc tgt tcc


Leu Ile Ala Pro Ala Val Arg Gly Gly Cys Cys Ser


 


aat cct gcc tgt tta gtg aat cat cta gaa atg tgt


Asn Pro Ala Cys Leu Val Asn His Leu Glu Met Cys


 


ggt aaa aga cgc tgatgcccca ggaccctctg aaccacgacg


Gly Lys Arg Arg


 


t
















TABLE 119





DNA Sequence (SEQ ID NO:373) and Protein Sequence


(SEQ ID NO:374) of P1.5















tct gat ggc agg gat gcc gca gcc aac gac aaa gcg


Ser Asp Gly Arg Asp Ala Ala Ala Asn Asp Lys Ala


 


tct gac ctg atc gct ctg acc gcc agg aga gat cca


Ser Asp Leu Ile Ala Leu Thr Ala Arg Arg Asp Pro


 


tgc tgt ttc aat cct gcc tgt aac gtg aat aat cca


Cys Cys Phe Asn Pro Ala Cys Asn Val Asn Asn Pro


 


cag att tgt ggt tgaagacgct gatgctccag gaccctctga


Gln Ile Cys Gly


 


accacgacgt
















TABLE 120





DNA Sequence (SEQ ID NO:375) and Protein Sequence


(SEQ ID NO:376) of P1.6















tct gat ggc agg gat gct gag aaa aca ggc ttt gac


Ser Asp Gly Arg Asp Ala Glu Lys Thr Gly Phe Asp


 


acg acc att gtg ccg gaa gac tgc tgt tcg gat cct


Thr Thr Ile Val Pro Glu Asp Cys Cys Ser Asp Pro


 


tcc tgt tgg agg ctg cat agt tta gct tgt act gga


Ser Cys Trp Arg Leu His Ser Leu Ala Cys Thr Gly


 


att gta aac cgc tgatgctcca ggaccctctg aaccacgacg


Ile Val Asn Arg


 


t
















TABLE 121





DNA Sequence (SEQ ID NO:377) and Protein Sequence


(SEQ ID NO:378) of P1.8















act gat ggc agg agt gct gca gcc ata gcg ttt gcc


Thr Asp Gly Arg Ser Ala Ala Ala Ile Ala Phe Ala


 


ctg atc gct ccg acc gtc tgc tgt act aat cct gcc


Leu Ile Ala Pro Thr Val Cys Cys Thr Asn Pro Ala


 


tgt ctc gtg aat aat ata cgc ttt tgt ggt gga aga


Cys Leu Val Asn Asn Ile Arg Phe Cys Gly Gly Arg


 


cgc tgatgcccca ggaccctctg aaccacgacg t


Arg
















TABLE 122





DNA Sequence (SEQ ID NO:379) and Protein Sequence


(SEQ ID NO:380) of Rg1.1















tct gat gga aga aat gcc gca agc gac gcc aaa gcg


Ser Asp Gly Arg Asn Ala Ala Ser Asp Ala Lys Ala


 


ttt ccc cgg atc gct cca atc gtc agg gac gaa tgc


Phe Pro Arg Ile Ala Pro Ile Val Arg Asp Glu Cys


 


tgt agc gat cct agg tgt cac ggg aat aat cgg gac


Cys Ser Asp Pro Arg Cys His Gly Asn Asn Arg Asp


 


cac tgt gct tgaagacgct gctgctccag gaccctctga


His Cys Ala


 


accacgacgt
















TABLE 123





DNA Sequence (SEQ ID NO:381) and Protein Sequence


(SEQ ID NO:382) of Rg1.3















tct gat ggc agg aat acc gcg gcc gac gaa aaa gcg


Ser Asp Gly Arg Asn Thr Ala Ala Asp Glu Lys Ala


 


tcc gac ctg atc tct caa act gtc aag aga gat tgc


Ser Asp Leu Ile Ser Gln Thr Val Lys Arg Asp Cys


 


tgt tcc cat cct ctc tgt aga tta ttt gtt cca gga


Cys Ser His Pro Leu Cys Arg Leu Phe Val Pro Gly


 


ctt tgt att tgaagacgct gctgctccag gaccctctga


Leu Cys Ile


 


Accacgact
















TABLE 124





DNA Sequence (SEQ ID NO:383) and Protein Sequence


(SEQ ID NO:384) of Rg1.4















tct gat ggc agg aat gcc gca gcc gac aac aaa gcg


Ser Asp Gly Arg Asn Ala Ala Ala Asp Asn Lys Ala


 


tct gac cta atc gct caa atc gtc agg aga gga tgc


Ser Asp Leu Ile Ala Gln Ile Val Arg Arg Gly Cys


 


tgt tcc cat cct gtc tgt aaa gtg agg tat cca gac


Cys Ser His Pro Val Cys Lys Val Arg Tyr Pro Asp


 


ctg tgt cgt tgaagacgct gctgctccag gaccctctga


Leu Cys Arg


 


Accacgacgt
















TABLE 125





DNA Sequence (SEQ ID NO:385) and Protein Sequence


(SEQ ID NO:386) of Rg1.5















tct gat ggc agg aat gcc gca gcc gac aac aga gcg


Ser Asp Gly Arg Asn Ala Ala Ala Asp Asn Arg Ala


 


tct gac cta atc gct caa atc gtc agg aga gga tgc


Ser Asp Leu Ile Ala Gln Ile Val Arg Arg Gly Cys


 


tgt tcc cat cct gcc tgt aat gtg aat aat cca cac


Cys Ser His Pro Ala Cys Asn Val Asn Asn Pro His


 


att tgt ggt tgaagacgct gctgctccag gaccctctga


Ile Cys Gly


 


accacgacgt
















TABLE 126





DNA Sequence (SEQ ID NO:387) and Protein Sequence


(SEQ ID NO:388) of Rg1.8















tct gat ggc agg aat gcc gca gcc gac aac aaa ccg


Ser Asp Gly Arg Asn Ala Ala Ala Asp Asn Lys Pro


 


tct gac cta atc gct caa atc gtc agg aga gga tgc


Ser Asp Leu Ile Ala Gln Ile Val Arg Arg Gly Cys


 


tgt tcg cat cct gtc tgt aaa gtg agg tat tca gac


Cys Ser His Pro Val Cys Lys Val Arg Tyr Ser Asp


 


atg tgt ggt tgaagacgct gctgctccag gaccctctga


Met Cys Gly


 


accacgacgt
















TABLE 127





DNA Sequence (SEQ ID NO:389) and Protein Sequence


(SEQ ID NO:390) of Sm1.4















tct gat ggc agg aat gca gag cga cga caa agc gtc


Ser Asp Gly Arg Asn Ala Glu Arg Arg Gln Ser Val


 


tgt cct ggt cgc tct ggc ccc agg gga gga tgt tgt


Cys Pro Gly Arg Ser Gly Pro Arg Gly Gly Cys Cys


 


tcc cac cct gcc tgt aag gtg cat ttt cca cac agt


Ser His Pro Ala Cys Lys Val His Phe Pro His Ser


 


tgt ggt tgacgacgct gatgctccag gaccctctga


Cys Gly


 


accacgacgt
















TABLE 128





DNA Sequence (SEQ ID NO:391) and Protein Sequence


(SEQ ID NO:392) of Sm1.5















tct gat ggc agg aat gcc gca gcc agc gac aga gcg


Ser Asp Gly Arg Asn Ala Ala Ala Ser Asp Arg Ala


 


tct gac gcg gcc cac cag gta tgc tgt tcc aac cct


Ser Asp Ala Ala His Gln Val Cys Cys Ser Asn Pro


 


gtc tgt cac gtg gat cat cca gaa ctt tgt cgt aga


Val Cys His Val Asp His Pro Glu Leu Cys Arg Arg


 


aga cgc tgatgctcca ggaccctctg aaccacgacg t


Arg Arg
















TABLE 129





DNA Sequence (SEQ ID NO:393) and Protein Sequence


(SEQ ID NO:394) of S1.5















tct gat ggc agg aat gcc gcg gcc aac gac aaa gcg


Ser Asp Gly Arg Asn Ala Ala Ala Asn Asp Lys Ala


 


tct gac ctg gtc gct ccg gcc atc agg gga tgc tgt


Ser Asp Leu Val Ala Pro Ala Ile Arg Gly Cys Cys


 


tcc cac cct gtc tgt aac ttg agt aat cca caa att


Ser His Pro Val Cys Asn Leu Ser Asn Pro Gln Ile


 


tgt cgt gga aga cgc tgatgctcca ggaccctctg


Cys Arg Gly Arg Arg


 


aaccacgacg t
















TABLE 130





DNA Sequence (SEQ ID NO:395) and Protein Sequence


(SEQ ID NO:396) of Tx1.5















ttt cat ggc agg aat gcc gca gcc aaa gcg tct ggc


Phe His Gly Arg Asn Ala Ala Ala Lys Ala Ser Gly


 


ctg gtc ggt ctg acc gac aag agg caa gaa tgc tgt


Leu Val Gly Leu Thr Asp Lys Arg Gln Glu Cys Cys


 


tct cat cct gcc tgt aac gta gat cat cca gaa att


Ser His Pro Ala Cys Asn Val Asp His Pro Glu Ile


 


tgt cgt tga


Cys Arg
















TABLE 131





DNA Sequence (SEQ ID NO:397) and Protein Sequence


(SEQ ID NO:398) of T1.1















act gat ggc agg agt gct gca gcc ata gcg ttt gcc


Thr Asp Gly Arg Ser Ala Ala Ala Ile Ala Phe Ala


 


ctg atc gct ccg acc gtc tgg gaa gga tgc tgt tct


Leu Ile Ala Pro Thr Val Trp Glu Gly Cys Cys Ser


 


aat cct gcc tgt ctc gtg aat cat ata cgc ttt tgt


Asn Pro Ala Cys Leu Val Asn His Ile Arg Phe Cys


 


ggt gga aga cgc tgatgcccca ggaccctctg aaccacgacg t


Gly Gly Arg Arg
















TABLE 132





DNA Sequence (SEQ ID NO:399) and Protein Sequence


(SEQ ID NO:400) of Vr1.3















tct aat ggc atg aat gcc gca gcc atc agg aaa gcg


Ser Asn Gly Met Asn Ala Ala Ala Ile Arg Lys Ala


 


tct gcc ctg gtg gct cag atc gcc cat cga gac tgc


Ser Ala Leu Val Ala Gln Ile Ala His Arg Asp Cys


 


tgt gac gat cct gcc tgc acc gtg aat aat cca ggc


Cys Asp Asp Pro Ala Cys Thr Val Asn Asn Pro Gly


 


ctt tgc act tgaagatgct gctgccccag gaccctctga


Leu Cys Thr


 


accacgacgt
















TABLE 133





DNA Sequence (SEQ ID NO:401) and Protein Sequence


(SEQ ID NO:402) of G1.2















tct gat ggc ggg aat gcc gca gca aaa gag tct gac


Ser Asp Gly Gly Asn Ala Ala Ala Lys Glu Ser Asp


 


gtg atc gct ctg acc gtc tgg aaa tgc tgt acc att


Val Ile Ala Leu Thr Val Trp Lys Cys Cys Thr Ile


 


cct tcc tgt tat gag aaa aaa aaa att aaa gca tgt


Pro Ser Cys Tyr Glu Lys Lys Lys Ile Lys Ala Cys


 


gtc ttt tgacgacgct gatgctccag gaccctctga


Val Phe


 


accacgacgt
















TABLE 134





DNA Sequence (SEQ ID NO:403) and Protein Sequence


(SEQ ID NO:404) of Rg1.12















tct gat ggc gca gtc gac gac aaa gcg ttg gat cga


Ser Asp Gly Ala Val Asp Asp Lys Ala Leu Asp Arg


 


atc gct gaa atc gtc agg aga gga tgc tgt ggc aat


Ile Ala Glu Ile Val Arg Arg Gly Cys Cys Gly Asn


 


cct gcc tgt agc ggc tcc tcg aaa gat gca ccc tct


Pro Ala Cys Ser Gly Ser Ser Lys Asp Ala Pro Ser


 


tgt ggt tgaagacgct gctgctccag gaccctctga


Cys Gly


 


accacgacgt









It will be appreciated that the methods and compositions of the instant invention can be incorporated in the form of a variety of embodiments, only a few of which are disclosed herein. It will be apparent to the artisan that other embodiments exist and do not depart from the spirit of the invention. Thus, the described embodiments are illustrative and should not be construed as restrictive.
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## Claims

1. An isolated α-conotoxin peptide selected from the group consisting of
(i) a peptide having the amino acid sequence Gly-Cys-Cys-Ser-Asp-Xaa5-Arg-Cys-Arg-Xaa4-Arg-Cys-Arg (SEQ ID NO:9), wherein 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, and or
(ii) a derivative thereof, wherein the derivative is a peptide of (i) in which a Ser residue may be substituted with Thr or a Ser residue modified to contain an O-glycan; an Arg residue may be substituted by Lys, ornithine, homoarginine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or an unnatural basic amino acid; a Tyr residue may be substituted with an unnatural hydroxy containing amino acid, a 3-hydroxyl or 2-hydroxyl isomer of Tyr or a corresponding O-sulpho-derivative or O-phospho-derivative; the Cys residues may be in D or L configuration or may be substituted with homocysteine in the D or L configuration or pairs of Cys residues may be replaced pairwise with a Ser/(Glu or Asp) combination or a Lys/(Glu or Asp) combination; an Asp residue may be substituted with a synthetic acidic bioisoteric amino acid surrogate; and
wherein the unnatural basic amino acid is selected from the group consisting of N-1-(2-pyrazolinyl)-Arg, 2-(4-piperinyl)-Gly, 2-(4-piperinyl)-Ala, 2-[3-(2S)pyrrolininyl)-Gly and 2-[3-(2S)pyrrolininyl)-Ala; the unnatural hydroxy containing amino acid is selected from the group consisting of 4-hydroxymethyl-Phe, 4-hydroxyphenyl-Gly, 2,6-dimethyl-Tyr and 5-amino-Tyr; and the synthetic acidic bioisoteric amino acid surrogate is selected from the group of a tetrazolyl derivative of Gly and a tetrazolyl derivative of Ala.

2. The isolated α-conotoxin peptide of claim 1, wherein Xaa4 is Tyr.

3. The isolated α-conotoxin peptide of claim 1, wherein Xaa4 is mono-iodo-Tyr.

4. The isolated α-conotoxin peptide of claim 1, wherein Xaa4 is di-iodo-Tyr.

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

6. An isolated α-conotoxin peptide precursor having the amino acid sequence of SEQ ID NO:244.

7. The isolated α-conotoxin peptide of claim 1, wherein Xaa5 is Pro.

8. The isolated α-conotoxin peptide of claim 1, wherein Xaa5 is hydroxy-Pro.