ALPHA-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.
Description
SEQUENCE SUBMISSION

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is entitled 2323250SequenceListing.txt, was created on Feb. 7, 2012 and is 252 kb in size. The information in the electronic format of the Sequence Listing is part of the present application and is incorporated herein by reference in its entirety.


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-, β- 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 Jan. 21, 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 Dec. 22, 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, 0-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; Xaa14 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-Xaa18, 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:









(SEQ ID NO: 4)







Asp-Xaa1-Cys-Cys-Ser-Asp-Ser-Arg-Cys-Gly-Xaa2-





Asn-Cys-Leu;










(SEQ ID NO: 5)







Ala-Cys-Cys-Ser-Asp-Arg-Arg-Cys-Arg-Xaa3-Arg-Cys;










(SEQ ID NO: 6)







Phe-Thr-Cys-Cys-Arg-Arg-Gly-Thr-Cys-Ser-Gln-His-Cys;










(SEQ ID NO: 7)







Asp-Xaa4-Cys-Cys-Arg-Arg-His-Ala-Cys-Thr-Leu-Ile-





Cys;










(SEQ ID NO: 8)







Asp-Xaa4-Cys-Cys-Arg-Xaa5-Xaa5-Cys-Thr-Leu-Ile-





Cys;










(SEQ ID NO: 9)







Gly-Cys-Cys-Ser-Asp-Xaa5-Arg-Cys-Arg-Xaa4-Arg-Cys-





Arg;










(SEQ ID NO: 10)







Gly-Gly-Cys-Cys-Ser-Asp-Xaa5-Arg-Cys-Ala-Xaa3-Arg-Cys;










(SEQ ID NO: 11)







Ile-Ala-Xaa3-Asp-Ile-Cys-Cys-Ser-Xaa1-Xaa5-Asp-





Cys-Asn-His-Xaa2-Cys-Val;


and










(SEQ ID NO: 12)







Gly-Cys-Cys-Ser-Asp-Xaa5-Arg-Cys-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:










(SEQ ID NO: 13)









Cys-Cys-Ser-Asp-Xaa5-Ala-Cys-Xaa2-Gln-Thr-Xaa5-Gly-Cys-Arg;












(SEQ ID NO: 14)









Cys-Cys-Xaa1-Asn-Xaa5-Ala-Cys-Arg-His-Thr-Gln-Gly-Cys;












(SEQ ID NO: 15)









Gly-Cys-Cys-Xaa3-His-Xaa5-Ala-Cys-Gly-Arg-His-Xaa4-Cys;












(SEQ ID NO: 16)









Ala-Xaa5-Cys-Cys-Asn-Asn-Xaa5-Ala-Cys-Val-Xaa2-His-Arg-Cys;












(SEQ ID NO: 17)









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












(SEQ ID NO: 18)









Xaa5-Xaa5-Cys-Cys-Asn-Asn-Xaa5-Ala-Cys-Val-Xaa2-His-Arg-Cys;












(SEQ ID NO: 19)









Asp-Xaa1-Asn-Cys-Cys-Xaa3-Asn-Xaa5-Ser-Cys-Xaa5-Arg-Xaa5-Arg-Cys-Thr;












(SEQ ID NO: 20)









Gly-Cys-Cys-Ser-Thr-Xaa5-Xaa5-Cys-Ala-Val-Leu-Xaa4-Cys;












(SEQ ID NO: 21)









Gly-Cys-Cys-Gly-Asn-Xaa5-Asp-Cys-Thr-Ser-His-Ser-Cys;












(SEQ ID NO: 42)









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












(SEQ ID NO: 154)









Gly-Cys-Cys-Xaa4-Asn-Xaa5-Val-Cys-Xaa2-Xaa2-Xaa4-Xaa4-Cys-Xaa3-Xaa2;












(SEQ ID NO: 155)









Xaa6-Xaa1-Xaa5-Gly-Cys-Cys-Arg-His-Xaa5-Ala-Cys-Gly-Xaa2-Asn-Arg-Cys;












(SEQ ID NO: 156)









Cys-Cys-Ala-Asp-Xaa5-Asp-Cys-Arg-Phe-Arg-Xaa5-Gly-Cys;












(SEQ ID NO: 157)









Gly-Cys-Cys-Xaa4-Asn-Xaa5-Ser-Cys-Xaa3-Xaa5-Xaa2-Thr-Xaa4-Cys-Ser-Xaa3-Xaa2;












(SEQ ID NO: 158)









Cys-Cys-Ser-Asn-Xaa5-Thr-Cys-Xaa2-Xaa1-Thr-Xaa4-Gly-Cys;












(SEQ ID NO: 159)









Cys-Cys-Ala-Asn-Xaa5-Ile-Cys-Xaa2-Asn-Thr-Xaa5-Gly-Cys;












(SEQ ID NO: 160)









Cys-Cys-Asn-Asn-Xaa5-Thr-Cys-Xaa2-Xaa1-Thr-Xaa4-Gly-Cys;












(SEQ ID NO: 161)









Cys-Cys-Ser-Asn-Xaa5-Val-Cys-Xaa2-Xaa1-Thr-Xaa4-Gly-Cys;












(SEQ ID NO: 162)









Gly-Gly-Cys-Cys-Ser-Xaa4-Xaa5-Xaa5-Cys-Ile-Ala-Ser-Asn-Xaa5-Xaa2-Cys-Gly;












(SEQ ID NO: 163)









Gly-Cys-Cys-Ser-His-Xaa5-Val-Cys-Ser-Ala-Met-Ser-Xaa5-Ile-Cys;












(SEQ ID NO: 164)









Gly-Cys-Cys-Xaa2-Asn-Xaa5-Xaa4-Cys-Gly-Ala-Ser-Xaa2-Thr-Xaa4-Cys;












(SEQ ID NO: 165)









Gly-Cys-Cys-Ser-Xaa4-Xaa5-Xaa5-Cys-Phe-Ala-Thr-Asn-Xaa5-Asp-Cys;












(SEQ ID NO: 166)









Gly-Gly-Cys-Cys-Ser-Xaa4-Xaa5-Xaa5-Cys-Ile-Ala-Asn-Asn-Xaa5-Leu-Cys-Ala;












(SEQ ID NO: 167)









Gly-Gly-Cys-Cys-Ser-Xaa4-Xaa5-Xaa5-Cys-Ile-Ala-Asn-Asn-Xaa5-Phe-Cys-Ala;












(SEQ ID NO: 168)









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



and











(SEQ ID NO: 169)








Asp-Cys-Cys-Ser-Asn-Xaa5-Xaa5-Cys-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-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 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:










(SEQ ID NO: 22)









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












(SEQ ID NO: 23)









Gly-Cys-Cys-Ser-Asn-Xaa5-Val-Cys-Arg-Gln-Asn-Asn-Ala-Xaa1-Xaa4-Cys-Arg;












(SEQ ID NO: 24)









Xaa5-Gln-Cys-Cys-Ser-His-Xaa5-Ala-Cys-Asn-Val-Asp-His-Xaa5-Xaa1-Ile-Cys-Arg;












(SEQ ID NO: 25)









Xaa5-Xaa1-Cys-Cys-Ser-His-Xaa5-Ala-Cys-Asn-Val-Asp-His-Xaa5-Xaa1-Ile-Cys-Arg;












(SEQ ID NO: 26)









Xaa5-Gln-Cys-Cys-Ser-His-Xaa5-Ala-Cys-Asn-Val-Asp-His-Xaa5-Xaa1-Ile-Cys-Asp;












(SEQ ID NO: 27)









Xaa5-Arg-Cys-Cys-Ser-His-Xaa5-Ala-Cys-Asn-Val-Asp-His-Xaa5-Xaa1-Ile-Cys-Arg;












(SEQ ID NO: 28)









Xaa5-Gln-Cys-Cys-Ser-His-Xaa5-Ala-Cys-Asn-Val-Asp-His-Xaa5-Gly-Ile-Cys-Arg;












(SEQ ID NO: 29)









Xaa5-Gln-Cys-Cys-Ser-His-Xaa5-Ala-Cys-Asn-Val-Asp-His-Xaa5-Xaa1-Thr-Cys-Arg;












(SEQ ID NO: 30)









Xaa5-Gln-Cys-Cys-Ser-His-Xaa5-Ala-Cys-Asn-Val-Asp-His-Xaa5-Xaa1-Val-Cys-Arg;












(SEQ ID NO: 31)









Xaa5-Gln-Cys-Cys-Ser-His-Xaa5-Ala-Cys-Asn-Ile-Asp-His-Xaa5-Xaa1-Ile-Cys-Arg;












(SEQ ID NO: 32)









Xaa5-Gln-Cys-Cys-Ser-His-Xaa5-Ala-Cys-Asn-Val-Asp-His-Xaa5-Xaa1-Ile-Cys-Arg-






Arg-Arg-Arg;











(SEQ ID NO: 33)









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












(SEQ ID NO: 34)









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












(SEQ ID NO: 35)









Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-Asn-Val-Asp-His-Xaa5-Xaa1-Ile-Cys;












(SEQ ID NO: 36)









Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-Ser-Gly-Xaa2-Thr-Gln-Xaa1-Xaa5-Cys-Arg-Xaa1-






Ser;











(SEQ ID NO: 37)









Xaa5-Cys-Cys-Ser-His-Xaa5-Ala-Cys-Ser-Gly-Asn-Asn-Xaa5-Xaa1-Phe-Cys-Arg-Gln;












(SEQ ID NO: 38)









Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-Ser-Gly-Asn-Asn-Xaa5-Xaa1-Phe-Cys-Arg-Gln;












(SEQ ID NO: 39)









Gly-Cys-Cys-Ser-His-Xaa5-Xaa5-Cys-Ala-Met-Asn-Asn-Xaa5-Asp-Xaa4-Cys;












(SEQ ID NO: 40)









Gly-Cys-Cys-Ser-His-Xaa5-Xaa5-Cys-Phe-Leu-Asn-Asn-Xaa5-Asp-Xaa4-Cys;












(SEQ ID NO: 41)









Gly-Cys-Cys-Ser-Asn-Xaa5-Xaa5-Cys-Ile-Ala-Xaa2-Asn-Xaa5-His-Met-Cys-Gly;












(SEQ ID NO: 43)









Gly-Cys-Cys-Ser-Asn-Xaa5-Ala-Cys-Ala-Gly-Asn-Asn-Xaa5-His-Val-Cys-Arg-Gln;












(SEQ ID NO: 44)









Gly-Cys-Cys-Ser-Arg-Xaa5-Ala-Cys-Ile-Ala-Asn-Asn-Xaa5-Asp-Leu-Cys;












(SEQ ID NO: 45)









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






Arg-Arg;











(SEQ ID NO: 46)









Gly-Gly-Cys-Cys-Ser-Phe-Xaa5-Ala-Cys-Arg-Xaa2-Xaa5-Arg-Xaa5-Xaa1-Met-Cys-Gly;












(SEQ ID NO: 47)









Xaa5-Xaa1-Cys-Cys-Ser-Asp-Xaa5-Arg-Cys-Asn-Ser-Ser-His-Xaa5-Xaa1-Leu-Cys-Gly;












(SEQ ID NO: 48)









Xaa5-Gln-Cys-Cys-Ser-Asp-Xaa5-Arg-Cys-Asn-Val-Gly-His-Xaa5-Xaa1-Leu-Cys-Gly;












(SEQ ID NO: 49)









Xaa6-Val-Cys-Cys-Ser-Asp-Xaa5-Arg-Cys-Asn-Val-Gly-His-Xaa5-Xaa1-Ile-Cys-Gly;












(SEQ ID NO: 50)









Gly-Cys-Cys-Ser-Arg-Xaa5-Xaa5-Cys-Ile-Ala-Asn-Asn-Xaa5-Asp-Leu-Cys;












(SEQ ID NO: 51)









Xaa5-Gln-Cys-Cys-Ser-His-Leu-Ala-Cys-Asn-Val-Asp-His-Xaa5-Xaa1-Ile-Cys-Arg;












(SEQ ID NO: 52)









Gly-Cys-Cys-Ser-Xaa4-Phe-Asp-Cys-Arg-Met-Met-Phe-Xaa5-Xaa1-Met-Cys-Gly-Xaa3-






Arg;











(SEQ ID NO: 53)









Gly-Gly-Cys-Cys-Ser-Phe-Ala-Ala-Cys-Arg-Xaa2-Xaa4-Arg-Xaa5-Xaa1-Met-Cys-Gly;












(SEQ ID NO: 54)









Gly-Gly-Cys-Cys-Phe-His-Xaa5-Val-Cys-Xaa4-Ile-Asn-Leu-Leu-Xaa1-Met-Cys-Arg-






Gln-Arg;











(SEQ ID NO: 55)









Ser-Ala-Thr-Cys-Cys-Asn-Xaa4-Xaa5-Xaa5-Cys-Xaa4-Xaa1-Thr-Xaa4-Xaa5-Xaa1-Ser-






Cys-Leu;











(SEQ ID NO: 56)









Ala-Cys-Cys-Ala-Xaa4-Xaa5-Xaa5-Cys-Phe-Xaa1-Ala-Xaa4-Xaa5-Xaa1-Arg-Cys-Leu;












(SEQ ID NO: 57)









Asn-Ala-Xaa1-Cys-Cys-Xaa4-Xaa4-Xaa5-Xaa5-Cys-Xaa4-Xaa1-Ala-Xaa4-Xaa5-Xaa1-Ile-






Cys-Leu;











(SEQ ID NO: 170)









Xaa1-Cys-Cys-Thr-Asn-Xaa5-Val-Cys-His-Ala-Xaa1-His-Gln-Xaa1-Leu-Cys-Ala-Arg-






Arg-Arg;











(SEQ ID NO: 171)









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












(SEQ ID NO: 172)









Xaa1-Cys-Cys-Thr-Asn-Xaa5-Val-Cys-His-Val-Xaa1-His-Gln-Xaa1-Leu-Cys-Ala-Arg-






Arg-Arg;











(SEQ ID NO: 173)









Xaa6-Xaa1-Cys-Cys-Ser-Xaa4-Xaa5-Ala-Cys-Asn-Leu-Asp-His-Xaa5-Xaa1-Leu-Cys;












(SEQ ID NO: 174)









Xaa5-Xaa1-Cys-Cys-Ser-Asp-Xaa5-Arg-Cys-Asn-Ser-Thr-His-Xaa5-Xaa1-Leu-Cys-Gly;












(SEQ ID NO: 175)









Leu-Asn-Cys-Cys-Met-Ile-Xaa5-Xaa5-Cys-Xaa3-Xaa2-Xaa2-Xaa4-Gly-Asp-Arg-Cys-Ser-






Xaa1-Val-Arg;











(SEQ ID NO: 176)









Ala-Phe-Gly-Cys-Cys-Asp-Leu-Ile-Xaa5-Cys-Leu-Xaa1-Arg-Xaa4-Gly-Asn-Arg-Cys-






Asn-Xaa1-Val-His;











(SEQ ID NO: 177)









Leu-Gly-Cys-Cys-Asn-Val-Thr-Xaa5-Cys-Xaa3-Xaa1-Xaa2-Xaa4-Gly-Asp-Xaa2-Cys-






Asn-Xaa1-Val-Arg;











(SEQ ID NO: 178)









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






Arg-Arg;











(SEQ ID NO: 179)









Leu-Asn-Cys-Cys-Ser-Ile-Xaa5-Gly-Cys-Xaa3-Asn-Xaa1-Xaa4-Xaa2-Asp-Arg-Cys-Ser-






Xaa2-Val-Arg;











(SEQ ID NO: 180)









Gly-Gly-Cys-Cys-Ser-His-Xaa5-Val-Cys-Xaa4-Phe-Asn-Asn-Xaa5-Gln-Met-Cys-Arg;












(SEQ ID NO: 181)









Gly-Gly-Cys-Cys-Ser-His-Xaa5-Val-Cys-Asn-Leu-Asn-Asn-Xaa5-Gln-Met-Cys-Arg;












(SEQ ID NO: 182)









Gly-Cys-Cys-Ser-His-Xaa5-Xaa5-Cys-Xaa4-Ala-Asn-Asn-Gln-Ala-Xaa4-Cys-Asn;












(SEQ ID NO: 183)









Gly-Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-Ser-Val-Thr-His-Xaa5-Xaa1-Leu-Cys;












(SEQ ID NO: 184)









Gly-Gly-Cys-Cys-Ser-Xaa4-Xaa5-Ala-Cys-Ser-Val-Xaa1-His-Gln-Asp-Leu-Cys-Asp;












(SEQ ID NO: 185)









Val-Ser-Cys-Cys-Val-Val-Arg-Xaa5-Cys-Xaa3-Ile-Arg-Xaa4-Gln-Xaa1-Xaa1-Cys-Leu-






Xaa1-Ala-Asp-Xaa5-Arg-Thr-Leu;











(SEQ ID NO: 186)









Xaa6-Asn-Cys-Cys-Ser-Ile-Xaa5-Gly-Cys-Xaa3-Xaa1-Xaa2-Xaa4-Gly-Asp-Xaa2-Cys-Ser-






Xaa1-Val-Arg;











(SEQ ID NO: 187)









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












(SEQ ID NO: 188)









Gly-Cys-Cys-Ser-Asn-Xaa5-Ile-Cys-Xaa4-Phe-Asn-Asn-Xaa5-Arg-Ile-Cys-Arg;












(SEQ ID NO: 189)









Xaa1-Cys-Cys-Ser-Gln-Xaa5-Xaa5-Cys-Arg-Xaa3-Xaa2-His-Xaa5-Xaa1-Leu-Cys-Ser;












(SEQ ID NO: 190)









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












(SEQ ID NO: 191)









Gly-Cys-Cys-Ala-Val-Xaa5-Ser-Cys-Arg-Leu-Arg-Asn-Xaa5-Asp-Leu-Cys-Gly-Gly;












(SEQ ID NO: 192)









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












(SEQ ID NO: 193)









Thr-Xaa5-Xaa1-Xaa1-Cys-Cys-Xaa5-Asn-Xaa5-Xaa5-Cys-Phe-Ala-Thr-Asn-Ser-Asp-Ile-






Cys-Gly;











(SEQ ID NO: 194)









Asp-Ala-Cys-Cys-Ser-Asp-Xaa5-Arg-Cys-Ser-Gly-Xaa2-His-Gln-Asp-Leu-Cys;












(SEQ ID NO: 195)









Xaa1-Asp-Cys-Cys-Ser-Asp-Xaa5-Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Leu-Cys;












(SEQ ID NO: 196)









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












(SEQ ID NO: 197)









Xaa1-Asp-Cys-Cys-Ser-Asp-Xaa5-Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Met-Cys;












(SEQ ID NO: 198)









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












(SEQ ID NO: 199)









Gly-Cys-Cys-Gly-Asn-Xaa5-Ser-Cys-Ser-Ile-His-Ile-Xaa5-Xaa4-Val-Cys-Asn;












(SEQ ID NO: 200)









Thr-Asp-Ser-Xaa1-Xaa1-Cys-Cys-Leu-Asp-Ser-Arg-Cys-Ala-Gly-Gln-His-Gln-Asp-






Leu-Cys-Gly;











(SEQ ID NO: 201)









Gly-Cys-Cys-Ser-Asn-Xaa5-Xaa5-Cys-Xaa4-Ala-Asn-Asn-Gln-Ala-Xaa4-Cys-Asn;












(SEQ ID NO: 202)









Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-Ser-Val-Asn-Asn-Xaa5-Asp-Ile-Cys;












(SEQ ID NO: 203)









Gly-Xaa2-Cys-Cys-Ile-Asn-Asp-Ala-Cys-Arg-Ser-Xaa2-His-Xaa5-Gln-Xaa4-Cys-Ser;












(SEQ ID NO: 204)









Gly-Cys-Cys-Xaa4-Asn-Ile-Ala-Cys-Arg-Ile-Asn-Asn-Xaa5-Arg-Xaa4-Cys-Arg;












(SEQ ID NO: 205)









Gly-Cys-Cys-Ser-His-Xaa5-Val-Cys-Arg-Phe-Asn-Xaa4-Xaa5-Xaa2-Xaa4-Cys-Gly;












(SEQ ID NO: 206)









Asp-Xaa1-Cys-Cys-Ala-Ser-Xaa5-Xaa5-Cys-Arg-Leu-Asn-Asn-Xaa5-Xaa4-Val-Cys-His;












(SEQ ID NO: 207)









Gly-Cys-Cys-Ser-Asn-Xaa5-Val-Cys-Xaa3-Gln-Asn-Asn-Ala-Xaa1-Xaa4-Cys-Arg-Xaa1-






Ser;











(SEQ ID NO: 208)









Gly-Cys-Cys-Ser-His-Xaa5-Xaa5-Cys-Ala-Gln-Asn-Asn-Gln-Asp-Xaa4-Cys;












(SEQ ID NO: 209)









Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-Ser-Gly-Asn-Asn-Arg-Xaa1-Xaa4-Cys-Arg-Xaa1-






Ser;











(SEQ ID NO: 210)









Asp-Xaa5-Cys-Cys-Ser-Xaa4-Xaa5-Asp-Cys-Gly-Ala-Asn-His-Xaa5-Xaa1-Ile-Cys-Gly;












(SEQ ID NO: 211)









Xaa1-Cys-Cys-Ser-Gln-Xaa5-Xaa5-Cys-Arg-Xaa3-Xaa2-His-Xaa5-Xaa1-Leu-Cys-Ser;












(SEQ ID NO: 212)









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












(SEQ ID NO: 213)









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












(SEQ ID NO: 214)









Xaa1-Xaa1-Cys-Cys-Ser-Asp-Xaa5-Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Met-Cys-Arg;












(SEQ ID NO: 215)









Gly-Gly-Cys-Cys-Ser-Asn-Xaa5-Ala-Cys-Leu-Val-Asn-His-Leu-Xaa1-Met-Cys;












(SEQ ID NO: 216)









Arg-Asp-Xaa5-Cys-Cys-Phe-Asn-Xaa5-Ala-Cys-Asn-Val-Asn-Asn-Xaa5-Gln-Ile-Cys;












(SEQ ID NO: 217)









Cys-Cys-Ser-Asp-Xaa5-Ser-Cys-Xaa3-Arg-Leu-His-Ser-Leu-Ala-Cys-Thr-Gly-Ile-Val-






Asn-Arg;











(SEQ ID NO: 218)









Cys-Cys-Thr-Asn-Xaa5-Ala-Cys-Leu-Val-Asn-Asn-Ile-Arg-Phe-Cys-Gly;












(SEQ ID NO: 219)









Asp-Xaa1-Cys-Cys-Ser-Asp-Xaa5-Arg-Cys-His-Gly-Asn-Asn-Arg-Asp-His-Cys-Ala;












(SEQ ID NO: 220)









Asp-Cys-Cys-Ser-His-Xaa5-Leu-Cys-Arg-Leu-Phe-Val-Xaa5-Gly-Leu-Cys-Ile;












(SEQ ID NO: 221)









Gly-Cys-Cys-Ser-His-Xaa5-Val-Cys-Xaa2-Val-Arg-Xaa4-Xaa5-Asp-Leu-Cys-Arg;












(SEQ ID NO: 222)









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












(SEQ ID NO: 223)









Gly-Cys-Cys-Ser-His-Xaa5-Val-Cys-Xaa2-Val-Arg-Xaa4-Ser-Asp-Met-Cys;












(SEQ ID NO: 224)









Gly-Gly-Cys-Cys-Ser-His-Xaa5-Ala-Cys-Xaa2-Val-His-Phe-Xaa5-His-Ser-Cys;












(SEQ ID NO: 225)









Val-Cys-Cys-Ser-Asn-Xaa5-Val-Cys-His-Val-Asp-His-Xaa5-Xaa1-Leu-Cys-Arg-Arg-






Arg-Arg;











(SEQ ID NO: 226)









Gly-Cys-Cys-Ser-His-Xaa5-Val-Cys-Asn-Leu-Ser-Asn-Xaa5-Gln-Ile-Cys-Arg;












(SEQ ID NO: 227)









Xaa6-Xaa1-Cys-Cys-Ser-His-Xaa5-Ala-Cys-Asn-Val-Asp-His-Xaa5-Xaa1-Ile-Cys-Arg;












(SEQ ID NO: 228)









Gly-Cys-Cys-Ser-Asn-Xaa5-Ala-Cys-Leu-Val-Asn-His-Ile-Arg-Phe-Cys-Gly;












(SEQ ID NO: 229)









Asp-Cys-Cys-Asp-Asp-Xaa5-Ala-Cys-Thr-Val-Asn-Asn-Xaa5-Gly-Leu-Cys-Thr;



and











(SEQ ID NO: 230)









Gly-Cys-Cys-Ser-Asn-Xaa5-Xaa5-Cys-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;
    • 511.7: 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;
    • O1.4: 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:









(SEQ ID NO: 231)







Cys-Cys-Thr-Ile-Xaa5-Ser-Cys-Xaa4-Xaa1-Xaa2-Xaa2-





Xaa2-Ile-Xaa2-Ala-Cys-Val-Phe


and










(SEQ ID NO: 232)







Gly-Cys-Cys-Gly-Asn-Xaa5-Ala-Cys-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 Jan. 21, 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 Dec. 22, 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 diethyliso-propylethylamine (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



Gly Arg Arg Arg







t

















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



Asn Pro Asp Cys Thr Ser His Ser Cys Asp







tgacgacgct 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


Asn Pro Ala Cys Val Lys His Arg Cys Gly





tgacgctgat 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 LysAsn 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


                                           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 cca gac tgt ggt cga cga cgc tgatgctcca


Ala 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 ccc 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


Ser Tyr Gly Arg Asn Ala Ala Ala Lys Ala Phe Glu





gtg agt tgc tgt gtc gtt cgc ccc tgt tgg att cgc


Val Ser Cys Cys Val Val Arg Pro Cys Trp Ile Arg





tat caa gag gaa tgt ctt gaa gca gat ccc agg acc


Tyr Gln Glu Glu Cys Leu Glu Ala Asp Pro Arg Thr





ctc tga


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 ggaccctctg


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 atggct gcg acc gtc agg gga tgc tgt


Ser Asp Leu MetAla Ala Thr Val Arg Gly Cys Cys





gcc gtt cct tcc tgt cgc ctc cgtaat cca gac ctt


Ala Val Pro Ser Cys Arg Leu ArgAsn Pro Asp Leu





tgt ggt gga gga cgc tgatgctcca


Cys Gly Gly Gly Arg





ggaccctctg 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 atcgct caa atc gtc agg aga gga tgc


Ser Asp Leu IleAla Gln Ile Val Arg Arg Gly Cys





tgt tcc cat cct gcc tgt aac gtgaat aat cca cac


Cys Ser His Pro Ala Cys Asn ValAsn 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) of Ms1.1















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 Glu





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


                                           Leu





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


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





gtg aat aat cca gac tat tgt ggt tgacgacgct


Val Asn Asn Pro Asp Tyr Cys Gly





gatgctccag 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 aaccacgacgt


Gly Lys Arg Arg
















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 accacgacg


Cys Gly





t
















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


Arg Arg





t
















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.


BIBLIOGRAPHY



  • Barnay, G. et al. (2000). J. Med. Chem.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

  • Nowak, L. et al. (1984). Nature 307:462-465.

  • Olivera, B. M. et al. (1984). U.S. Pat. No. 4,447,356.

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

  • Olivera, B. M. et al. (1996). U.S. Pat. No. 5,514,774.

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

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

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

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

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

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

  • Vale et al. (1978). U.S. Pat. No. 4,105,603.

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

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

  • Zhou L. M., et al. (1996). J. Neurochem. 66:620-628.

  • U.S. Pat. No. 3,972,859.

  • U.S. Pat. No. 3,842,067.

  • U.S. Pat. No. 3,862,925.

  • U.S. Pat. No. 5,550,050.

  • PCT Published Application WO 92/19195.

  • PCT Published Application WO 94/25503.

  • PCT Published Application WO 95/01203.

  • PCT Published Application WO 95/05452.

  • PCT Published Application WO 96/02286.

  • PCT Published Application WO 96/02646.

  • PCT Published Application WO 96/11698.

  • PCT Published Application WO 96/40871.

  • PCT Published Application WO 96/40959.

  • PCT Published Application WO 97/12635.


Claims
  • 1. A substantially pure α-conotoxin peptide selected from the group consisting of:
  • 2. The substantially pure α-conotoxin peptide of claim 1, which is modified to contain an O-glycan, an S-glycan or an N-glycan.
  • 3. A substantially pure α-conotoxin peptide having the generic 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; Xaa2 is Pro or hydroxy-Pro; Xaas 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; and the C-terminus contains a free carboxyl group or an amide group.
  • 4. A substantially pure α-conotoxin peptide of generic formula II of claim 3 selected from the group consisting of:
  • 5. The substantially pure α-conotoxin peptide of claim 3, which is modified to contain an O-glycan, an S-glycan or an N-glycan.
  • 6. The substantially pure α-conotoxin peptide of claim 4 which is modified to contain an O-glycan, an S-glycan or an N-glycan.
  • 7. A substantially pure α-conotoxin peptide selected from the group consisting of:
  • 8. The substantially pure α-conotoxin peptide of claim 7, which is modified to contain an β-glycan, an S-glycan or an N-glycan.
  • 9. A substantially pure α-conotoxin peptide selected from the group consisting of:
  • 10. The substantially pure α-conotoxin peptide of claim 9, which is modified to contain an O-glycan, an S-glycan or an N-glycan.
CROSS-REFERENCE TO RELATED APPLICATION

The present application is a division of U.S. patent application Ser. No. 13/042,832 filed Mar. 8, 2011, now U.S. Pat. No. 8,110,549, which in turn is a division of U.S. patent application Ser. No. 12/706,911 filed 17 Feb. 2010, now U.S. Pat. No. 7,902,153, which in turn is a division of U.S. patent application Ser. No. 11/869,480 filed 9 Oct. 2007, now U.S. Pat. No. 7,666,840, which in turn is a division of U.S. patent application Ser. No. 10/895,372 filed Jul. 21, 2004, now U.S. Pat. No. 7,279,549, which in turn is a division of U.S. patent application Ser. No. 09/493,795 filed Jan. 28, 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 Jan. 29, 1999. Each application is incorporated herein by reference.

Government Interests

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.

Provisional Applications (1)
Number Date Country
60118381 Jan 1999 US
Divisions (5)
Number Date Country
Parent 13042832 Mar 2011 US
Child 13367839 US
Parent 12706911 Feb 2010 US
Child 13042832 US
Parent 11869480 Oct 2007 US
Child 12706911 US
Parent 10895372 Jul 2004 US
Child 11869480 US
Parent 09493795 Jan 2000 US
Child 10895372 US