AU2001271657A1 - I-superfamily conotoxins - Google Patents

Description

TITLE OF THE INVENTION I-SUPERFAMILY CONOTOXINS

[0001] This invention was made with Government support under Grant No. PO1 GM48677 awarded by the National Institute of General Medical Sciences, National Institutes of Health, Bethesda, Maryland. The United States Government has certain rights in the invention.

BACKGROUND OF THE INVENTION

[0002] The invention relates to relatively short peptides (termed I-conotoxins herein), about 30-50 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 four disulfide bonds. The I-conotoxins are members ofthe I-Superfamily of conotoxins.

[0003] 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.

[0004] Conus is a genus of predatory marine gastropods (snails) which envenomate their prey. Venomous cone snails use a highly developed apparatus to deliver their cocktail of toxic conotoxins into their prey. In fish-eating species such as Conus magus the cone detects the presence of the fish using chemosensors in its siphon. When close enough the cone extends its proboscis and impales the fish with a hollow harpoon-like tooth containing venom. This immobilizes the fish and enables the cone snail to wind it into its mouth via the tooth held at the end of its proboscis. For general information on Conus and their venom see the website address http://grimwade.biochem.unimelb.edu.au/cone/ referenc.html. Prey capture is accomplished through a sophisticated arsenal of peptides which target specific ion channel and receptor subtypes. Each Conus species venom appears to contain a unique set of 50-200 peptides. The composition of the venom differs greatly between species and between individual snails within each species, each optimally evolved to paralyse it's prey. The active components of the venom are small peptides toxins, typically 12-30 amino acid residues in length and are typically highly constrained peptides due to their high density of disulphide bonds.

[0005] The venoms consist of a large number of different peptide components that when separated exhibit a range of biological activities: when injected into mice they elicit a range of physiological responses from shaking to depression. The paralytic components ofthe venom that have been the focus of recent investigation are the α-, ω- and μ-conotoxins. All of these conotoxins act by preventing neuronal communication, but each targets a different aspect of the process to achieve this. The α-conotoxins target nicotinic ligand gated channels, the μ- conotoxins target the voltage-gated sodium channels and the ω -conotoxins target the voltage- gated calcium channels (Olivera et al., 1985). For example a linkage has been established between α-, αA- & ψ-conotoxins and the nicotinic ligand-gated ion channel; ω-conotoxins and the voltage-gated calcium channel; μ-conotoxins and the voltage-gated sodium channel; δ- conotoxins and the voltage-gated sodium channel; K-conotoxins and the voltage-gated potassium channel; conantokins and the ligand-gated glutamate (NMD A) channel. For a partial list of Conus peptides and their amino acid sequences see the website address http://pir.georgetown.edu.

[0006] However, the structure and function of only a small minority of these peptides have been determined to date. For peptides where function has been determined, three classes of targets have been elucidated: voltage-gated ion channels; ligand-gated ion channels, and G- protein-linked receptors.

[0007] Conus peptides which target voltage-gated ion channels include those that delay the inactivation of sodium channels, as well as blockers specific for sodium channels, calcium channels and potassium channels. Peptides that target ligand-gated ion channels include antagonists of NMDA and serotonin receptors, as well as competitive and noncompetitive nicotinic receptor antagonists. Peptides which act on G-protein receptors include neurotensin and vasopressin receptor agonists. The unprecedented pharmaceutical selectivity of conotoxins is at least in part defined by specific disulfide bond frameworks combined with hypervariable amino acids within disulfide loops (for a review see Mclntosh et al., 1998).

[0008] There are drugs used in the treatment of pain, which are known in the literature and to the skilled artisan. See, for example, Merck Manual, 16th Ed. (1992). However, there is a demand for more active analgesic agents with diminished side effects and toxicity and which are non-addictive. The ideal analgesic would reduce the awareness of pain, produce analgesia over a wide range of pain types, act satisfactorily whether given orally or parenterally, produce minimal or no side effects, be free from tendency to produce tolerance and drug dependence. [0009] Due to the high potency and exquisite selectivity of the conopeptides, several are in various stages of clinical development for treatment of human disorders. For example, two Conus peptides are being developed for the treatment of pain. The most advanced is ω-conotoxin MVIIA (ziconotide), an N-type calcium channel blocker (see Heading, C, 1999; U.S. Patent No. 5,859,186). ω-Conotoxin MVIIA, isolated from Conus magus, is approximately 1000 times more potent than morphine, yet does not produce the tolerance or addictive properties of opiates. ω-Conotoxin MVIIA has completed Phase III (final stages) of human clinical trials and is now awaiting U.S. Food and Drug Administration approval as a therapeutic agent. ω-Conotoxin MVIIA is introduced into human patients by means of an implantable, programmable pump with a catheter threaded into the intrathecal space. Preclinical testing for use in post-surgical pain is being carried out on another Conus peptide, contulakin-G, isolated from Conus geographus (Craig et al. 1999). Contulakin-G is a 16 amino acid O-linked glycopeptide whose C-terminus resembles neurotensin. It is an agonist of neurotensin receptors, but appears significantly more potent than neurotensin in inhibiting pain in in vivo assays.

[0010] In view of a large number of biologically active substances in Conus species it is desirable to further characterize them and to identify peptides capable of treating disorders involving voltage gated ion channels, such as stroke and pain. Surprisingly, and in accordance with this invention, Applicants have discovered novel conotoxins that can be useful for the treatment of disorders involving voltage gated ion channels and could address a long felt need for a safe and effective treatment.

SUMMARY OF THE INVENTION

[0011] The invention relates to relatively short peptides (termed I-conotoxins herein), about 30-50 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 four disulfide bonds. The I-conotoxins are useful for treating disorders involving voltage gated ion channels as described herein.

[0012] More specifically, the present invention is directed to I-conotoxin peptides having the general formula I:

Xaa₁-Xaa₂-Xaa₃-Xaa₄-Cys-Xaa₅-Xaa₆-Xaa₇-Xaa₈-Xaa₉-Xaa₁₀-Cys-Xaa₁₁-Xaa₁₂-Xaai₃- Xaa₁₄-Xaa₁₅-Cys-Cys-Xaa₁₆-Xaa₁₇-Xaa₁₈-Cys-Cys-Xaa₁₉-Xaa₂₀-Gly-Xaa₂₁-Cys-Xaa₂₂-Xaa₂₃- Xaa₂₄-X a₂₅-Xaa₂₆-Xaa₂₇-Xaa₂₈-Xaa₂9-Xaa3₀-Xaa3₁-Cys-Xaa3₂-Xaa₃₃-Xaa₃₄-Xaa3₅- aa₃₆-Xaa₃₇-

Xa ₃₈-Xaa₃₉-Xaa₄₀-Xaa₄₁ (SEQ ID NO:l), wherein Xaaj is des-Xaa_! or Gly; aa₂ is des-Xaa^ Pro, hydroxy-Pro (Hyp), Ala, His or Gly; Xaa_?, is des-Xaag, Ser, Val, Pro, Hyp, Thr, g-Ser (where g is glycosylation), g-Thr, g-Hyp or any synthetic hydroxylated amino acid; Xaa₄ is des- Xaa₄, Gly, Glu, γ-carboxy-Glu (Gla), Phe, Pro, Hyp, Arg, Lys, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid or Xaa₄ is pyro-Glu if Xaa_l5 Xaa_j and Xaa^ are all des-Xaa; Xaa₅ is an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains such as Leu (D or L), lie and Val or non-natural derivatives ofthe aliphatic amino acid, Lys, Arg, ornithine, homo- Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys, any synthetic basic amino acid, Gly, Tip (D or L), neo-Trp, halo-Trp (D or L) or any synthetic aromatic amino acid; Xaa₆ is Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl- Lys, N,N'-dimethyl-Lys, N,N',N"-trirnethyl-Lys, any synthetic basic amino acid, Ala, an aliphatic amino acids bearing linear or branched saturated hydrocarbon chains such as Leu (D or L), He and Val or non-natural derivatives of the aliphatic amino acid, Thr, Ser, g-Thr or g-Ser; Xaa₇ is Gly, Asp, Glu, Gla, Asn, Gin or any synthetic acidic amino acid; Xaa₈ is Gly, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"- trimethyl-Lys, any synthetic basic amino acid, Asp, Glu, Gla, Asn, Gin or any synthetic acidic amino acid; Xaag is Ala, Val, Met, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N- methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa₁₀ is Ala, His, Ser, Thr, Pro, Hyp, g-Ser, g-Thr, g-Hyp, any synthetic hydroxylated amino acid, Asn, Gin, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'- dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa_π is Gly, Ser, Thr, g-Ser, g-Thr, Asp, Glu, Gla, any synthetic acidic amino acid, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa₁₂ is Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di- halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, any synthetic aromatic amino acid, Gin, Asn or Leu (D or L); Xaa^ is Ser, Thr, g-Ser, g-Thr or His; Xaa₁₄ is Ala, Gla, Glu, Asp, Asn, Gin, any synthetic acidic amino acid, Ser, Thr, g-Ser, g-Thr, His, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa₁₅ is Asp, Glu, Gla, Asn, Gin, any synthetic acidic amino acid or His; Xaa₁₆ is des-Xaa₁₆, Gly, His, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any synthetic hydroxylated amino acid, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl- Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa is des- Xaa₁₇, His, Ser, Thr, g-Ser, g-Thr, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N- methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys, any synthetic basic amino acid, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic aromatic amino acid; Xaa,₈ is Val, Asn, Lys, Arg, ornithine, homo- Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa₁₉ is des-Xaa₁₉, Leu (D or L), Pro, Hyp, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic aromatic amino acid; Xaa^ is Gly, He, Ser, Thr, g-Ser, g-Thr, His, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"- trimethyl-Lys, any synthetic basic amino acid, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono- halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic aromatic amino acid; Xaa^ is Ser, Thr, g-Ser, g-Thr, an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains such as Leu (D or L), He and Val or non-natural derivatives of the aliphatic amino acid, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'- dimethyl-Lys, N,N',N"-trimethyl-Lys, any synthetic basic amino acid, Phe, Tyr, meta-Tyr, ortho- Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic aromatic amino acid; Xaa^ is Ala, Gin, Gla, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa^ is Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any synthetic hydroxylated amino acid, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl- Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa^ is Gin, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp or any synthetic hydroxylated amino acid; Xaa^ is des- Xaa^, Ser, Thr, g-Ser, g-Thr or any synthetic hydroxylated amino acid; Xaa^ is des-Xaa^, Asn, Gin, Ser, Thr, g-Asn, g-Ser, g-Thr or any synthetic hydroxylated amino acid; Xaa^ is des-Xaa^, Val, Gla, Trp (D or L), neo-Trp, halo-Trp (D or L), any aromatic synthetic amino acid, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"- trimethyl-Lys or any synthetic basic amino acid; Xaa^ is des-Xaa^, an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains such as Leu (D or L), He and Val or non-natural derivatives of the aliphatic amino acid; Xaa^ is des-Xaa^, an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains such as Leu (D or L), He and Val or non-natural derivatives ofthe aliphatic amino acid; Xaa_jo is des-Xaa₃₀, He, Ser, Pro, Hyp, Thr, g- Ser, g-Thr, g-Hyp, any synthetic hydroxylated amino acid, Phe, Tyr, meta-Tyr, ortho-Tyr, nor- Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic aromatic amino acid; Xa^ is des-Xaa^ or Gly; Xaa₃₂ is Ser, Thr, g-Ser, g-Thr, Trp (D or L), neo-Trp, halo-Trp (D or L), any aromatic synthetic amino acid, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa^ is Val, Ser, Thr, g-Ser, g-Thr, Trp (D or L), neo-Trp, halo-Trp (D or L) or any aromatic synthetic amino acid; Xaa^ is Gly, He, Asp, Glu, Gla, Asn, Ser, Thr, g- Asn, g-Ser or g-Thr; Xaa^ is des-Xaa^, Val, Met, Gin, Pro, Hyp, Ser, Thr, g-Ser, g-Thr, g-Hyp or any synthetic hydroxylated amino acid; Xaa^ is des-Xaa^, Val, Thr, Ser, g-Thr, g-Ser, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic aromatic amino acid; Xaa^ is des-Xaa^, Gin, Asn, Thr, Ser, g-Ser, g- Ser, g-Asn, Met, Leu, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O- sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, any synthetic aromatic amino acid, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaagg is des-Xaagg, Leu, Ser, Thr, g-Ser, g-Thr, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"- trimethyl-Lys or any synthetic basic amino acid; Xaa^ is des-Xaa^, He, Ala, Thr, Ser, g-Ser, g- Thr, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa₄₀ is des-Xaa₄₀, Asp, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"- trimethyl-Lys or any synthetic basic amino acid; and Xaa₄₁ is des-Xaa₄₁, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic aromatic amino acid, with the proviso that the peptide is not J029 as defined below. 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 amino acid, e.g., tetrazolyl derivatives of Gly and Ala. The nonnatural derivatives of the aliphatic amino acids include those synthetic derivatives bearing non-natural aliphatic branched or linear side chains C_nH_2n+2 up to and including n=8. The Met residues may be substituted with norleucine (Nle). The halogen is iodo, chloro, fluoro or bromo; preferably iodo for halogen substituted-Tyr and bromo for halogen- substituted Trp. [0013] J029 has the sequence Gly-Xaa-Ser-Phe-Cys-Lys-Ala-Asp-Glu-Lys-Xaa-Cys- Glu-Tyr-His-Ala-Asp-Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Ala-Xaa-Ser-Thr-Asn-Trp- Ile-Leu-Xaa-Gly-Cys-Ser-Thr-Ser-Ser-Phe-Phe-Lys-Ile (SEQ ID NO:2), wherein Xaa is Pro or hydroxy-Pro. [0014] The present invention is also directed to novel specific I-conotoxin peptides within general formula I having the mature toxin sequences set forth in Table 1. The present invention is further directed to I-conotoxins having the amino acid sequences set forth in Tables 2-4.

[0015] In addition, the present invention is directed to the above I-contoxins in which the Arg residues may be substituted by Lys, ornithine, homoargine, nor-Lys, N-methyl-Lys, N,N- dimethyl-Lys, N,N,N-trirnethyl-Lys or any synthetic basic amino acid; the Lys residues may be substituted by Arg, ornithine, homoargine, nor-Lys, or any synthetic basic amino acid; the Tyr residues may be substituted with any synthetic hydroxy containing amino acid; the Ser residues may be substituted with Thr or any synthetic hydroxylated amino acid; the Thr residues may be substituted with Ser or any synthetic hydroxylated amino acid; the Phe and Trp residues may be substituted with any synthetic aromatic amino acid; and the Asn, Ser, Thr or Hyp residues may be glycosylated. The Cys residues may be in D or L configuration and may optionally be substituted with homocysteine (D or L). The Tyr residues may also be substituted with the 3- hydroxyl or 2-hydroxyl isomers (meta-Tyr or ortho-Tyr, respectively) and corresponding O- sulpho- and O-phospho-derivatives. The acidic amino acid residues may be substituted with any synthetic acidic amino acid, e.g., tetrazolyl derivatives of Gly and Ala. The aliphatic amino acids may be substituted by synthetic derivatives bearing non-natural aliphatic branched or linear side chains C_nH_2n+2 up to and including n=8. The Leu residues may be substituted with Leu (D). The Glu residues may be substituted with Gla. The Gla residues may be substituted with Glu. The N-terminal Gin residues may be substituted with pyroGlu. The Met residues may be substituted with norleucine (Nle).

[0016] The present invention is further directed to derivatives of the above peptides and peptide derivatives which are acylic permutations in which the cyclic permutants retain the native bridging pattern of native toxin. See Craik et al. (2001). [0017] Examples of synthetic aromatic amino acid include, but are not limited to, such as nitro-Phe, 4-substituted-Phe wherein the substituent is C]-C₃ alkyl, carboxyl, hyrdroxymethyl, sulphomethyl, halo, phenyl, -CHO, -CN, -SO₃H and -NHAc. Examples of synthetic hydroxy containing amino acid, include, but are not limited to, such as 4-hydroxymethyl-Phe, 4- hydroxyplienyl-Gly, 2,6-dimethyl-Tyr and 5-amino-Tyr. Examples of synthetic basic amino acids include, but are not limited to, N-l-(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 synthetic basic amino acids, synthetic hydroxy containing amino acids or synthetic aromatic amino acids are described in Building Block Index, Version 3.0 (1999 Catalog, pages 4-47 for hydroxy containing amino acids and aromatic amino acids and pages 66-87 for basic amino acids; see also http://www.amino-acids.com), incorporated herein by reference, by and available from RSP Amino Acid Analogues, Inc., Worcester, MA. Examples of synthetic acid amino acids include those derivatives bearing acidic functionality, including carboxyl, phosphate, sulfonate and synthetic tetrazolyl derivatives such as described by Ornstein et al. (1993) and in U.S. Patent No. 5,331,001, each incorporated herein by reference.

[0018] Optionally, in the peptides of general formula I and the specific peptides described above, the Asn residues may be modified to contain an N-glycan and the Ser, Thr and Hyp residues may be modified to contain an O-glycan (e.g., g-N, g-S, g-T and g-Hyp). In accordance with the present invention, a glycan shall mean any N-, S- or O-linked mono-, di-, tri-, poly- or oligosaccharide that can be attached to any hydroxy, amino or thiol group of natural or modified amino acids by synthetic or enzymatic methodologies known in the art. The monosaccharides making up the glycan can include D-allose, D-altrose, D-glucose, D-mannose, D-gulose, D-idose, D-galactose, D-talose, D-galactosamine, D-glucosamine, D-N-acetyl- glucosamine (GlcNAc), D-N-acetyl-galactosamine (GalNAc), D-fucose or D-arabinose. These saccharides may be structurally modified, e.g., with one or more O-sulfate, O-phosphate, O- acetyl or acidic groups, such as sialic acid, including combinations thereof. The gylcan may also include similar polyhydroxy groups, such as D-penicillamine 2,5 and halogenated derivatives thereof or polypropylene glycol derivatives. The glycosidic linkage is beta and 1-4 or 1-3, preferably 1-3. The linkage between the glycan and the amino acid may be alpha or beta, preferably alpha and is 1-.

[0019] 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. Serial No. 09/420,797 filed 19 October 1999 and in PCT Application No. PCT/US99/24380 filed 19 October 1999 (PCT Published Application No. WO 00/23092), each incorporated herein by reference. A preferred glycan is Gal(βl-»3)GalNAc(αl-»). [0020] Optionally, in the peptides of general formula I and the specific peptides described above, pairs of Cys residues may be replaced pairwise with isoteric lactam or ester- thioether replacements, such as Ser/(Glu or Asp), Lys/(Glu or Asp), Cys/(Glu or Asp) or Cys/ Ala 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. Thioether analogs may be readily synthesized using halo-Ala residues commercially available from RSP Amino Acid Analogues.

[0021] The peptides of the general formula and the specific peptides disclosed herein contain 8 Cys residues leading to 4 disulfide bridges. Related peptides called Janus faced atrachatoxins (J-ACTXs) have been isolated from the Australian funnel web spider (Hadronyche versutd) (King et al., 2000). The peptides of the present invention can be aligned with, these peptides as shown below for the I-Superfamily peptides Rl 1.9 and Rl 1.7. The alignment of all ofthe I-Superfamily peptides is set forth in Tables 2-4 herein.

JACTX-Hvla TICTGADRPCAA CCP—CCPGTSCQGPESNGVVYCRNF (SEQ ID NO: 3)

JACTX-Hvlb TICTGADRPCAA CCP—CCPGTSCQGPEPNGVSYCRND (SEQ ID NO: 4) JACTX-Hvlc AICTGADRPCAA CCP—CCPGTSCKA-ESNGVSYCRKDEP (SEQ ID NO: 5)

R11.9 GPSFCKADEKPCEYHADCCN—CCLSGICAPSTNWILPGCSTSSFFKI^Λ (SEQ ID NO: 6)

R11.7 GPSFCKADEKPCEYHSDCCN—CCLSGICAPSTN ILPGCSTSSFFKI^Λ (SEQ ID NO : 7 )

Based on alignment of the peptides of the present invention with the J-ACTXs, the preferred disulfide bridging is as follows: Cysl-Cys6, Cys2-Cys7, Cys3-Cys-4 and Cys5-Cys8, wherein Cysl refers to the first Cys residue in the sequence ofthe I-Superfamily peptides, Cys2 refers to the second Cys residue in the sequence ofthe I-Superfamily peptides, etc.

[0022] The present invention is also directed to the identification of the nucleic acid sequences encoding these peptides and their propeptides and the identication of nucleic acid sequences of additional related I-conotoxin peptides. Thus, the present invention is directed to nucleic acids coding for the conotoxin peptide precursors (or conotoxin propeptides) set forth in

Table 1. The present invention is further directed to the conotoxin propeptides set forth in Table

1.

[0023] The present invention is further directed to a method of treating disorders associated with voltage gated ion channel disorders in a subject comprising administering to the subject an effective amount of the pharmaceutical composition comprising a therapeutically effective amount of a I-conotoxin peptide described herein or a pharmaceutically acceptable salt or solvate thereof. The present invention is also directed to a pharmaceutical composition comprising a therapeutically effective amount of a I-conotoxin peptide described herein or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.

[0024] Another embodiment of the invention contemplates a method of identifying compounds that mimic the therapeutic activity ofthe instant peptide, comprising the steps of: (a) conducting a biological assay on a test compound to determine the therapeutic activity; and (b) comparing the results obtained from the biological assay of the test compound to the results obtained from the biological assay of the peptide. The peptide is labeled with any conventional label, preferably a radioiodine on an available Tyr. Thus, the invention is also directed to radioiodinated I-conotoxins.

BRIEF DESCRIPTION OF THE FIGURES [0025] Figure 1 shows the muscle response as recorded extracellularly for electrical stimulation ofthe motor nerve of a cutaneus pectoris muscle before and after administration of I- conotoxin Rl 1.19. The peptide was introduced just before the 8^th trace. The tracings below the

8^th trace represent controls and the tracings above the 8^th trace represent experimental. Vertical units are millivolts, horizontal units are milliseconds. [0026] Figure 2 shows response of motor nerve and muscle to the effect of Rl 1.19 with units the same as in Figure 1. The bottom three traces represent activity recorded extracellularly from muscle, and the remaining traces are those from motor nerve.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT [0027] The invention relates to relatively short peptides (termed I-conotoxins herein), about 30-50 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 four disulfide bonds. The I-conotoxins are members of the I-Superfamily of conotoxins. The I- conotoxins are useful for treating disorders involving voltage gated ion channels. [0028] The present invention, in another aspect, relates to a pharmaceutical composition comprising an effective amount of an I-conotoxin peptide, a mutein thereof, an analog thereof, an active fragment thereof or pharmaceutically acceptable salts or solvates. Such a pharmaceutical composition has the capability of acting at voltage gated ion channels, and are thus useful for treating a disorder or disease of a living animal body, including a human, which disorder or disease is responsive to the partial or complete blockade of voltage gated ion channels of the central nervous system comprising the step of administering to such a living animal body, including a human, in need thereof a therapeutically effective amount of a pharmaceutical composition ofthe present invention.

[0029] The membranes found at the surface of mammalian cells perform functions of great importance relating to the integrity and activities of cells and tissues. Of particular interest is the study of ion channel biochemistry, physiology, pharmacology and biokinetics. These ion channels, which include sodium (Na), potassium (K) and calcium (Ca) channels are present in all mammalian cells and control a variety of physiological and pharmacological processes.

[0030] For example, attention has been focused on the potassium channel, particularly its involvement in normal cellular homeostasis and its possible association with and derangements relating to a variety of disease states and immune responses. Considerable research has been expended and is currently underway in order not only to devise a treatment or prophylaxis against such devastating diseases, but also to study the underlying etiology(ies) such that a better understanding can be gained as to common denominators, if any, that would more directly focus a plan of attack for conquering them. Diseases having a particular association with such channels include autoimmune diseases and other proliferative disorders such as cancers. Autoimmune diseases include rheumatoid arthritis, type-1 diabetes mellitus (insulin dependent), multiple sclerosis, myasthenia gravis, systematic lupus erythematosus, Sjogren's syndrome, mixed connective tissue disease, experimental allergic encephalomyelitis (EAE), to name a few.

[0031] Potassium channels comprise a large and diverse group of proteins that, through maintenance of the cellular membrane potential, are fundamental in normal biological function. These channels are vital in controlling the resting membrane potential in excitable cells and can be broadly sub-divided into three classes: voltage-gated K⁺ channels, Ca²⁺ activated K⁺ channels and ATP-sensitive K⁺ channels. Many disorders are associated with abnormal flow of potassium ions through these channels. These disorders include multiple sclerosis, other demyelinating diseases (such as acute dissenmiated encephalomyelitis, optic neuromyelitis, adrenoleukodystrophy, acute transverse myelitis, progressive multifocal leukoencephalopathy), sub-acute sclerosing panencephalomyelitis (SSPE), metachromatic leukodystrophy, Pelizaeus- Merzbacher disease, spinal cord injury, botulinum toxin poisoning, Huntington's chorea, compression and entrapment neuropathies (such as carpal tunnel syndrome, ulnar nerve palsy), cardiovascular disorders (such as cardiac arrhythmias, congestive heart failure), reactive gliosis, hyperglycemia, immunosuppression, ***e addiction, cancer, cognitive dysfunction, disorders resulting from defects in neurotransmitter release (such as Eaton-Lambert syndrome), and reversal of the actions of curare and other neuromuscular blocking drugs.

[0032] Activators of K_ATP channels have therapeutic significance for the treatment of asthma, cardiac ischemia and cerebral ischemia, among others.

[0033] Asthma: Asthma is a serious and common condition that effects approximately 12 million people in the United States alone. This disorder is particularly serious in children and it has been estimated that the greatest number of asthma patients are those under the age of 18 (National Health Survey, National Center of Health Statistics, 1989). The disease is characterized by chronic inflammation and hyper-responsiveness of the airway which results in periodic attacks of wheezing and difficulty in breathing. An attack occurs when the airway smooth muscle become inflamed and swells as a result of exposure to a trigger substance. In severe cases, the airway may become blocked or obstructed as a result of the smooth muscle contraction. Further exacerbating the problem is the release of large quantities of mucus which also act to block the airway. Chronic asthmatics are most commonly treated prophylactically with inhaled corticosteroids and acutely with inhaled bronchodilators, usually β-2 agonists. However, chronic treatment with inhaled corticosteroids has an associated risk of immune system impairment, hypertension, osteoporosis, adrenal gland malfunction and an increased susceptibility to fungal infections (Rakel, 1997). In addition use of β-2 agonists has been reported in some cases to cause adverse reactions including tremor, tachycardia and palpitations and muscle cramps (Rakel, 1997). Therefore, there is great potential in developing anti- asthmatic agents with fewer side-effects. [0034] K⁺ channel openers have been shown to be effective relaxants of airway smooth muscle reducing hyperactivity induced obstruction of intact airway. In cryopreserved human bronchi (Muller-Schweinitzer and Fozard, 1997) and in the isolated guinea pig tracheal preparation (Lin et al, 1998; Ando et al., 1997; Nielson-Kudsk, 1996; Nagai et al., 1991). K_ATP openers produced relaxation whether the muscle was contracted spontaneously or induced by a range of spasmogens. Under these conditions, the K⁺ channel openers are thought to be acting to produce a K⁺ ion efflux and consequent membrane hyperpolarization. As a result, voltage- sensitive Ca²⁺ channels would close and intracellular calcium levels would drop, producing muscular relaxation. The development of new and more specific K_ATP openers may offer a novel approach both to the prophylactic and symptomatic treatment of asthma.

[0035] K_ATP channels are present in many tissue types beyond just the target tissue, therefore their activation may result in unwanted side effects. In particular, as K_ATP channels are found in vascular smooth muscle, it is possible that in addition to the beneficial anti-asthmatic properties of K_ATP openers there could be an associated drop in blood pressure. It is possible that delivering the compound in inhalant form directly to the airway smooth muscle will allow the concentration of the compound to be reduced significantly thereby minimizing adverse reactions. [0036] Cardiac Ischemia: While numerous subtypes of potassium channels in cardiac tissue have not yet been fully characterized, openers of K_ATP channels show great promise as cardioprotective agents. The beneficial vasodilatory effects afforded by K⁺ channel openers in patients with angina pectoris are now well established (Chen et al., 1997; Goldschmidt et al., 1996; Yamabe et al., 1995; Koike et al., 1995). Furthermore, the activation of K_ATP channels appears also to be involved in the acute preconditioning of the myocardium following brief ischemic periods, acting to reduce the risk (Pell et al., 1998) and size of the reperfusion infarct (Kouchi et al, 1998).

[0037] Direct evidence for the cytoprotective properties of K_ATP channels was demonstrated by Jovanovic et al. (1998a). In these studies, the DNA encoding for the Kir6.2/SUR2A (cardiac K_ATP) channel were transfected in COS-7 monkey cells and the degree of calcium loading monitored. Untransfected cells were demonstrated to be vulnerable to the increases in intracellular calcium seen following hypoxiareoxygenation. However, the transfection of the cells with the K_ATP channel conferred resistance to the potentially damaging effects of the hypoxia-reoxygenation. Thus, the cardiac K_ATP channels are likely to play a significant role in protecting the myocardium against reperfusion injury.

[0038] Cerebral Ischemia: Although treatment of cerebral ischemia has advanced significantly over the past 30 years, cerebral ischemia (stroke) still remains the third leading cause of death in the United States. More than 500,000 new stroke/ischemia cases are reported each year. Even though initial mortality is high (38%), there are close to three million survivors of stroke in the United States, and yearly cost for rehabilitation of these patients in the United States is close to $17 billion (Rakel, 1997). [0039] The initial cellular effects occur very rapidly (a matter of minutes) after an ischemic episode, whereas the actual cellular destruction does not occur until several hours or days following the infarction. Initial effects include depolarization due to bioenergetic failure, and inactivation of Na⁺ channels. Voltage-gated calcium channels are activated resulting in a massive rise in intracellular calcium. Further exacerbating the problem is a large transient release of glutamate which itself increases both Na⁺ and Ca²⁺ influx through ionotropic glutamate receptors. Glutamate also binds to metabotropic receptors, which results in activation of the inositol phosphate pathway. This sets off a cascade of intracellular events, including further release of calcium from intracellular stores. It is now well accepted that this initial overload of intracellular calcium ultimately leads to the delayed cytotoxicity that is seen hours or days later.

[0040] Recently it has been reported that dopaminergic neurons exposed to a very short hypoxic challenge will hyperpolarize primarily through an opening of K_ATP channels (Guatteo et al., 1998). This stimulatory effect was suggested to be a direct result of the increased metabolic demand and the consequent drop in intracellular ATP levels. Furthermore Jovanovic et al. (1998b) recently reported that cells transfected with DNA encoding for Kir6.2/SUR1 (neuronal K_ATP) channel showed increased resistance to injury caused through hypoxia-reoxygenation. Therefore, the opening of K_ATP channels may serve a vital cytoprotective role during short periods of reduced oxygen in neuronal tissue. Thus, there is great therapeutic potential in developing compounds that not only will act to prevent this calcium influx prophylactically, but will aid in reestablishing the normal resting membrane potential in damaged tissue. Treatment with I-conotoxin peptides of the present invention will act to open K_ATP channels, inducing membrane hyperpolarization and indirectly producing closure of the voltage-gated Ca²⁺ channels, thereby preventing or reducing deleterious effects of a massive calcium influx. [0041] The present invention is also directed to the use of I-conopeptides as a local anesthetic for treating pain. The I-conopeptides have long lasting anesthetic activity and are particularly useful for spinal anesthesia, either administered acutely for post-operative pain or via an intrathecal pump for severe chronic pain situations.

[0042] The present invention is further directed to the use of I-conopeptides as neuromuscular blockers and for treating neuromuscular disorders. As such, the I-conopeptides are useful for providing relaxation of muscle, for treating benign essential blepharospasm and other forms of focal dystonia and for anti-wrinkle use. Thus, in one aspect, the I-conopeptides are useful as neuromuscular blocking agents in conjunction with surgery or for intubation ofthe trachea by conventional parenteral administration e.g., intramuscular or intravenous administration in solution. In a second aspect, the I-conopeptides are useful as agents for treating neuromuscular disorders such as myofacial pain syndrome, chronic muscle spasm, dystonias and spasticity.

[0043] The primary factor detrimental to neurons in neurological disorders associated with deficient oxygen supply or mitochondrial dysfunction is insufficient ATP production relative to their requirement. As a large part of the energy consumed by brain cells is used for maintenance of the Na⁺ gradient across the cellular membrane, reduction of energy demand by down-modulation of voltage-gated Na(+)-channels is one strategy for neuroprotection. In addition, preservation of the inward Na⁺ gradient may be beneficial because it is an essential driving force for vital ion exchanges and transport mechanisms such as Ca²⁺ homeostasis and neurotransmitter uptake. Thus, the I-conopeptides of the present invention are useful as neuroprotectants. [0044] Voltage-gated calcium channels are present in neurons, and in cardiac, smooth, and skeletal muscle and other excitable cells, and are known to play a variety of roles in membrane excitability, muscle contraction, and cellular secretion, such as in synaptic transmission (McCleskey). In neuronal cells, voltage-gated calcium channels have been classified by their electrophysiological as well as by their biochemical (binding) properties. Six classes of physiologically distinct calcium channels have been identified to date, namely the T, L, N, P, Q, and R-type channels.

[0045] It is well known that an accumulation of calcium (calcium overload) in the brain is seen after anoxia, ischemia, migraine and other hyperactivity periods ofthe brain, such as after epileptic convulsions. An uncontrolled high concentration of calcium in the cells of the central nervous system (CNS) is known to cause most of the degenerative changes connected with the above diseases. Compounds which can block the calcium channels of brain cells are therefore useful in the treatment of stroke, anoxia, ischemia, migraine, psychosis, or epilepsy, any other convulsive disorder and in the prevention ofthe degenerative changes connected with the same.

[0046] Compounds blocking the so called I-type calcium channels in the CNS are useful for the treatment of the above disorders by directly blocking the calcium uptake in the CNS. Further, it is well known that the so called N- and P-types of calcium channels, as well as possibly other types of calcium channels, are involved in the regulation of neurotransmitter release. Compounds blocking the N- and/or P-types of calcium channels indirectly and very powerfully prevent calcium overload in the CNS after the hyperactivity periods of the brain as described above by inhibiting the enhanced neurotransmitter release seen after such hyperactivity periods of the CNS, and especially the neurotoxic, enhanced glutamate release after such hyperactivity periods of the CNS. Furthermore, blockers of the N- and/or P-types of calcium channels, as dependent upon the selectivity of the compound in question, inhibit the release of various other neurotransmitters such as aspartate, GABA, glycine, dopamine, serotonin and noradrenaline.

[0047] Thus, the pharmaceutical compositions of the present invention are useful as neuroprotectants, anticonvulsants, anxiolytics, analgesics, muscle relaxants or adjuvants to general anesthetics. A "neurological disorder or disease" is a disorder or disease of the nervous system including, but not limited to, global and focal ischemic and hemorrhagic stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage as in cardiac arrest or neonatal distress, epilepsy, anxiety, and neurodegenerative disease. In addition, a "neurological disorder or disease" is a disease state and condition in which a neuroprotectant, anticonvulsant, anxiolytic, analgesic, muscle relaxant and/or adjunct in general anesthesia may be indicated, useful, recommended or prescribed. A "neurodegenerative disease" is a disease including, but not limited to, Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis (ALS). [0048] A "neuroprotectant" is a compound capable of preventing the neuronal death associated with a neurological disorder or disease. An "anticonvulsant" is a compound capable of reducing convulsions produced by conditions such as simple partial seizures, complex partial seizures, status epilepticus, and trauma-induced seizures such as occur following head injury, including head surgery. An "anxiolytic" is a compound capable of relieving the feelings of apprehension, uncertainty and fear that are characteristic of anxiety. An "analgesic" is a compound capable of relieving pain by altering perception of nociceptive stimuli without producing anesthesia or loss of consciousness. A "muscle relaxant" is a compound that reduces muscular tension. A "adjunct in general anesthesia" is a compound useful in conjunction with anesthetic agents in producing the loss of ability to perceive pain associated with the loss of consciousness.

[0049] The invention relates as well to methods useful for treatment of neurological disorders and diseases, including, but not limited to, global and focal ischemic and hemorrhagic stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage such as in cardiac arrest or neonatal distress, epilepsy or other convulsive disorders, movement disorders (such as tardive dyskinesia and acute dystonic reactions), inflammation, anxiety, schizophrenia and neurodegenerative diseases such as Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis (ALS), without undesirable side effects.

[0050] Thus, in one embodiment, the invention provides a method of reducing/alleviating/ decreasing the perception of pain by a subject or for inducing analgesia, including local, in a subject comprising administering to the subject an effective amount of the pharmaceutical composition comprising a therapeutically effective amount of a L-conotoxin peptide described herein or a pharmaceutically acceptable salt or solvate thereof. The pain may be acute, persistent, migraine, inflammatory, nociceptive or neuropathic pain.

[0051] In a second embodiment, the invention provides a method of treating stroke, head or spinal cord trauma or injury, anoxia, hypoxia-induced nerve cell damage, ischemia, migraine, psychosis, anxiety, schizophrenia, inflammation, movement disorder, epilepsy, any other convulsive disorder or in the prevention ofthe degenerative changes connected with the same in a subject comprising administering to the subject an effective amount of the pharmaceutical composition comprising a therapeutically effective amount of a I-conotoxin peptide described herein or a pharmaceutically acceptable salt or solvate thereof.

[0052] In a third embodiment, the invention provides a method of treating neurodegenerative diseases such as Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis (ALS) in a subject comprising administering to the subject an effective amount of the -pharmaceutical composition comprising a therapeutically effective amount of a I-conotoxin peptide described herein or a pharmaceutically acceptable salt or solvate thereof. [0053] In a fourth embodiment, the invention provides a method of treating multiple sclerosis, other demyelinating diseases, SSPE, metachromatic leukodystrophy, Pelizaeus- Merzbacher disease, botulinum toxin poisoning, compression and entrapment neuropathies, cardiovascular disorders, reactive gliosis, hyperglycemia, immunosuppression, ***e addiction, cancer, cognitive dysfunction, disorders resulting from defects in neurotransmitter release (such as Eaton-Lambert syndrome), and reversal of the actions of curare and other neuromuscular blocking drugs. [0054] In a fifth embodiment, the invention provides a method for providing a neuromuscular block or for treating neuromuscular disorders, such as methods for providing relaxation of muscle, for treating benign essential blepharospasm and other forms of focal dystonia and for anti-wrinkle use. Thus, in one aspect, the I-conopeptides are useful as neuromuscular blocking agents in conjunction with surgery or for intubation of the trachea by conventional parenteral administration e.g., intramuscular or intravenous administration in solution. In a second aspect, the I-conopeptides are useful as agents for treating neuromuscular disorders such as myofacial pain syndrome, chronic muscle spasm, dystonias and spasticity.

[0055] In a sixth embodiment, the I-conopeptides ofthe present invention are also useful to reduce neurotoxic injury associated with conditions of hypoxia, anoxia or ischemia which typically follows stroke, cerebrovascular accident, brain or spinal chord trauma, myocardial infarct, physical trauma, drownings, suffocation, perinatal asphyxia, or hypoglycemic events.

[0056] The I-conotoxin peptides described herein are sufficiently small to be chemically synthesized. General chemical syntheses for preparing the foregoing I-conotoxin peptides are described hereinafter. Various ones ofthe I-conotoxin peptides can also be obtained by isolation and purification from specific Conus species using the technique described in U.S. Patent Nos. 4,447,356 (Olivera et al., 1984); 5,514,774; 5,719,264; and 5,591,821, as well as in PCT published application WO 98/03189, the disclosures of which are incorporated herein by reference. [0057] Although the I-conotoxin peptides of the present invention can be obtained by purification from cone snails, because the amounts of I-conotoxin peptides obtainable from individual snails are very small, the desired substantially pure I-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 I-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 I-conotoxin peptides depends of course upon correct determination ofthe amino acid sequence. [0058] The I-conotoxin peptides can also be produced by recombinant DNA techniques well known in the art. Such techniques are described by Sambrook et al. (1989). A gene of interest (i.e., a gene that encodes a suitable I-conotoxin peptide) can be inserted into a cloning site of a suitable expression vector by using standard techniques. These techniques are well known to those skilled in the art. The expression vector containing the gene of interest may then be used to transfect the desired cell line. Standard transfection techniques such as calcium phosphate co-precipitation, DEAE-dextran transfection or electroporation may be utilized. A wide variety of host/expression vector combinations may be used to express a gene encoding a conotoxin peptide of interest. Such combinations are well known to a skilled artisan. The peptides produced in this manner are isolated, reduced if necessary, and oxidized to form the correct disulfide bonds.

[0059] One method of forming disulfide bonds in the I-conotoxin 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.

[0060] 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.

[0061] 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., dicyclohexylcarbodumide or diisopropylcarbonyldimidazole, various active esters, e.g., esters of N-hydroxyphthalimide or N-hydroxy-succinimide, and the various cleavage reagents, to carry out reaction in solution, with subsequent isolation and purification of intermediates, is well known classical peptide methodology. Classical solution synthesis is described in detail in the treatise, "Methoden der Organischen Chemie (Houben-Weyl): Synthese von Peptiden," (1974). Techniques of exclusively solid-phase synthesis are set forth in the textbook, "Solid-Phase Peptide Synthesis," (Stewart and Young, 1969), and are exemplified by the disclosure of U.S. Patent 4,105,603 (Vale et al., 1978). The fragment condensation method of synthesis is exemplified in U.S. Patent 3,972,859 (1976). Other available syntheses are exemplified by U.S. Patents No. 3,842,067 (1974) and 3,862,925 (1975). The synthesis of peptides containing - carboxyglutamic acid residues is exemplified by Rivier et al. (1987), Nishiuchi et al. (1993) and Zhou et al. (1996). [0062] 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 ofthe 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 ofthe residues having labile side chains.

[0063] As far as the selection of a side chain amino protecting group is concerned, generally one is chosen which is not removed during deprotection ofthe 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.

[0064] 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, CA) and from Lab. Systems, Inc. The preparation of such a resin is described by Stewart and Young (1969). BHA and MBHA resin supports are commercially available, and are generally used when the desired polypeptide being synthesized has an unsubstituted amide at the C- terminus. Thus, solid resin supports may be any of those known in the art, such as one having the formulae -O-CH₂-resin support, -NH BHA resin support, or -NH-MBHA resin support. When the unsubstituted amide is desired, use of a BHA or MBHA resin is preferred, because cleavage directly gives the amide. In case the N-methyl amide is desired, it can be generated from an N-methyl BHA resin. Should other substituted amides be desired, the teaching of U.S. Patent No. 4,569,967 (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).

[0065] 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).

[0066] After removal ofthe 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). [0067] 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).

[0068] Each protected amino acid or amino acid sequence is introduced into the solid- phase reactor in about a twofold or more excess, and the coupling may be carried out in a medium of dimethylformamide (DMF):CH₂C1₂ (1:1) or in DMF or CH₂C1₂ alone. In cases where intermediate coupling occurs, the coupling procedure is repeated before removal ofthe 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).

[0069] 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.

[0070] 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. [0071] The peptides are also synthesized using an automatic synthesizer. Amino acids are sequentially coupled to an MBHA Rink resin (typically 100 mg ofresin) beginning at the C- terminus using an Advanced Chemtech 357 Automatic Peptide Synthesizer. Couplings are carried out using 1,3-diisopropylcarbodimide in N-methylpyrrolidinone (NMP) or by 2-(lH- benzotriazole- 1-yl)- 1,1, 3, 3 -tetramethyluronium hexafluorophosphate (HBTU) and diethylisopro- pylethylamine (DIE A). 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.

[0072] On the basis of the amino acid sequence of any of the I-conotoxins described herein, oligonucleotide primers are synthesized and used in 5' and 3' RACE (rapid amplification of cDNA ends) procedures to isolate the gene encoding the precursor proteins. Alternatively, the DNA to be probed is DNA which is isolated and cloned in accordance with conventional techniques using general procedures well known in the art, such as described in Olivera et al. (1996). As is common with conotoxin peptides, the identified DNAs coding for I-conotoxins code for precursor peptides which are translationally modified to yield the I-conotoxin peptides.

[0073] Additional conotoxin peptides are identified by cloning by reverse transcription- polymerase chain reaction (RT-PCR) from cone snail venom duct mRNA. The PCR primers are based on the DNA sequences coding for the precursor peptides described herein. RT-PCR of venom duct mRNA produces a product of about 250-300 nucleotides in Conus species that express conotoxin genes. The PCR product is then cloned into a plasmid vector and individual clones are sequenced to determine the sequence of various conotoxin genes. Alternatively, cDNA libraries are prepared from Conus venom duct using conventional techniques. DNA from single clones is 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 250 nucleotides are sequenced and screened for similarity in sequence to the propeptide described herein. In this manner, conotoxins having the basic structure and activity described herein are cloned from many Conus species. [0074] Muteins, analogs or active fragments, of the foregoing conotoxin peptides are also contemplated here. See, e.g., Hammerland et al. (1992). Derivative muteins, analogs or active fragments of the conotoxin peptides may be synthesized according to known techniques, including conservative amino acid substitutions, such as outlined in U.S. Patent Nos. 5,545,723 (see particularly col. 2, line 50~col. 3, line 8); 5,534,615 (see particularly col. 19, line 45~col. 22, line 33); and 5,364,769 (see particularly col. 4, line 55-col. 7, line 26), each herein incorporated by reference. [0075] Pharmaceutical compositions containing a compound of the present invention or its pharmaceutically acceptable salts or solvates 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 analgesic amount ofthe 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 (e.g., to maintain disulfide bridges intact, including among others, lactate buffer and methionine), stabilizing agents, preservatives and the like. For examples of delivery methods, see U.S. Patent No. 5,844,077.

[0076] "Pharmaceutical composition" means physically discrete coherent portions suitable for medical administration. "Pharmaceutical composition in dosage unit form" means physically discrete coherent units suitable for medical administration, each containing a daily dose or a multiple (up to four times) or a sub-multiple (down to a fortieth) of a daily dose ofthe active compound in association with a carrier and/or enclosed within an envelope. Whether the composition contains a daily dose, or for example, a half, a third or a quarter of a daily dose, will depend on whether the pharmaceutical composition is to be administered once or, for example, twice, three times or four times a day, respectively.

[0077] The term "salt", as used herein, denotes acidic and/or basic salts, formed with inorganic or organic acids and/or bases, preferably basic salts. While pharmaceutically acceptable salts are preferred, particularly when employing the compounds of the invention as medicaments, other salts find utility, for example, in processing these compounds, or where non-medicament-type uses are contemplated. Salts of these compounds may be prepared by art-recognized techniques. [0078] Examples of such pharmaceutically acceptable salts include, but are not limited to, inorganic and organic addition salts, such as hydrochloride, sulphates, nitrates or phosphates and acetates, trifluoroacetates, propionates, succinates, benzoates, citrates, tartrates, fumarates, maleates, methane-sulfonates, isothionates, theophylline acetates, salicylates, respectively, or the like. Lower alkyl quaternary ammonium salts and the like are suitable, as well. [0079] As used herein, the term "pharmaceutically acceptable" carrier means a non-toxic, inert solid, semi-solid liquid filler, diluent, encapsulating material, formulation auxiliary of any type, or simply a sterile aqueous medium, such as saline. Some examples of the materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt, gelatin, talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol, polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline, Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible substances used in pharmaceutical formulations.

[0080] Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. Examples of pharmaceutically acceptable antioxidants include, but are not limited to, water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like; oil soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, aloha-tocopherol and the like; and the metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

[0081] 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.

[0082] 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. [0083] A variety of administration routes are available. The particular mode selected will depend of course, upon the particular drug selected, the severity ofthe disease state being treated and the dosage required for therapeutic efficacy. The methods of this invention, generally speaking, may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects. Such modes of administration include oral, rectal, sublingual, topical, nasal, transdermal or parenteral routes. The term "parenteral" includes subcutaneous, intravenous, epidural, irrigation, intramuscular, release pumps, or infusion.

[0084] For example, administration of the active agent according to this invention may be achieved using any suitable delivery means, including: (a) pump (see, e.g., Lauer & Hatton (1993), Zimm et al. (1984) and Ettinger et al.

(1978));

(b), microencapsulation (see, e.g., U.S. Patent Nos. 4,352,883; 4,353,888; and 5,084,350);

(c) continuous release polymer implants (see, e.g., U.S. Patent No. 4,883,666); (d) macroencapsulation (see, e.g., U.S. Patent Nos. 5,284,761, 5,158,881, 4,976,859 and

4,968,733 and published PCT patent applications WO92/19195, WO 95/05452);

(e) naked or unencapsulated cell grafts to the CNS (see, e.g., U.S. Patent Nos. 5,082,670 and 5,618,531);

(f) injection, either subcutaneously, intravenously, intra-arterially, intramuscularly, or to other suitable site; or

(g) oral administration, in capsule, liquid, tablet, pill, or prolonged release formulation. [0085] In one embodiment of this invention, an active agent is delivered directly into the CNS, preferably to the brain ventricles, brain parenchyma, the intrathecal space or other suitable CNS location, most preferably intrathecally.

[0086] Alternatively, targeting therapies may be used to deliver the active agent more specifically to certain types of cells, 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, if it would otherwise require too high a dosage, or if it would not otherwise be able to enter target cells.

[0087] The active agents, which are peptides, can also be administered in a cell based delivery system in which a DNA sequence encoding an active agent is introduced into cells designed for implantation in the body of the patient, especially in the spinal cord region. Suitable delivery systems are described in U.S. Patent No. 5,550,050 and published PCT Application Nos. WO 92/19195, WO 94/25503, WO 95/01203, WO 95/05452, WO 96/02286, WO 96/02646, WO 96/40871, WO 96/40959 and WO 97/12635. Suitable DNA sequences can be prepared synthetically for each active agent on the basis of the developed sequences and the known genetic code.

[0088] The active agent is preferably administered in an therapeutically effective amount. By a "therapeutically effective amount" or simply "effective amount" of an active compound is meant a sufficient amount of the compound to treat or alleviate pain or to induce analgesia at a reasonable benefit/risk ratio applicable to any medical treatment. The actual amount administered, and the rate and time-course of administration, will depend on the nature and severity of the condition being treated. Prescription of treatment, e.g. decisions on dosage, timing, etc., is within the responsibility of general practitioners or spealists, and typically takes account ofthe disorder to be treated, the condition ofthe individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of techniques and protocols can be found in Remington 's Parmaceutical Sciences.

[0089] Dosage may be adjusted appropriately to achieve desired drug levels, locally or systemically. Typically the conopeptides ofthe 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, and most preferably from about 1.0 mg/kg to about 50 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. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Continuous dosing over, for example 24 hours or multiple doses per day are contemplated to achieve appropriate systemic levels of compounds.

[0090] Advantageously, the compositions are formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredients. Tablets, coated tablets, capsules, ampoules and suppositories are examples of dosage forms according to the invention.

[0091] It is only necessary that the active ingredient constitute an effective amount, i.e., such that a suitable effective dosage will be consistent with the dosage form employed in single or multiple unit doses. The exact individual dosages, as well as daily dosages, are determined according to standard medical principles under the direction of a physician or veterinarian for use humans or animals.

[0092] The pharmaceutical compositions will generally contain from about 0.0001 to 99 wt. %, preferably about 0.001 to 50 wt. %, more preferably about 0.01 to 10 wt.% of the active ingredient by weight ofthe total composition. In addition to the active agent, the pharmaceutical compositions and medicaments can also contain other pharmaceutically active compounds. Examples of other pharmaceutically active compounds include, but are not limited to, analgesic agents, cytokines and therapeutic agents in all of the major areas of clinical medicine: When used with other pharmaceutically active compounds, the conotoxin peptides of the present invention may be delivered in the form of drug cocktails. A cocktail is a mixture of any one of the compounds useful with this invention with another drug or agent. In this embodiment, a common administration vehicle (e.g., pill, tablet, implant, pump, injectable solution, etc.) would contain both the instant composition in combination supplementary potentiating agent. The individual drugs of the cocktail are each administered in therapeutically effective amounts. A therapeutically effective amount will be determined by the parameters described above; but, in any event, is that amount which establishes a level of the drags in the area of body where the drugs are required for a period of time which is effective in attaining the desired effects. [0093] The practice of the present invention employs, unless otherwise indicated, conventional techniques of chemistry, molecular biology, microbiology, recombinant DNA, genetics, immunology, cell biology, cell culture and transgenic biology, which are within the skill of the art. See, e.g., Maniatis et al, 1982; Sambrook et al, 1989; Ausubel et al, 1992; Glover, 1985; Anand, 1992; Guthrie and Fink, 1991; Harlow and Lane, 1988; Jakoby and Pastan, 1979; Nucleic Acid Hybridization (B. D. Hames & S. J. Higgins eds. 1984); Transcription And Translation (B. D. Hames & S. J. Higgins eds. 1984); Culture Of Animal Cells (R. I. Freshney, Alan R. Liss, Inc., 1987); Immobilized Cells And Enzymes (IRL Press, 1986); B. Perbal, A Practical Guide To Molecular Cloning (1984); the treatise, Methods In Enzymology (Academic Press, Inc., N.Y.); Gene Transfer Vectors For Mammalian Cells (J. H. Miller and M. P. Calos eds., 1987, Cold Spring Harbor Laboratory); Methods In Enzymology, Vols. 154 and 155 (Wu et al. eds.), Immunochemical Methods In Cell And Molecular Biology (Mayer and Walker, eds., Academic Press, London, 1987); Handbook Of Experimental Immunology, Volumes I-IV (D. M. Weir and C. C. Blackwell, eds., 1986); Riott, Essential Immunology, 6th Edition, Blackwell Scientific Publications, Oxford, 1988; Hogan et al., Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986).

EXAMPLES [0094] 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 I-Conotoxins [0095] Crude venom was extracted from venom ducts (Cruz et al., 1976), and the components were purified as previously described (Cartier et al., 1996). The crude extract from venom ducts was purified by reverse phase liquid chromatography (RPLC) using a Vydac C₁₈ semi-preparative column (10 x 250 mm). Further purification of bioactive peaks was done on a Vydac C₁₈ analytical column (4.6 x 220 mm). The effluents were monitored at 220 nm. Peaks were collected, and aliquots were assayed for activity. Throughout purification, HPLC fractions were assayed by means of intracerebral ventricular (i.c.v.) injection into mice (Clark et al., 1981).

[0096] 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).

[0097] In accordance with this method, peptides U026, GH-015, R11.14 and R11.19 were obtained.

EXAMPLE 2

Synthesis of Conopeptides [0098] 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- (lH-benzoxriol-l-yl)-l,l,3,3,-tetramethyluronium tetrafluoroborated coupling using an ABI model 430A peptide sythesizer with amino acid derivatives purchased from Bachem (Torrence CA). Orthogonal protection was used on cysteines: two cysteines were protected as the stable Cys(S-acetamidomethyl), while the other two cysteines 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 the Cys(S-acetamidomethyl). The peptides were dissolved in 0.1% TFA and 60% acetonitrile and purified by RPLC on a Vydac C₁₈ preparative column (22 x 250 mm) and eluted at a flow rate of 20 mL/min with a gradient of acetonitrile in 0.1% TFA. [0099] The disulfide bridges in the conopeptides were formed as described in Cartier et al. (1996). Briefly, the disulfide bridges between one pair of cysteines 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 prepartive column (22 x 250 mm) and eluted with a gradient of acetonitrile in 0.1% TFA. Removal of S-acetamidomethyl groups and closure ofthe disulfide bridge between the other pair of cysteines was carried out simultaneously be iodine oxidation. The cyclic peptides were purified by RPLC on a Vydac C₁₈ prepartive column (22 x 250 mm) and eluted with a gradient of acetonitrile in 0.1% TFA. HPLC fractions were assayed by means of intracerebral ventricular (i.c.v.) injection into mice (Clark et al., 1981). The most active cyclic peptide is the one having the same disulfide bond arrangement as the native peptide.

EXAMPLE 3 Isolation of DNA Encoding I-Conotoxins

[0100] DNA coding for I-conotoxins was isolated and cloned in accordance with conventional techniques using general procedures well known in the art, such as described in Olivera et al. (1996). Alternatively, cDNA libraries was prepared from Conus venom duct using conventional techniques. DNA from single clones was amplified by conventional techniques using primers which correspond approximately to the Ml 3 universal priming site and the Ml 3 reverse universal priming site. Clones having a size of approximately 300-500 nucleotides were sequenced and screened for similarity in sequence to known I-conotoxins isolated in Example 1. The DNA sequences and encoded propeptide sequences are set forth in Table 1. DNA sequences coding for the mature toxin can also be prepared on the basis of the DNA sequences set forth in these Tables. An alignment of the I-Superfamily conotoxins by type are set forth in Tables 2-4.

TABLE 1

Type I

Name: GH-015

Species : radiatus

Isolated: Yes

Cloned: Yes

DNA Sequence:

TTCGCCAGCTATTTAGGTGACACTATAGAATACTCAAGCTTGCΆTGCCTGCAGGTCGACTCTΆGAGGATC CAGGCTTCAGACGAGGACAACCCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTCAAATCCTAATCATA GAAGAAGGCAAAAATATCTGCTGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCT GGCATCAGTGACTGGGGAGAAGTCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGC TGTAAGAAAGACAGAAAGCCATGCTCGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTG CACCAAGCACAAATTGGATTTTACCTGGATGCTCGACGAGTACGTTCACTTGACGCGCTGACTTTCAGCC AGCTAGGCCATGCCTAGGTCCTCATGCACATTCACATTTGCTGTGAATTGAATTCATGTGCATTAAAGCC ATTAGGCGTAGAAAGAT (SEQ ID NO: 8)

Translation:

MKLCLTFL VLMILASVTGEKSSKHTLSRAARVKNRGCKKDRKPCSYHADCCNCCLSGICAPSTNWILPG CSTSTFT (SEQ ID NO: 9) Toxin Sequence: Gly-Cys- ys-Lys-Asp-Arg- ys-Xaa3-Cys-Ser-Xaa5-His-Ala-Asp-Cys-Cys-Asn- Cys-Cys-Leu-Ser-Gly-Ile-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4-Ile-Leu-Xaa3- Gly-Cys-Ser~Thr-Ser-T r-Phe-Thr-^Λ (SEQ ID NO: 10)

Name: J029

Species : radiatus

Isolated: Yes

Cloned: Yes

DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC TGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAA GTCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTTTTGTAAGGCAGAC GAAAAGCCATGCGAGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTGCACCAAGCACAA ATTGGATTTTACCTGGATGCTCGACGAGTTCGTTCTTCAAGATCTGACTTTCAGCCAGCTAGGCCATGCC TAGGTCCTCATGCACATTCACATTTGCTGTGAATTGAATTCATGTGCATTAAAGCCATTAGGCGTAGAAA GATGAAAAAA (SEQ ID NO: 11) Translation:

MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNRGPSFCKADEKPCEYHADCCNCCLSGICAPSTNWI LPGCSTSSFFKI (SEQ ID NO: 12)

Toxin Sequence : Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asp-Xaal-Lys-Xaa3-Cys-Xaal-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4- Ile-Leu-Xaa3-Gly-Cys-Ser-T r-Ser-Ser-Phe-Phe-Lys-Ile-^Λ (SEQ ID NO: 13)

Name: Rll.l

Species : radiatus

Isolated: No

Cloned: Yes DNA Sequence:

CGGAATTCCGATCAGCACTTCGCAGCAGTCGAGGCTTTGATATCCTAATCATAGAAGAAGGCAAAAATAT CTGCTGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGG AGAAGTTAAGCGAGCAAACACTGCGTCGTGCTGCTAGGAAAAACAAAGGCCATGTTCCATGCGGGAAAGA CGGAAGGAAATGCGGGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTAAACCAAGCACA AGTTGGACTGGATGCTCGACGAGTACCGTTCGATTGACGCGCTGACTTTCAGCCAGCTAGGCCA^'TGCCTA GGTCCTCATGCACATTCACATTTGCTGTGAATTGAATTCATGTGCATTAAAGCCATTAGGCGTAGAAAGA TTAAA (SEQ ID NO: 14)

Translation: MKLCLTFLLVLMILASVTGEKLSEQTLRRAARKNKGHVPCGKDGRKCGYHADCCNCCLSGICKPSTSWTG CSTSTVRLTR (SEQ ID NO: 15)

Toxin Sequence :

Gly-His-Val-Xaa3-Cys-Gly-Lys-Asp-Gly-Arg- ys-Cys-Gly-Xaa5-His-Ala-Asp- Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys- ys-Xaa3-Ser-Thr-Ser-Xaa4-Thr- Gly-Cys-Ser-T r-Ser-Thr-Val-Arg-Leu-Thr-Arg-^Λ (SEQ ID NO: 16)

Name: R11.2

Species : radiatus

Isolated: No Cloned: Yes

DNA Sequence:

AATCATAGAAGAAGGCAAAAATATCTGCTGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGA TGATTCTGGCATCAGTGACTGGGGAGAAGTTAAGCAAGCATACACTGAGTCATGCTACTAGGAGACCCAA CAAAGGCGCTGTTCCATGCGGGAAAGACGGAAGGCAATGCAGGAATCATGCAGATTGCTGTAATTGCTGT CCCATTGGAACCTGTGCACCAAGCACAAATTGGATTTTACCTGGATGCTCGACGGGTCCGTTCATGACGC GCTGACTTTCAGCCAGCTAGGCCATGCCTAGGTCCTCATGCACATTCACATTTGCTGTGAATTGAATTAA TGTGCATTAAAGCCATTAGGCGTAGAAAGATGAAA (SEQ ID NO: 17)

Translation:

MKLC TFLLVLMILASVTGEKLSKHT SHATRRPNKGAVPCGKDGRQCRNHADCCNCCPIGTCAPSTN I LPGCSTGPFMTR (SEQ ID NO: 18) Toxin Sequence:

Gly-Ala-Val-Xaa3-Cys-Gly-Lys-Asp-Gly-Arg-Gln-Cys-Arg-Asn-His-Ala-Asp- Cys-Cys-Asn-Cys-Cys-Xaa3-Ile-Gly-Thr-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4- Ile-Leu-Xaa3-Gly-Cys-Ser-Thr-Gly-Xaa3-Phe-Met-Thr-Arg-^Λ (SEQ ID NO: 19)

Name: R11.3

Species : radiatus

Isolated: No

Cloned: Yes

DNA Sequence:

CAGACGAGGACATCCCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAG GCAAAAATATCTGCTGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCA GTGACTGGGGAGAAGTTAAGCGAGCAAACACTGCGTCGTGCTGCTAGGAAAAACAAAGGCCCTCGATGCT GGGTCGGCCGTGTCCATTGCACCTATCATAAAGACTGCTGTCCGTCGGTATGTTGTTTCAAGGGAAGGTG TAAACCACAATCATGGGGATGCTGGTCGGGTCCGACCTAGGCGTGCTGGCCTTGAGGCAgCTAGGCCATG CCTAGGTCCTCATGCACATTCACATTTGCTGTGAATTGAATTCATGTGCATTAAAGCCATTANGCGTAGA AAGATTAAAAA (SEQ ID NO: 20) Translation:

MKLCLTFLLV MILASVTGEKLSEQTLRRAARKNKGPRCWVGRVHCTYHKDCCPSVCCFKGRCKPQSWGC WSGPT (SEQ ID NO: 21)

Toxin Sequence: Gly-Xaa3-Arg-Cys-Xaa4-Val-Gly-Arg-Val-His-Cys-Thr-Xaa5-His-Lys-Asp- Cys-Cys-Xaa3-Ser-Val-Cys-Cys-Phe-Lys-Gly-Arg-Cys-Lys-Xaa3-Gln-Ser- Xaa4-Gly-Cys-Xaa4-Ser-Gly-Xaa3-Thr-^Λ (SEQ ID NO: 22)

Name: R11.4

Species : radiatus

Isolated: No

Cloned: Yes DNA Sequence:

CCCAGCTATCAGCACTCCGCAGGCTTCAGACGAGGACATCCCAGCTATCAGCACTTCGCAGCAGTCGAGG CTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGCTGGTCAATATGAAGCTGTGCCTGACGTTCC TTCTTGTTCTGΆTGATTCTGGCΆTCAGTGACTGGGGAGAAGTCAAGCAAGCΆTACACTGΆGTCGTGCTGC TAGGGTAAAAAACAGAGGCCCTAGTTTTTGTAAGGCAGACGAAAAGCCATGCAAGTATCATGCAGATTGC TGTAACTGCTGTCTCGGTGGAATCTGTAAACCAAGCACAAGTTGGATTGGATGCTCGACGAATGTGTTCT TGACGCGCTGACTTTCAGCCAGCTAGGCCATGCCTAGGTCCTCATGCACATTCACATTTGCTGTGAATTG

AATTCATGTGCATTAAAGCCATTAGGCGTAGAAAGATGAAAAAA (SEQ ID NO: 23)

Translation: MKLC TFLLVLMILASVTGΞKSSKHTLSRAARVKNRGPSFCKADEKPCKYHADCCNCCLGGICKPSTS I GCSTNVFLTR (SEQ ID NO: 24)

Toxin Sequence:

Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asp-Xaal- ys-Xaa3-Cys-Lys-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Gly-Gly-Ile-Cys- ys-Xaa3-Ser-Thr-Ser-Xaa4- Ile-Gly-Cys-Ser-Thr-Asn-Val-P e-Leu-Thr-Arg-^A (SEQ ID NO: 25)

Name: R11.5

Species : radiatus

Isolated: No

Cloned: Yes

DNA Sequence: CGGAATTCCGCGGAATTCCGCCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAG AAGAAGGCAAAAATATCTGCTGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTG GCATCAGTGACTGGGGAGAAGTTAAGCAAGCATACACTGAGTCATGCTGCTAGGAGACCCAACAAAGGCG CTGTTCCATGCGGGAAAGACGGAAGGCAATGCAGGAATCATGCAGATTGCTGTAATTGCTGTCCCATTGG AACCTGTGCACCAAGCACAAATTGGATTTTACCTGGATGCTCGACGGGTCAATTCATGACCGCTGACTTT TAGCCAGCTAGGCCATGCCTAGGTCTTATGCACATTACATTTGCTGGGAATGAATTATTGTGCATTAAAG CCATAGGCGTTAAAGATGGAAAAAAA (SEQ ID NO: 26)

Translation:

MKLCLTFLLVLMILASVTGEKLSKHTLSHAARRPNKGAVPCGKDGRQCRNHADCCNCCPIGTCAPSTNWI PGCSTGQFMTADF (SEQ ID NO: 27)

Toxin Sequence:

Gly-Ala-Val-Xaa3-Cys-Gly-Lys-Asp-Gly-Arg-Gln-Cys-Arg-Asn-His-Ala-Asp- Cys-Cys-Asn-Cys-Cys-Xaa3-Ile-Gly-Thr-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4- Ile-Leu-Xaa3-Gly-Cys-Ser-Thr-Gly-Gln-P e-Met-T r-Ala-Asp-Phe-^Λ (SEQ ID NO:28)

Name: R11.7

Species : radiatus

Isolated: No

Cloned: Yes

DNA Sequence: CAGACGAGGACAACCCAGCTATCAGCACTTCGCAGCAGTCAGGCTTTGAAATCCTAATCATAGAAGAAGG CAAAAATATCTGCTGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAG TGACTGGGGAGAAGTCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTT TTGTAAGGCAGACGAAAAGCCATGCGAGTATCATTCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGT GCACCAAGCACAAATTGGATTTTACCTGGATGCTCGACGAGTTCGTTCTTCAAGATCTGACTTTCAGCCA GCTAGGCCATGCCTAGGTCCTCATGCACATTCACATTTGCTGTGAATTGAATTCATGTGCATTAAAGCCA TTAGGCGTAGAAAGATGAAA (SEQ ID NO: 29)

Translatio :

MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNRGPSFCKADEKPCEYHSDCCNCCLSGICAPSTNWI PGCSTSSFFKI (SEQ ID NO: 30) Toxin Sequence:

Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asp-Xaal-Lys-Xaa3-Cys-Xaal-Xaa5-His-Ser- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4- Ile-Leu-Xaa3-Gly-Cys-Ser-Thr-Ser-Ser-Phe-Phe-Lys-Ile-^Λ (SEQ ID NO: 31)

Name: Rll.10

Species : radiatus

Isolated: No

Cloned: Yes

DNA Sequence :

CGAGGACATCCCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAA AAATATCTGCTGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGA CTGGGGAGAAGTTAAGCGAGCAAACACTGCGTCGTGCTGCTAGGAAAAACAAAGGCCATGTTCCATGCGG GAAAGACGGAAGGAAATGCGGGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTAAACCA AGCACAAGTTGGACTGGATGCTCGACGAGTACCGTTCAATTGACGCGCTGACTTTCAGCCAGCTAGGCCA TGCCTAGGTCCTCATGCACATTCACATTTGCTGTGAATTGAATTCATGTGCATTAAAGCCATTAGGCGTA GAAAGATGAAAAA (SEQ ID NO: 32)

Translation:

MKLCLTFLLVLMILASVTGEKLSEQTLRRAARKNKGHVPCGKDGRKCGYHADCCNCCLSGICKPSTS TG CSTSTVQLTR (SEQ ID NO: 33)

Toxin Sequence :

Gly-His-Val-Xaa3-Cys-Gly-Lys-Asp-Gly-Arg-Lys-Cys-Gly-Xaa5-His-Ala-Asp- Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Lys-Xaa3-Ser-Thr-Ser-Xaa4-Thr- Gly-Cys-Ser-Thr-Ser-Thr-Val-Gln-Leu-T r-Arg- (SEQ ID NO: 34)

Name: Rll.ll

Species : radiatus

Isolated: No

Cloned: Yes

DNA Sequence :

CAGACGAGGACATCCCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAG GCAAAAATATCTGCTGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCC GTGACTGGGGAGAAGTCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAAAGGCCATGTTT CATGCGGGAAAGACGGAAGGGCATGCGATTATCATGCAGATTGCTGTAACTGCTGTCTCGGTGGAATCTG TAAACCAAGCACAAGTTGGATTGGATGCTCGACGAATGTGTTCTTGACGCGCTGACTTTCAGCCAGCTAG GCCATGCCTAGGTCCTCATGCACATTCACATTTGCTGTGAATTGAATTCATGTGCATTAAAGCCATTAGG CGTAGAAAGATGAAAAAA (SEQ ID NO: 35)

Translation : KLCLTFLLVL ILASVTGEKSSKHTLSRAARVKNKGHVSCGKDGRACDYHADCCNCCLGGICKPSTSWI GCSTNVFLTR (SEQ ID NO: 36) Toxin Sequence:

Gly-His-Val-Ser-Cys-Gly-Lys-Asp-Gly-Arg-Ala-Cys-Asp-Xaa5-His-Ala-Asp- Cys-Cys-Asn-Cys-Cys- eu-Gly-Gly-Ile-Cys-Lys-Xaa3-Ser-Thr-Ser-Xaa4-Ile- Gly-Cys-Ser-T r-Asn-Val-P e-Leu-Thr-Arg-^Λ (SEQ ID NO: 37) Name: Rll.12

Species: radiatus

Isolated: No

Cloned: Yes

DNA Sequence:

CAGCTATCAACACTTCgCAGCAgTCGAGGCTTTGAAATcCTAATCATAGAAGAAGGCAAAAATATcTGCT GGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATcAGTGACTGGGGAGAAG TTAAGCGAGCAAACACTGCGTCgtGCTGCTAGGAAAAACAAAGGCCATGTTCCATGCGGGAAAGACCGAA GGAAATGCGGGtATCATGCAGATTGCTGtAATTGCTGtCTCAGTGGAATCTGTAAACCAAGCACAAGTTG GACTGGATGCTCGACGAGTACGTTTTTATTGACGCGCTGACTTTCAGCCAgCTAGGCCATGCCTAGGTCC TCATGCaCATTCACATTTGCTGTGAATTGAATTCATGTGCATTAAAGCCATTTGGCGTaGAAAGATGAAA AAA (SEQ ID NO:38) Translation:

MKLCLTFLLVLMILASVTGEKLSEQTLRRAARKNKGHVPCGKDRRKCGYHADCCNCCLSGICKPSTSWTG CSTSTFLLTR (SEQ ID NO: 39)

Toxin Sequence: Gly-His-Val-Xaa3-Cys-Gly-Lys-Asp-Arg-Arg-Lys-Cys-Gly-Xaa5-His-Ala-Asp- Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Lys-Xaa3-Ser-Thr-Ser-Xaa4-T r- Gly-Cys-Ser-Thr-Ser-Thr-Phe-Leu-Leu-Thr-Arg-^Λ (SEQ ID NO: 40)

Name: R11.13

Species : radiatus

Isolated: No

Cloned: Yes DNA Sequence:

GGCTTCAGACGAGGACATCCCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGA AGAAGGCAAAAATATCTGCTGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGG CATCAGTGACTGGGGAGAAGTTAAGCGAGCAAACACTGCGTCGTGCTGCTAGGAAAAACAAAGGCCATGT TCCATGCGGGAAAGACGGAAGGAAATGCGGGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATC TGTAAACCAAGCACAAGTTGGACTGGATGCTCGACGAGTACGTTTTTATTGACGCGCTGACTTTCAGCCA GCTAGGCCATGCCTAGGTCCTCATGCACATTCACATTTGCTGTGAATTGAATTCATGTGCATTAAAGCCA TTAGGCGTAGAAAGATGAAAAAA (SEQ ID NO: 41)

Translation : MKLCLTFLLVLMILASVTGEKLSEQTLRRAARKNKGHVPCGKDGRKCGYHADCCNCCLSGICKPSTSWTG CSTSTFLLTR (SEQ ID NO: 42)

Toxin Sequence:

Gly-His-Val-Xaa3-Cys-Gly-Lys-Asp-Gly-Arg-Lys-Cys-Gly-Xaa5-His-Ala-Asp- Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Lys-Xaa3-Ser-T r-Ser-Xaa4-Thr- Gly-Cys-Ser-Thr-Ser-Thr-P e-Leu-Leu-Thr-Arg- (SEQ ID NO: 43)

Name: R11.14

Species : radiatus

Isolated: Yes

Cloned: Yes

DNA Sequence: GCTTCAGACGAGGACAACCCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAA GAAGGCAAAAATATCTGCTGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGC ATCAGTGACTGGGGAGAAGTCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCT AGTTTTTGTAAGGCAAACGGAAAGCCATGCTCGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAA TCTGTAAACCAAGCACAAATGTGATTTTACCTGGATGCTCGACGAGTTCGTTCTTCAGGATCTGACTTTC AGCCAGCTAGGCCATGCCTAGGTTCTCATGCACATTCACATTTGCTGTGAATTGAATTCATGTGCATTAA AGCCATTAGGCGTAGAAAGATGAAAAAAAAA (SEQ ID NO: 44)

Translation:

MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNRG-PSFCKANGKPCSYHADCCNCCLSGICKPSTNVI LPGCSTSSFFRI (SEQ ID NO: 45)

Toxin Sequence:

Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asn-Gly-Lys-Xaa3-Cys-Ser-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Lys-Xaa3-Ser-Thr-Asn-Val- Ile-Leu-Xaa3-Gly-Cys-Ser-Thr-Ser-Ser-Phe-Phe-Arg-Ile-^Λ (SEQ ID NO: 46)

Name : R11 . 15

Species : radiatus

Isolated: No

Cloned: Yes

DNA Sequence:

CAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGCT GGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAAG TTAAGCGAGCAAACACTGCGTCGTGCTGCTAGGAAAAACAAAGGCCATGTTCCATGCGGGAAAGACGGAA GGAAATGCGGGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTAAACCAAGCACAAGTTG GACTGGATGCTCGACGAGTACGTTCAATTGACGCGCTGACTTTCAGCCAGCTAGGCCATGCCTAGGTCCT CATGCACATTCACATTTGCTGTGAATTGAATTCATGTGCATTAAAGCCATTAGGCGTAAAAGATGAAAAA AAAAA (SEQ ID NO:47)

Translation:

MKLCLTFLLVLMILASVTGEKLSEQTLRRAARKNKGHVPCGKDGRKCGYHADCCNCCLSGICKPSTS TG CSTSTFN (SEQ ID NO: 48) Toxin Sequence:

Gly-His-Val-Xaa3-Cys-Gly-Lys-Asp-Gly-Arg-Lys-Cys-Gly-Xaa5-His-Ala-Asp- Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Lys-Xaa3-Ser-Thr-Ser-Xaa4-Thr- Gly-Cys-Ser-Thr-Ser-Thr-Phe-Asn-^Λ (SEQ ID NO: 49)

Name: R11.16

Species: radiatus

Isolated: No

Cloned: Yes

DNA Sequence:

GCTTCAGACGAGGACATCCCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAA

GAAGGCAAAAATATCTGCTGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGC

ATCAGTGACTGGGGAGAAGTCAAGCAAGCATACACTGAGTCgTGCTGcTAGGGTAAAAAACAAAGGCCAT GTTCCATGCGGGAAAGACGGAAGGAAATGCGGGTATCATACACATTGCTGTAATTGCTGTCTCAGTGGAA

TCTGTAAACCAAGCACAAGTTTGATTGGATGCTCGACGAGTTCGTTCACTTGACGCGCTGACTTTCAGCC

AGCTAGGCCATGCCTAGGTCCTCATGCACATTCACATTTGCTGTGAATTGAATTCATGTGCATTAAAGCC

ATTAGGCGTAGAAAGATT (SEQ ID NO: 50) Translation: MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNKGHVPCGKDGRKCGYHTHCCNCCLSGICKPSTSLI GCSTSSFT (SEQ ID NO: 51)

Toxin Sequence:

Gly-His-Val-Xaa3-Cys-Gly-Lys-Asp-Gly-Arg-Lys-Cys-Gly-Xaa5-His-T r-His- Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Lys-Xaa3-Ser-Thr-Ser-Leu-Ile- Gly-Cys-Ser-Thr-Ser~Ser-Phe-Thr-^Λ (SEQ ID NO: 52)

Name : R11 . 17

Species : radiatus

Isolated: No

Cloned: Yes DNA Sequence:

GATCCCCAAGCTATTTAGGTGACACTATAGAATACTCAAGCTTGCATGCCTGCAGGTCGACTCTAGAGGA TCCCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCT GCTGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAG AAGTCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTTTTGTAAGGCAA ACGGAAAGCCATGCTCGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTGCACCAAGCAC AAATTGGATTTTACCTGGATGCTCGACGAGTTCGTTCTTCAAGATCTGACTTTCAGCCAgCTAGGCCATG CCTAgGTCCTCATGCACATTCACATTTGCTGTGAATTGAATTCATGTGCATTAAAGCCATTAgGCGTAGA AAGATGAA (SEQ ID NO: 53) Translation:

MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNRGPSFCKANGKPCSYHADCCNCCLSGICAPSTNWI LPGCSTSSFFKI (SEQ ID NO: 54)

Toxin Sequence : Gly-Xaa3-Ser-P e-Cys-Lys-Ala-Asn-Gly-Lys-Xaa3-Cys-Ser-Xaa5-His-Ala-

Asp-Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4- Ile-Leu-Xaa3-Gly-Cys-Ser-Thr-Ser-Ser-Phe-Phe-Lys-Ile-^Λ (SEQ ID NO: 55)

Name: R11.18

Species : radiatus

Isolated: No

Cloned: Yes DNA Sequence:

CCCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTG CTGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGA AGTCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAAAGGCGCTGTTCCATGCGGGAAAGA CGGAAGGCAATGCAGGAATCATGCAGATTGCTGTAATTGCTGTCCCTTTGGAACCTGTGCACCAAGCACA AATCGGATTTTACCTGGATGCTCGACGGGTATGTTCTTGACGCGCTGACTTTCAGCCAGCTAGGCCATGC CTAGGTCCTCATGCACATTCACATTTGCTGTGAATTGAATTCATGTGCATTAAAGCCATTAGGCGTA (SEQ ID NO:56)

Translation: MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNKGAVPCGKDGRQCRNHADCCNCCPFGTCAPSTNRI LPGCSTGMFLTR (SEQ ID NO: 57)

Toxin Sequence:

Gly-Ala-Val-Xaa3-Cys-Gly-Lys-Asp-Gly-Arg-Gln-Cys-Arg-Asn-His-Ala-Asp- Cys-Cys-Asn-Cys-Cys-Xaa3-Phe-Gly-Thr-Cys-Ala-Xaa3-Ser-Thr-Asn-Arg-Ile- Leu-Xaa3-Gly-Cys-Ser-Thr-Gly-Met-Phe-Leu-Thr-Arg-^Λ (SEQ ID NO: 58) Name: J029 [OllP]

Species : radiatus Isolated: Yes

Cloned: Yes

Toxin Sequence :

Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asp-Xaal-Lys-Xaa3-Cys-Xaal-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4- Ile-Leu-Xaa3-Gly-Cys-Ser-Thr-Ser-Ser-Phe-Phe-Lys-Ile-^Λ (SEQ ID NO: 59)

Name: R11.19

Species : radiatus

Isolated: Yes

Cloned: No

Toxin Sequence: Xaa2-Cys-Lys-Thr-Asn-Lys-Met-Ser-Cys-Ser-Leu-His-Xaal-Xaal-Cys-Cys- Arg-Phe-Arg-Cys-Cys-Phe-His-Gly-Lys-Cys-Gln-T r-Ser-Val-Phe-Gly-Cys- Xaa4-Val-Asp-Xaa3-^Λ (SEQ ID NO: 60)

Name: Call.l

Species: caracteristicus

Isolated: No

Cloned: Yes DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAΆGGCAAAΆCCATCTGG TGGTCAGTATGAAGCTGTGTGTGACGTTTCTTCTTGTTCTGGTGATTCTGCCATCGGTGACCGGGGAGAA GTCTAGCGAGCGTACACGGATTGGTGCTGTTCTGAAAGGCCATTGGTGCGGATACCCAGGAGAACGCGGA TGCCGATATCATAGCCAATGCTGTGGGGACATGTGTTGTTACGACCGCAAGTGTGTTGCGACTGCTATGC CATGTGACTTTCCCTACTAGTGCGATGGACCTAGGCGTGCTGGCCTTGTGGCAGACTCGCTCAGTATGCC TGACCTGTCCAAGTGAAACGACCGGACACGATCGTCGTATTCCTTTGCCAAGAGCTAGCTAGGCCATGCC TAGG (SEQ ID NO: 61)

Translation: MKLCVTFLLVLVILPSVTGEKSSERTRIGAVLKGHWCGYPGERGCRYHSQCCGDMCCYDRKCVATAMPCD FPY (SEQ ID NO: 62)

Toxin Sequence:

Gly-His-Xaa4-Cys-Gly-Xaa5-Xaa3-Gly-Xaal-Arg-Gly-Cys-Arg-Xaa5-His-Ser- Gln-Cys-Cys-Gly-Asp-Met-Cys-Cys-Xaa5-Asp-Arg-Lys-Cys-Val-Ala-Thr-Ala- Met-Xaa3-Cys-Asp-Phe-Xaa3-Xaa5-^Λ (SEQ ID NO: 63)

Name: Mil.9 Species : magus

Isolated: No

Cloned: Yes

DNA Sequence: CCGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAGGGCAAAAATATCTGCT GGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAAG TCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCTGTAAGAAAGACAGAAAGCCAT GCTCGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGGATCTGTGCACCAAGCACAAATTGGATTTT ACCTGGATGCTCGACGAGTACGTTCACTTGACGCGCTGACTTTCAGCCAGCTAGGCCATGCCTAGG (SEQ ID NO: 64)

Translation:

MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNRGCKKDRKPCSYHADCCNCCLSGICAPSTN ILPG CSTSTFT (SEQ ID NO: 65) Toxin Sequence:

Gly-Cys-Lys-Lys-Asp-Arg-Lys-Xaa3-Cys-Ser-Xaa5-His-Ala-Asp-Cys-Cys-Asn- Cys-Cys-Leu-Ser-Gly-Ile-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4-Ile-Leu-Xaa3- Gly-Cys-Ser-Thr-Ser-Thr-Phe-Thr-^Λ (SEQ ID NO: 66)

Name: Mil.13

Species : magus

Isolated: No

Cloned: Yes

DNA Sequence:

CCGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAGTCATAGAAGAAGGCAAAAATATCTGCT GGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCCGTGACTGGGGAGAAG TCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAAAGGCCATGTTTCATGCGGGAAAGACG GAAGGGCATGCGATTATCATGCAGATTGCTGTAACTGCTGTCTCGGTGGAATCTGTAAACCAAGCACAAG TTGGATTGGATGCTCGACGAATGTGTTCTTGACGCGCTGACTTTCAGCCAGCTAGGCCATGCCTAGG (SEQ ID NO: 67)

Translation: MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNKGHVSCGKDGRACDYHADCCNCCLGGICKPSTSWI GCSTNVFLTR (SEQ ID NO: 68)

Toxin Sequence:

Gly-His-Val-Ser-Cys-Gly-Lys-Asp-Gly-Arg-Ala-Cys-Asp-Xaa5-His-Ala-Asp- Cys-Cys-Asn-Cys-Cys-Leu-Gly-Gly-Ile-Cys-Lys-Xaa3-Ser-Thr-Ser-Xaa4-Ile- Gly-Cys-Ser-Thr-Asn-Val-Phe-Leu-Thr-Arg-^A (SEQ ID NO: 69)

Name: S11.5

Species : striatus

Isolated: No

Cloned: Yes

DNA Sequence: CCGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGCT GGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAAG TCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTTTTGTAAGGCAAACG GAAAGCCATGCTCGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTAAACCAAGCACAAA TGTGATTTTACCTGGATGCTCGACGAGTTCGTTCTTCAGGATCTGACTTTCAGCCAGCTAGGCCATGCCT AGG (SEQ ID NO: 70)

Translation :

MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNRGPSFCKANGKPCSYHADCCNCCLSGICKPSTNVI LPGCSTSSFFRI (SEQ ID NO: 71)

Toxin Sequence : Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asn-Gly-Lys-Xaa3-Cys-Ser-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Lys-Xaa3-Ser-Thr-Asn-Val- Ile-Leu-Xaa3-Gly-Cys-Ser-Thr-Ser-Ser-Phe-P e-Arg-Ile-^A (SEQ ID NO : 72 )

Name: Sll.l

Species: striatus

Isolated: No

Cloned: Yes

DNA Sequence :

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGCAAAAACATCTGG TGGTCAGTATGAAGCTGTGTGTGACGTTTCTTCTTGTTCTGGTGATTCTGCCATCAGTAACTGGGGAGGA GTCTAGCGAGCGTACACTGAGTGGTGCTACTCTGACAGGCGATCGGGGAACGTGCTCATTCTTAGGACAA GGATGCGGAGATCATTCCGACTGCTGTTGGAACATGTGTTGTGCCAGCGAAATGTGCGTTGTGACTCTCC TTCAATGTAAATGATTTCCCTTCTAGGGCGATGGACCTAGGCGTGCTGGCCTAGCGGTAGACTCGCTCAG TATGCCTGATCTGTCTGAGTGAAACGACCTGACACGATCCGTCGTATTCCTTTGCCAAGAGCCAGCTAGG CCATGCCTAGG (SEQ ID NO: 73) Translation:

MKLCVTFLLVLVILPSVTGEESSERTLSGATLTGDRGTCSFLGQGCGDHSDCCWNMCCASEMCVVTLLQC K (SEQ ID NO:74)

Toxin Sequence : Gly-T r-Cys-Ser-Phe-Leu-Gly-Gln-Gly-Cys-Gly-Asp-His-Ser-Asp-Cys-Cys-

Xaa4-Asn-Met-Cys-Cys-Ala-Ser-Xaal-Met-Cys-Val-Val-Thr-Leu-Leu-Gln-Cys- Lys-^A (SEQ ID NO: 75)

Name: S11.2

Species : striatus

Isolated: No

Cloned: Yes DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC TGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAA GTCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCTGTAAGAAAGACAGAAAGCCA TGCTCGTATCAGGCAGATTGCTGTAATTGCTGTCCCATTGGAACCTGTGCACCAAGCACAAATTGGATTT TACCTGGATGCTCGACGGGTCCGTTCATGGCGCGCTGACTTTCAGCCAGCTAGGCCATGCCTAGG (SEQ ID NO:76)

Translation:

MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNRGCKKDRKPCSYQADCCNCCPIGTCAPSTNWILPG CSTGPFMAR (SEQ ID NO: 77)

Toxin Sequence:

Gly-Cys-Lys-Lys-Asp-Arg-Lys-Xaa3-Cys-Ser-Xaa5-Gln-Ala-Asp-Cys-Cys-Asn- Cys-Cys-Xaa3-Ile-Gly-Thr-Cys-Ala-Xaa3-Ser-T r-Asn-Xaa4-Ile-Leu-Xaa3- Gly-Cys-Ser-Thr-Gly-Xaa3-Phe-Met-Ala-Arg-^A (SEQ ID NO: 78)

Name: S11.3

Species : striatus

Isolated: No

Cloned: Yes DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC

TGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAA GTCAAGCAAGCATACACTGGGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTTTTGTAAGGCAGAC

GAAAAGCCATGCAΆGTATCATGCAGATTGCTGTAACTGCTGTCTCGGTGGAΆTCTGTAAACCAΆGCACAA GTTGGATTGGATGCTCGACGAATGTGTTCTTGACGCGCTGACTTTCAGCCAGCTAGGCCATGCCTAGG

(SEQ ID NO:79) Translation:

MKLCLTFLLVLMILASVTGEKSSKHTLGRAARVKNRGPSFCKADEKPCKYHADCCNCCLGGICKPSTS I GCSTNVFLTR (SEQ ID NO: 80)

Toxin Sequence: Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asp-Xaal-Lys-Xaa3-Cys-Lys-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Gly-Gly-Ile-Cys-Lys-Xaa3-Ser-Thr-Ser-Xaa4- Ile-Gly-Cys-Ser-Thr-Asn-Val-P e-Leu-Thr-Arg-^A (SEQ ID NO: 81)

Name: S11.4

Species : striatus

Isolated: No

Cloned: Yes DNA Sequence:

CCGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGCT GGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAAG TCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTTTTGTAAGGCAGACG AAAAGCCATGCAAGTATCATGCAGGTTGCTGTAACTGCTGTCTCGGTGGAATCTGTAAACCAAGCACAAG TTGGATTGGATGCTCGACGAATGTGTTCTTGACGCGCTGACTTTCAGCCAGCTAGGCCATGCCTAGG (SEQ ID NO:82)

Translation:

MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNRGPSFCKADEKPCKYHAGCCNCCLGGICKPSTSWI GCSTNVFLTR (SEQ ID NO: 83)

Toxin Sequence:

Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asp-Xaal-Lys-Xaa3-Cys-Lys-Xaa5-His-Ala- Gly-Cys-Cys-Asn-Cys-Cys-Leu-Gly-Gly-Ile-Cys-Lys-Xaa3-Ser-Thr-Ser-Xaa4- Ile-Gly-Cys-Ser-Thr-Asn-Val-P e-Leu-Thr-Arg-^A (SEQ ID NO: 84)

Name: Call.2

Species: caracteristicus Isolated: No

Cloned: Yes

DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGCAAAACCATCTGG TGGTCAGTATGAAGCTGTGTGTGACGTTTCTTCTTGTTCTGGTGATTCTGCCATCGGTGACCGGGGAGAA GTCTAGCGAGCGTACACGGATTGGTGCTGTTCTGAAAGGCCATTGGTGCGGATACCTAGGAGAACGCGGA TGCCGATATCATAGCCAATGCTGTGGGGACATGTGTTGTTACGACCGCAAGTGTGTTGTGACTGCTATGC CATGTGACTTTCCCTACTAGTGCGATGGACCTAGGCGTGCCGGCCTTGTGGCAGACTCGCTCAGTATGCC TGATCTGTCCAAGTGAAACGACCGGACACGATCGTCGTATTCCTTTGCCAAGAGCCAGCTAGGCCATGCC TAGG (SEQ ID NO: 85) Translation:

MKLCVTFLLVLVILPSVTGEKSSERTRIGAVLKGHWCGYLGERGCRYHSQCCGDMCCYDRKC TAMPCD FPY (SEQ ID NO: 86)

Toxin Sequence:

Gly-His-Xaa4-Cys-Gly-Xaa5-Leu-Gly-Xaal-Arg-Gly-Cys-Arg-Xaa5-His-Ser- Gln-Cys-Cys-Gly-Asp-Met-Cys-Cys-Xaa5-Asp-Arg-Lys-Cys-Val-Val-Thr-Ala- Met-Xaa3-Cys-Asp-Phe-Xaa3-Xaa5-^A (SEQ ID NO: 87)

Name: Call.3

Species: caracteristicus

Isolated: No Cloned: Yes

DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGCAAAACCATCTGG TGGTCAGTATGAAGCTGTGTGTGACGTTTCTTCTTGTTCTGGTGATTCTGCCATCGGTGACCGGGGAGAA GTCTAGCGAGCGTACACGGATTGGTGCTGTTCTGAAAGGCCATTGGTGCGGATACCCAGGAGAACGCGGA TGCCGATATCATAGCCAATGCTGTGGGGACATGTGTTGTTACGACCGCAAGTGTGTTGTGACTGCTATGC CATGTGACTTTCCCTACTAGTGCGATGGACCTAGGCGTGCTGGCCTTGTGGCAGACTCGCTCAGTATGCC TGATCTGTCCAAGTGAAACGACCGGACACGATCGTCGTATTCCTTTGCCAAGAGCCAGCTAGGCCATGCC TAGG (SEQ ID NO: 88)

Translation:

MKLCVTFLLVLVILPSVTGEKSSERTRIGAVLKGHWCGYPGERGCRYHSQCCGDMCCYDRKCVVTAMPCD FPY (SEQ ID NO: 89) Toxin Sequence:

Gly-His-Xaa4-Cys-Gly-Xaa5-Xaa3-Gly-Xaal-Arg-Gly-Cys-Arg-Xaa5-His-Ser- Gln-Cys-Cys-Gly-Asp-Met-Cys-Cys-Xaa5-Asp-Arg-Lys-Cys-Val-Val-Thr-Ala- Met-Xaa3-Cys-Asp-Phe-Xaa3-Xaa5-^A (SEQ ID NO: 90)

Name: Call.4

Species: caracteristicus

Isolated: No

Cloned: Yes

DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGCAAAACCATCTGG TGGTCAGTATGAAGCTGTGTGTGACGTTTCTTCTTGTTCTGGTGATTCTGCCATCGGTGACCGGGGAGAA GTCTAGCGAGCGTACACGGATTGGTGCTGTTCTGAAAGGCCATTGGTGCGGATACCTAGGAGAACGCGGA TGCCGATATCATAGCCAATGCTGTGGGGACATGTGTTGTTACGACCGCAAGTGTGCTGTGACTGCTATGC CATGTGACTTTCCCTACTAGTGCGATGGACCTAGGCGTGCTGGCCTTGTGGCAGACTCGCTCAGTATGCC TGATCTGTCCAAGTGAAACGACCGGACACGATCGTCGTATTCCTTTGCCAAGAGCCAGCTAGGCCATGCC TAGG (SEQ ID NO: 91) Translation:

MKLCVTFLLVLVILPSVTGEKSSERTRIGAVLKGHWCGYLGERGCRYHSQCCGDMCCYDRKCAVTAMPCD FPY (SEQ ID NO: 92)

Toxin Sequence : Gly-His-Xaa4-Cys-Gly-Xaa5-Leu-Gly-Xaal-Arg-Gly-Cys-Arg-Xaa5-His-Ser- Gln-Cys-Cys-Gly-Asp-Met-Cys-Cys-Xaa5-Asp-Arg-Lys-Cys-Ala-Val-Thr-Ala- Met-Xaa3-Cys-Asp-Phe-Xaa3-Xaa5-^A ( SEQ ID NO : 93 )

Name: Call.5

Species: caracteristicus

Isolated: No

Cloned: Yes

DNA Sequence:

CCGCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCATAGAAGAAGGCAAAACCATCTGGT GGTCAGTATGAAGCTGTGTGTGACGTTTCTTCTTGTTCTGGTGATTCTGCCATCGGTGACCGGGGAGAAG TCTAGCGAGCGTACACGGATTGGTGCTGTTCTGAAAGGCCATTGGTGCGGATACCCAGGAGAACGCGGAT GCCGATATCATAGCCAATGCTGTGGGGACATGTGTTGTTACGACCGCATGTGTGTTGTGACTGCTATGCC ATGTGACTTTCCCTACTAGTGCGATGGACCTAGGCGTGCTGGCCTTGTGGCAGACTCGCTCAGTATGCCT GATCTGTCCAAGTGAAACGACCGGACACGATCGTCGTATTCCTTTGCCAAGAGCCAGCTAGGCCATGCCT AGG (SEQ ID NO: 94) Translation:

MKLCVTFLLVLVILPSVTGEKSSERTRIGAVLKGHWCGYPGERGCRYHSQCCGDMCCYDRMCVVTAMPCD FPY (SEQ ID NO: 95)

Toxin Sequence: Gly-His-Xaa4-Cys-Gly-Xaa5-Xaa3-Gly-Xaal-Arg-Gly-Cys-Arg-Xaa5-His-Ser- Gln-Cys-Cys-Gly-Asp-Met-Cys-Cys-Xaa5-Asp-Arg-Met-Cys-Val-Val-Thr-Ala- Met-Xaa3-Cys-Asp-Phe-Xaa3-Xaa5-^A (SEQ ID NO: 96)

Name: Call.6

Species: caracteristicus

Isolated: No

Cloned: Yes DNA Sequence:

CCAGCTATAGCACTTCGCAGCAGNCGAGGCTTTAAAATCCTAATCATAGAAGAAGGCAAAACCATCTGGT GGTCAGTATGAAGCTGTGTGTGACGTTTCTTCTTGTTCTGGTGATTCTGCCATCGGTGACCGGGGAGAAG TCTAGCGAGCGTACACGGATTGGTGCTGTTCTGAAAGGCCATTGGTGCGGATACCTAGGAGAACGCGGAT GCCGATATCATGGCCAATGCTGTGGGGACATGTGTTGTTACGACCGCAAGTGTGTTGTGACTGCTATGCC ATGTGACTTTCCCTACTAGTGCGATGGACCTAGGCGTGCTGGCCTTGTGGCAGACTCGCTCAGTATGCCT GATCTGTCCAAGCGAAACGACCGGACACGATCGTCGTATTCCTTTGCCAAGAGCCAGCTAGGCCATGCCT AGG (SEQ ID NO: 97)

Translation: MKLCVTFLLVLVILPSVTGEKSSERTRIGAVLKGHWCGYLGERGCRYHGQCCGDMCCYDRKCVVTAMPCD FPY (SEQ ID NO: 98)

Toxin Sequence :

Gly-His-Xaa4-Cys-Gly-Xaa5-Leu-Gly-Xaal-Arg-Gly-Cys-Arg-Xaa5-His-Gly- Gln-Cys-Cys-Gly-Asp-Met-Cys-Cys-Xaa5-Asp-Arg-Lys-Cys-Val-Val-Thr-Ala- Met-Xaa3-Cys-Asp-Phe-Xaa3-Xaa5-^A (SEQ ID NO: 99)

Name: Call.7 Species: caracteristicus Isolated: No Cloned: Yes

DNA Sequence:

CCGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGCT GGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGTGAGG TCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTTTTGTAAGGCAAACG GAAAGCCATGCTCGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTGAACCAAGCACAAA TGTGATTTTACCTGGATGCTCGACGAGTTCGTTCTTCAGGATCTGACTTTCAGCCAGCTAGGCCATGCCT AGG (SEQ ID NO: 100)

Translation:

MKLCLTFLLVLMILASVTGVRSS HTLSRAARVKNRGPSFCKANGKPCSYHADCCNCCLSGICEPSTNVI LPGCSTSSFFRI (SEQ ID NO: 101) Toxin Sequence :

Gly-Xaa3-Ser-P e-Cys-Lys-Ala-Asn-Gly-Lys-Xaa3-Cys-Ser-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys~Cys-Leu-Ser-Gly-Ile-Cys-Xaal-Xaa3-Ser-Thr-Asn-Val- Ile-Leu-Xaa3-Gly-Cys-Ser-Thr-Ser-Ser-P e-Phe-Arg-Ile- (SEQ ID NO: 102)

Name: Mll.l

Species : magus

Isolated: No

Cloned: Yes

DNA Sequence:

CCGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAGTCCTAATCATAGAAGAAGGCAAAAATATCTGCT

GGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAAG

TTGAGCAAGCATACACTGAGTCATGCTGCTAGGAGACCCAACAAAGGCGCTGTTCCATGCGGGAAAGACG GAAGGCAATGCAGGAATCATGCAGATTGCTGTAATTGCTGTCCCATTGGAACCTGTGCACCAAGCACAAA

TTGGATTTTACCTGGATGCTCGACGGGTCAATTCATGACGCGCTGACTTTCAGCCAGCTAGGCCATGCCT

AGG (SEQ ID NO: 103)

Translation : MKLCLTFLLVLMILASVTGEKLSKHTLSHAARRPNKGAVPCGKDGRQCRNHADCCNCCPIGTCAPSTN I LPGCSTGQFMTR (SEQ ID NO: 104)

Toxin Sequence :

Gly-Ala-Val-Xaa3-Cys-Gly-Lys-Asp-Gly-Arg-Gln-Cys-Arg-Asn-His-Ala-Asp- Cys-Cys-Asn-Cys-Cys-Xaa3-Ile-Gly-Thr-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4-

Ile-Leu-Xaa3-Gly-Cys-Ser-Thr-Gly-Gln-Phe-Met-Thr-Arg-^Λ (SEQ ID NO: 105)

Name: Mil.2 Species : magus

Isolated: No

Cloned: Yes

DNA Sequence: CCAGCTATCAGCACTTCGCAGCAGNNGAGGCTTTAAAATCCTAATCGTAGAAGAAGGCAAAAACATCTGG TGTCAGTATGAAGCTGTGTGTGACGTTTCTTCTTGTTCTGGTGATTCTGCCATCAGTAACTGGGGAGAAG TCTAGCGAGCGTACACTGAGTGGTGCTGCTCTGAGAGGCGATCGGAGAACGTGCTCAAACAAAGGACAAC AATGCGGAGATGATTCCGACTGCTGTTGGCATTTGTGTTGTGTGAACAACAAGTGCGCTCACTTGATCCT ATTATGTAACTTATAGTGCGATGGACCTAGGCGTGCTGGCCTAGCAGCCGACTCGCTCAGTATGCCTGAT CTGTCCGAGTGACCTGACACGATCCGTCGTATTCCTTTGCCAAGAGCCAGCTAGGCCATGCCTAGG (SEQ ID NO:106) Translation:

MKLCVTFLLVLVILPSVTGEKSSERTLSGAALRGDRRTCSNKGQQCGDDSDCC HLCCVNNKCAHLILLC NL (SEQ ID NO: 107)

Toxin Sequence:

Thr-Cys-Ser-Asn-Lys-Gly-Gln-Gln-Cys-Gly-Asp-Asp-Ser-Asp-Cys-Cys-Xaa4- His-Leu-Cys-Cys-Val-Asn-Asn-Lys-Cys-Ala-His-Leu-Ile-Leu-Leu-Cys-Asn- Leu-^A (SEQ ID NO: 108)

Name: Mil.3

Species : magus

Isolated: No Cloned: Yes

DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGNTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC TGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAA GTCAAGCAAGCATACACTGAGTCGTGCTGCCAGGGTAAAAAACAGAGGCCCgAGTTTTTGTAAGGCAGAC GAAAAGCCATGCGAGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTGCACCAAGCACAA ATTGGATTTTACCTGGATGCTCGACGAGTTCGTTCTTCGAGATCTGACTTTCAGCCAGCTAGGCCATGCC TAGG (SEQ ID NO: 109) Translation:

MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNRGPSFCKADEKPCEYHADCCNCCLSGICAPSTNWI LPGCSTSSFFEI (SEQ ID NO: 110)

Toxin Sequence : Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asp-Xaal-Lys-Xaa3-Cys-Xaal-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4- Ile-Leu-Xaa3-Gly-Cys-Ser-Thr-Ser-Ser-Phe-P e-Xaal-Ile-^A (SEQ ID NO.lll)

Name: Mil.4

Species : magus

Isolated: No

Cloned: Yes

DNA Sequence:

CCGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGCT GGTCAATATGAGGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAAG TCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTTTTGTAAGGCAGACG AAAAGCCATGCGAGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTGCACCAAGCACAAA TTGGATTTTACCTGGATGCTCGACGAGTTCGTTCTTCAAGACCTGACTTTCAGCTAGCTAGGCCATGCCT AGG (SEQ ID NO: 112)

Translation: MRLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNRGPSFCKADEKPCEYHADCCNCCLSGICAPSTNWI LPGCSTSSFFKT (SEQ ID NO: 113)

Toxin Sequence :

Gly-Xaa3-Ser-P e-Cys-Lys-Ala-Asp-Xaal-Lys-Xaa3-Cys-Xaal-Xaa5-His-Ala- Asρ-Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4- Ile-Leu-Xaa3-Gly-Cys-Ser-Thr-Ser-Ser-Phe-Phe-Lys-Thr-^A (SEQ ID NO: 114) Name: Mil.5

Species : magus Isolated: No

Cloned: Yes

DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGATATCCTAATCATAGAAGAAGGCAAAAATATCTGC TGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAA

GTTAAGCGAGCAAACACTGCGTCGTGCTGCTAGGAAAAACAAAGGCCATGTTCCATGCGGGAAAGACGGA

AGGAAATGCGGGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTAAACCAAGCACAAGTT

GGACTGGATGCTCGACGAGTACGTTCGATTGACGCGCTGACTTTCAGCTAGCTAGGCCATGCCTAGG

(SEQ ID NO:115)

Translation:

MKLCLTFLLVLMILASVTGEKLSEQTLRRAARKNKGHVPCGKDGRKCGYHADCCNCCLSGICKPSTS TG

CSTSTFD (SEQ ID NO: 116) Toxin Sequence:

Gly-His-Val-Xaa3-Cys-Gly-Lys-Asp-Gly-Arg-Lys-Cys-Gly-Xaa5-His-Ala-Asp- Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Lys-Xaa3-Ser-Thr-Ser-Xaa4-Thr- Gly-Cys-Ser-Thr-Ser-Thr-Phe-Asp-^Λ (SEQ ID NO: 117)

Name: Mil.6

Species : magus

Isolated: No

Cloned: Yes

DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGCAAAAACATCTGG TGGTCAGTATGAAGCTGTGTGTGACGTTTCTTCTTGTTCTGGTGATTCTGCCATCAGTAACTGGGGAGGA GTCTAGCGAGCGTACACTGAGTGGTGCTACTCTGACAGGCGATCGGGGAATGTGCTCACTCTTAGGACAA CGATGCGGAGATCATTCCGACTGCTGTTGGGACATGTGTTGTGCCAGCGAAATGTGCGTTGTGACTTTCC TTCCATGTAAATGATTTCCCTACTAGGGCGATGGACCTAGGCGTGCTGGCCTAGCGGTAGACTCGCTCAG TATGCCTGATCTGTCTGAGTGAAACGACCTGACACGATCCGTCGTATTCCTTTGCCAAGAGCCAGCTAGG CCATGCCTAGG (SEQ ID NO: 118) Translation:

MKLCVTFLLVLVILPSVTGEESSERTLSGATLTGDRGMCSLLGQRCGDHSDCCWDMCCASEMCWTFLPC K (SEQ ID NO: 119)

Toxin Sequence: Gly-Met-Cys-Ser-Leu-Leu-Gly-Gln-Arg-Cys-Gly-Asp-His-Ser-Asp-Cys-Cys- Xaa4-Asp-Met-Cys-Cys-Ala-Ser-Xaal-Met-Cys-Val-Val-Thr-P e-Leu-Xaa3- Cys-Lys-^A (SEQ ID NO: 120)

Name: Mil.7

Species : magus

Isolated: No

Cloned: Yes DNA Sequence: CCAGCTATCAGCACTTCGCAGCAGTCGNGGNTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC TGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAA GTCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTTTTGTAAGGCAAAC GGAAAGCCATGCTCGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTAAACCAAGCACAA ATGTGATTTTACCTGGATGCTCGACGAGTTCGCTCTTCAGGATCTGACTTTCAGCTAGCTAGGCCATGCC TAGG (SEQ ID NO: 121)

Translation:

MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNRGPSFCKANGKPCSYHADCCNCCLSGICKPSTNVI LPGCSTSSLFRI (SEQ ID NO: 122)

Toxin Sequence:

Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asn-Gly-Lys-Xaa3-Cys-Ser-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Lys-Xaa3-Ser-Thr-Asn-Val- Ile-Leu-Xaa3-Gly-Cys-Ser-T r-Ser-Ser-Leu-Phe-Arg-Ile-^A (SEQ ID NO: 123)

Name: Mil.8

Species : magus

Isolated: No

Cloned: Yes

DNA Sequence:

CCGCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGCAAAAACATCTGGT GGTCAGTATGAAGCTGTGTGTGACGTTTCTTCTTGTTCTGGTGATTCTGCCATCAGTAACTGGGGTGAAG TCTAGCGAGCGTACACTGAGTGGTGCTGCTCTGAGAGGCGATCGGGGAACGTGCTCAGGCAGAGGACAAG AATGCAAACATGATTCCGACTGCTGTGGGCATTTGTGTTGTGCCGGCATAACGTGCCAATTCACTTACAT TCCATGTAAATGATTTCCCTACTAGTGCGATGGACCTAGGCGTGCTGGCCTAGCGGTAGACTCGCTCAGT ATGCCTGATCTGTCCGAGTGAAACGACCTGACATGATCCGTCGTATTCCTTTGCCAAGAGCCAGCTAGGC CATGCCTAGG (SEQ ID NO: 124)

Translation:

MKLCVTFLLVLVILPSVTGVKSSERTLSGAALRGDRGTCSGRGQECKHDSDCCGHLCCAGITCQFTYIPC K (SEQ ID NO:125)

Toxin Sequence :

Gly-Thr-Cys-Ser-Gly-Arg-Gly-Gln-Xaal-Cys-Lys-His-Asp-Ser-Asp-Cys-Cys- Gly-His-Leu-Cys-Cys-Ala-Gly-Ile-Thr-Cys-Gln-Phe-Thr-Xaa5-Ile-Xaa3-Cys- Lys-^A (SEQ ID NO:126)

Name: Call.8

Species: caracteristicus

Isolated: No Cloned: Yes

DNA Sequence:

CCGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGCT GGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAAG TCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTTTTGTAAGGCAGACG^' AAAAGCCATGCGAGTATCATGCAGATTGCTGTAATTGCTTTCTCAGTGGAATCTGTGCACCAAGCACAAA TTGGATTTTACCTGGATGCTCGACGAGTTCGTTCTTCAAGATCTGACTTTCAGCCAGCTAGGCCATGCCT AGG (SEQ ID NO: 127) Translation: MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNRGPSFCKADEKPCEYHADCCNCFLSGICAPSTNWI LPGCSTSSFFKI (SEQ ID NO: 128)

Toxin Sequence: Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asp-Xaal-Lys-Xaa3-Cys~Xaal-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Phe-Leu-Ser-Gly-Ile-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4- Ile-Leu-Xaa3-Gly-Cys-Ser-Thr-Ser-Ser-Phe-Phe-Lys-Ile-^A (SEQ ID NO: 129)

Name: Call.9

Species: caracteristicus

Isolated: No

Cloned: Yes DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC TGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAA GTCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTTTTGTAAGGCAGAC GAAAAGCCATGCAAGTATCATGCAGATTGCTGTAACTGCTGTCTCGGTGGAATCTGTAAACCAAGCACAA GTTGGATTGGATGCTCGACGAATGTGTTCCTGACGCGCTGACTTTCAGCCAGCTAGGCCATGCCTAGG (SEQ ID NO:130)

Translation:

MKLCLTFLLVLMILASVTGΞKSSKHTLSRAARVKNRGPSFCKADEKPCKYHADCCNCCLGGICKPSTSWI GCSTNVFLTR (SEQ ID NO: 131)

Toxin Sequence:

Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asp-Xaal-Lys-Xaa3-Cys-Lys-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Gly-Gly-Ile-Cys-Lys-Xaa3-Ser-Thr-Ser-Xaa4- Ile-Gly-Cys-Ser-Thr-Asn-Val-Phe-Leu-T r-Arg- (SEQ ID NO: 132)

Name: Call.10

Species: caracteristicus Isolated: No

Cloned: Yes

DNA Sequence:

CCGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGCT GGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAAG TCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTTTTGTAAGGCAGACG AAAAGCCATGCAAGTATCATGCAGATTGCTGTAACTGCTGTCTCGGTGGAATCTGTAAACCAAGCACAAG TTGGATTGGATGCTCGACGAATGTGTTCTTGACGCGCTGACTTTCAGCCAGCTAGGCCATGCCTAGG (SEQ ID NO: 133)

Translation :

MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNRGPSFCKADEKPCKYHADCCNCCLGGICKPSTSWI GCSTNVFLTR (SEQ ID NO: 134) Toxin Sequence:

Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asp-Xaal-Lys-Xaa3-Cys-Lys-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Gly-Gly-Ile-Cys-Lys-Xaa3-Ser-Thr-Ser-Xaa4- Ile-Gly-Cys-Ser-T r-Asn-Val-P e-Leu-Thr-Arg-^A (SEQ ID NO: 135) Name: Call.11 Species: caracteristicus Isolated: No Cloned: Yes

DNA Sequence :

CCAGCTATCAGCACTTCGCAGCAGTCGAGGNTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC TGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCCGTGACTGGGGAGAA GTTAAGCGAGCAAACACTGCGCCGTGCTGCTAGGAAAAACAAAGGCCCTCGATGCTGGGTCGGCCGTGTC CATTGCACCTATCATAAAGACTGCTGTCCGTCGGTATGTTGTTTCAAGGGAAGGTGTAAACCACAATCAT GGGGATGCTGGTCGGGTCCGACCTAGGCGTGCTGGCCTTGAGGCAGCTAGGCCATGCCTAGG (SEQ ID N0:136)

Translation: MKLCLTFLLVLMILASVTGEKLSEQTLRRAARKNKGPRCWVGRVHCTYHKDCCPSVCCFKGRCKPQS GC WSGPT (SEQ ID NO: 137)

Toxin Sequence :

Gly-Xaa3-Arg-Cys-Xaa4-Val-Gly-Arg-Val-His-Cys-Thr-Xaa5-His-Lys-Asp- Cys-Cys-Xaa3-Ser-Val-Cys-Cys-Phe-Lys-Gly-Arg-Cys-Lys-Xaa3-Gln-Ser- Xaa4-Gly-Cys-Xaa4-Ser-Gly-Xaa3-Thr-^A (SEQ ID NO: 138)

Name: Call.12 Species: caracteristicus

Isolated: No

Cloned: Yes

DNA Sequence: CCAGCTATCAGCACTTCGCAGCAGNNGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC TGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAA GTCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTTTTGTAAGGCAGAC GAAAAGCCATGCGAGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTGCACCAAGCACAA ATTGGATTTTACCTGGATGCTCGACGAGTTCGTTCTTCAAGATCTGACTTTCAGCCAGCTAGGCCATGCC TAGG (SEQ ID NO: 139)

Translation:

MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNRGPSFCKADEKPCEYHADCCNCCLSGICAPSTNWI LPGCSTSSFFKI (SEQ ID NO: 140)

Toxin Sequence :

Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asp-Xaal-Lys-Xaa3-Cys-Xaal-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4- Ile-Leu-Xaa3-Gly-Cys-Ser-Thr-Ser-Ser-P e-Phe-Lys-Ile-^A (SEQ ID NO: 141)

Name: Call.14

Species: caracteristicus

Isolated: No Cloned: Yes

DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC

TGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAA GTCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTTTTGTAAGGCAAAC

GGAAAGCCATGCTCGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTAAACCAAGCACAA ATGTGATTTTACCTGGATGCTCGACGAGTTCGTTCTTCAGGATCTGACTTTCAGCCAGCTAGGCCATGCC TAGG (SEQ ID NO: 142)

Translation: MKLCLTFLLVL ILASVTGEKSSKHTLSRAARVKNRGPSFCKANGKPCSYHADCCNCCLSGICKPSTNVI LPGCSTSSFFRI (SEQ ID NO: 143)

Toxin Sequence:

Gly-Xaa3-Ser-P e-Cys-Lys-Ala-Asn-Gly-Lys-Xaa3-Cys-Ser-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Lys-Xaa3-Ser-Thr-Asn-Val- Ile-Leu-Xaa3-Gly-Cys-Ser-Thr-Ser-Ser-Phe-P e-Arg-Ile-^A (SEQ ID NO: 144)

Name: S11.6

Species : striatus

Isolated: No

Cloned: Yes

DNA Sequence: CCGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAGGGCAAAAATATCTGCT GGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAAG TCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTTTTGTAAGGCAGACG AAAAGCCATGCGAGTATCATGCAGATTGCTGTAATTGCTGTCTCAGCGGAATCTGTGCACCAAGCACAAA TTGGATTTTACCTGGATGCTCGACGAGTTCGTTCTTCAAGATCTGACTTTCAGCTAGCTAGGCCATGCCT AGG (SEQ ID NO: 145)

Translation :

MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNRGPSFCKADEKPCEYHADCCNCCLSGICAPSTNWI LPGCSTSSFFRI (SEQ ID NO: 146)

Toxin Sequence :

Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asp-Xaal-Lys-Xaa3-Cys-Xaal-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4- Ile-Leu-Xaa3-Gly-Cys-Ser-T r-Ser-Ser-P e-Phe-Lys-Ile-^A (SEQ ID NO: 147)

Name: S11.7

Species : striatus

Isolated: No

Cloned: Yes

DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC TGGTCAATATGAAGCTGTGCCTGGCGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAA GTCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCTGTAAGAAAGACAGAAAGCCA TGCTCGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTGCACCAAGCACAAATTGGATTT TACCTGGATGCTCGACGAGTACGTTCACTTGACGCGCTGACTTTCAGCCAGCTAGGCCATGCCTAGG (SEQ ID NO:148) Translation:

MKLCLAFLLVLMILASVTGEKSSKHTLSRAARVKNRGCKKDRKPCSYHADCCNCCLSGICAPSTN ILPG CSTSTFT (SEQ ID NO: 149)

Toxin Sequence: Gly-Cys-Lys-Lys-Asp-Arg-Lys-Xaa3-Cys-Ser-Xaa5-His-Ala-Asp-Cys-Cys-Asn- Cys-Cys-Leu-Ser-Gly-Ile-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4-Ile-Leu-Xaa3- Gly-Cys-Ser-Thr-Ser-Thr-Phe-Thr-^A ( SEQ ID NO : 150 )

Name: S11.8

Species: striatus

Isolated: No

Cloned: Yes

DNA Sequence:

CCGCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGCAAAAATATCTGCT GGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAAG TCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTTTTGTAAGGCAGACG AAAΆGCCATGCAΆGTATCATGCAGATTGCTGTAACTGCTGTCTCGGTGGAATCTGTAAACCAΆGCACAAG TTGGATTGGATGCTCGACGAATGTGTTCTTGACGCGCTGACTTTCAGCCAGCTAGGCCATGCCTAGG

(SEQ ID NO:151)

Translation: MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNRGPSFCKADEKPCKYHADCCNCCLGGICKPSTSWI GCSTNVFLTR (SEQ ID NO: 152)

Toxin Sequence :

Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asp-Xaal-Lys-Xaa3-Cys-Lys-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Gly-Gly-Ile-Cys-Lys-Xaa3-Ser-Trιr-Ser-Xaa4- Ile-Gly-Cys-Ser-Thr-Asn-Val-Phe-Leu-Thr-Arg-^A (SEQ ID NO: 153)

Name: Btll.l

Species : betulinus

Isolated: No

Cloned: Yes

DNA Sequence: CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGGAAACATATCTGG TGGTCAGTATGAAGCTGTGTGTGGCGTTTCTTCTTGTTCTGGTGATTCTGCCATCGGTGATTGGGGGGAA GCCTAGCGAGCGTACACTGAGTGGTGCTACTCGGAGAGGCGATCGGAGAATGTGCTTATCCCTAGGACAA AGATGCGAACGTCATTCCAACTGCTGTGGCTATCTGTGTTGTTTCTACGACAAGTGTGTTGTGACTGCCA TAGGGTGTGGCCACTACTAGTGCGATGGACCTAGGCGCGCTGGCCCTGTGGCAGACTCGCTCAGTATGCC TGATCTGTCCAAGTGACACGACCTGACACGATCGTCGTATTCCTTTGCCAAGAGTCAGCTAGGCCATGCC TAGG (SEQ ID NO: 154)

Translation :

MKLCVAFLLVLVILPSVIGGKPSERTLSGATRRGDRRMCLSLGQRCERHSNCCGYLCCFYDKCVVTAIGC GHY (SEQ ID NO: 155)

Toxin Sequence :

Met-Cys-Leu-Ser-Leu-Gly-Gln-Arg-Cys-Xaal-Arg-His-Ser-Asn-Cys-Cys-Gly- Xaa5-Leu-Cys-Cys-Phe-Xaa5-Asp-Lys-Cys-Val-Val-Thr-Ala-Ile-Gly-Cys-Gly- His-Xaa5-^A ( SEQ ID NO : 156)

Name: Btll.2

Species : betulinus

Isolated: No

Cloned: Yes DNA Sequence:

CCGCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGGAAACATATCTGGT GGTCAGTATGAAGCTGTGTGTGGCGTTTCTTCTTGTTCTGGTGATTCTGCCATCGGTGATTGGGGGGAAG CCTAGCGAGCGTACACTGAGTGGTGCTACTCGGAGAGGCGATCGGAGAATGTGCTCATTCCTAGGACAAA GATGCGAACGTCATTTCAACTGCTGTGGCGACCTGTGTTGTTTCGACGACATGTGTCTTGTGGCTGCCAT AGGGTGTGGCTACTAATAATGCGATGGACCTAGGCGCGCTGGCTCTGTGGCAGGCTCGTTCAGTATGCCT GATCTGTCCAAGTGACACGACCTGACACGATCGTCGTATTTCTTTGCCAAGAGCCAGCTAGGCCATGCCT AGG (SEQ ID NO: 157)

Translation:

MKLCVAFLLVLVILPSVIGGKPSERTLSGATRRGDRRMCSFLGQRCERHFNCCGDLCCFDDMCLVAAIGC GY (SEQ ID NO: 158) Toxin Sequence:

Met-Cys-Ser-Phe-Leu-Gly-Gln-Arg-Cys-Xaal-Arg-His-Phe-Asn-Cys-Cys-Gly- Asp-Leu-Cys-Cys-P e-Asp-Asp-Met-Cys-Leu-Val-Ala-Ala-Ile-Gly-Cys-Gly- Xaa5-^A (SEQ ID NO: 159)

Name: Btll.3

Species : betulinus

Isolated: No

Cloned: Yes

DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGNNGAGGCTTTAAAATCCTAATCGTAGAAGAAGGGAAACATATCTGG TGGTCAGTATGAAGCTGTGTGTGGCGTTTCTTCTTGTTCTGGTGATTCTGCCATCGGTGATTGGGGGGAA GCCTAGCGAGCGTACACTGAGTGGTGCTACTCGGAGAGGCGATCGGAGAATCTGCTCATTCCTAGGATGC GAACGTCATTTCAACTGCTGTGGCGATCTGTGTTGTTTCGACGACATGTGTGTTGTGACTGCCATAGGGT GTGGCCACTAGTAGTGCGACGGACCTAGGCGCGCTGGCCCTGTGGCAGACTCGCTCAGTATGCCTGATCT GTCCAAGTGACACGACCTGACACGATCGTCGTATTCCTTTGCCAAGAGTTAGCTAGGCCATGCCTAGG (SEQ ID NO:160) Translation:

MKLCVAFLLVLVILPSVIGGKPSERTLSGATRRGDRRICSFLGCERHFNCCGDLCCFDDMCVVTAIGCGH (SEQ ID NO:161)

Toxin Sequence : Ile-Cys-Ser-Phe-Leu-Gly-Cys-Xaal-Arg-His-Phe-Asn-Cys-Cys-Gly-Asp-Leu- Cys-Cys-Phe-Asp-Asp-Met-Cys-Val-Val-Thr-Ala-Ile-Gly-Cys-Gly-His-^A (SEQ ID NO:162)

Name: Btll.4

Species : betulinus

Isolated: No

Cloned: Yes DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGGAAACATATCTGG TGGTCAGTATGAAGCTGTGTGTGGCGTTTCTTCTTGTTCTGGTGATTCTGCCATCGGTGATTGGGGGGAA GCCTAGCGAGCGTACACTGAGTGGTGCTACTCGGAGAGGCGATCGGAGAATGtGCTTATCCCTAGGACAA CGATGCGGACGTCATTCCAACTGCTGTGGCTATCTGTGTTGTTTCTACGACAAGTGTGTTGTGACTGCCA TAGGGTGTGGCCACTACTAGTGCGATGGACCTAGGTGCGCTGGCCCTGTGGCAGACTCGCTCAGTATGCC TGATCTGTCCAAGTGACACGACCTGACACGATCGTCGTATTCCTTTGCCAAGAGTCAGCTAGGCCATGCC TAGG (SEQ ID NO: 163)

Translation: MKLCVAFLLVLVILPSVIGGKPSERTLSGATRRGDRRMCLSLGQRCGRHSNCCGYLCCFYDKCVVTAIGC GHY (SEQ ID NO: 164)

Toxin Sequence:

Met-Cys-Leu-Ser-Leu-Gly-Gln-Arg-Cys-Gly-Arg-His-Ser-Asn-Cys-Cys-Gly- Xaa5-Leu-Cys-Cys-Phe-Xaa5-Asp-Lys-Cys-Val-Val-Thr-Ala-Ile-Gly-Cys-Gly- His-Xaa5-^Λ (SEQ ID NO: 165)

Name: Btll.5

Species : betulinus

Isolated: No

Cloned: Yes

DNA Sequence: CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGGAAACATATCTGG TGGTCAGTATGAAGCTGTGTGTGGCGTTTCTTCTTGTTCTGGTGATTCTGCCATCGGTGATTGGGGGGAA GCCTAGCGAGCGTACACTGAGTGGTGCTACTCGGAGAGGCGATCGGAGAATGTGCCTATCCCTAGGACAA AGATGCGAACGTCATTCCGACTGCTGTGGCTATCTGTGTtGTTTCTACGACAAGTGTGTTGTGACTGCCA TAGGGTGTGGCCACTACTAGTGCGATGGACCTAGGCGCGCTGGCCCTGTGGCAGACTCGCTCAGTATGCC TGATCTGTCCAAGTGACACGACCTGACACGGTCGTCGTATTCCTTTGCCAAGAGTCAGCTAGGCCATGCC TAGG (SEQ ID NO: 166)

Translation:

MKLCVAFLLVLVILPSVIGGKPSERTLSGATRRGDRRMCLSLGQRCERHSDCCGYLCCFYDKCWTAIGC GHY (SEQ ID NO: 167)

Toxin Sequence:

Met-Cys-Leu-Ser-Leu-Gly-Gln-Arg-Cys-Xaal-Arg-His-Ser-Asp-Cys-Cys-Gly- Xaa5-Leu-Cys-Cys-Phe-Xaa5-Asp-Lys-Cys-Val-Val-Thr-Ala-Ile-Gly-Cys-Gly- His-Xaa5-^A ( SEQ ID NO : 168 )

Name: Btll.6

Species : betulinus

Isolated: No

Cloned: Yes

DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC TGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAA GTCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAAAGGCCATGTTCCATGCGGGAAAGAC GGAAGGAAATGCGGGTATCATACACATTGCTGTAΆTTGCTGTCTCAGTGGAΆTCTGTAAACCAAGCACAA GTTTGATTGGATGCTCGACGAGTTCGTTCACTTGACGCGCTGACTTTCAGCCAGCTAGGCCATGCCTAGG

(SEQ ID NO:169)

Translation:

MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKNKGHVPCGKDGRKCGYHTHCCNCCLSGICKPSTSLI GCSTSSFT (SEQ ID NO: 170) Toxin Sequence: Gly-His-Val~Xaa3-Cys-Gly-Lys-Asp-Gly-Arg-Lys-Cys-Gly-Xaa5-His-Thr-His- Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Lys-Xaa3-Ser-T r-Ser-Leu-Ile- Gly-Cys-Ser-Thr-Ser-Ser-Phe-Thr-^A ( SEQ ID NO : 171 )

Name: Btll.7

Species: betulinus

Isolated: No

Cloned: Yes

DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGGAAACATATCTGG TGGTCAGTATGAAGCTGTGTGTGGCGTTTCTTCTTGTTCTGGTGATTCTGCCATCGGTGATTGGGGGGAA GCCTAGCGAGCGTACACTGAGTGGTGCTACTCGGAGAGGCGATCGGAGAATGTGCTTATCCCTAGGACAA AGATGCGAACGTCATTCCAACTGCTGTGGCTATCTGTGTTGCTTCTACGACAAGTGTGTTGTGACTGCCG TAGGGTGTGGCCACTACTAGTGCGATGGACCTAGGCGCGCTGGCCCTGTGGCAGACTCGCTCAGTATGCC TGATCTGTCCAAGTGACACGACCTGACACGATCGTCGTATTCCTTTGCCAAGAGTCAGCTAGGCCAGCCT AGG (SEQ ID NO: 172) Translation:

MKLCVAFLLVLVILPSVIGGKPSERTLSGATRRGDRRMCLSLGQRCERHSNCCGYLCCFYDKCWTAVGC GHY (SEQ ID NO: 173)

Toxin Sequence: Me -Cys-Leu-Ser-Leu-Gly-Gln-Arg-Cys-Xaal-Arg-His-Ser-Asn-Cys-Cys-Gly- Xaa5-Leu-Cys-Cys-Phe-Xaa5-Asp-Lys-Cys-Val-Val-Thr-Ala-Val-Gly-Cys-Gly- His-Xaa5-^A (SEQ ID NO: 174)

Name: Btll.8

Species : betulinus

Isolated: No

Cloned: Yes DNA Sequence:

CAGGCTTTAAAATCCTAATCGTAGAAGAAGGGAAACATATCTGGTGGTAGTATGAAGCTGTGTGTGGCGT TTCTTCTTGTTCTGGTGATTCTGCCATCGGTGATTGGGGGGAAGCCTAACGAGCGTACACTGAGTGGTGC TACTCGGAGAGGCGATCGGAGAATGTGCTTATCCCTAGGACAAAGATGCGAACGTCATTCCAACTGCTGT GGCTATCTGTGTTGCTTCTACGACAAGTGTGTTATGACTGCCATAGGGTGTGGCCACTACTAGTGCGATG GACCTAGGCGCGCTGGCCCTGTGGCAGACTCGCTCAGTATGCCTGATCTGTCCAAGTGACACGACCTGAC ACGATCGTCGTATTCCTTTGACAAGAGTAACGCTAGGCCATGCCTAGG (SEQ ID NO: 175)

Translation:

MKLCVAFLLVLVILPSVIGGKPNERTLSGATRRGDRRMCLSLGQRCERHSNCCGYLCCFYDKCVMTAIGC GHY (SEQ ID NO: 176)

Toxin Sequence:

Met-Cys-Leu-Ser-Leu-Gly-Gln-Arg-Cys-Xaal-Arg-His-Ser-Asn-Cys-Cys-Gly- Xaa5-Leu-Cys-Cys-Phe-Xaa5-Asp-Lys-Cys-Val-Met-T r-Ala-Ile-Gly-Cys-Gly- His-Xaa5-^A ( SEQ ID NO : 177 ) Name: Fill.l

Species : figulinus

Isolated: No

Cloned: Yes

DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC TGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAA GTCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAGCAAAGGCCATGTTTCATGCGGGAAAGAC GGAAGGGCATGCGATTATCATGCAGATTGCTGTAACTGCTGTCTCGGTGGAATCTGTAAACCAAGCACAA GTTGGATTGGATGCTCGACGAATGTGTTCTTGACGCGCTGACTTTCAGCTAGCTAGGCCATGCCTAGG (SEQ ID NO: 178)

Translatio : MKLCLTFLLVLMILASVTGEKSSKHTLSRAARVKSKGHVSCGKDGRACDYHADCCNCCLGGICKPSTSWI GCSTNVFLTR (SEQ ID NO: 179)

Toxin Sequence:

Gly-His-Val-Ser-Cys-Gly-Lys-Asp-Gly-Arg-Ala-Cys-Asp-Xaa5-His-Ala-Asp- Cys-Cys-Asn-Cys-Cys-Leu-Gly-Gly-Ile-Cys-Lys-Xaa3-Ser-Thr-Ser-Xaa4-Ile- Gly-Cys-Ser-Thr-Asn-Val-Phe-Leu-Thr-Arg- (SEQ ID NO: 180)

Name: Fill.2

Species : figulinus

Isolated: No

Cloned: Yes

DNA Sequence: CCGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTACT GGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGCGACTGGGGAGAAG TCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTTTTGTAAGGCAGACG AAAAGCCATGCGAGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTGCACCAAGCACAAA TTGGATTTTACCTGGATGCTCGACGAGTTCGTTCTTCAAGATCTGACTTTCAGCCAGCTAGGCCATGCCT AGG (SEQ ID NO: 181)

Translation:

MKLCLTFLLVLMILASATGEKSSKHTLSRAARVKNRGPSFCKADEKPCEYHADCCNCCLSGICAPSTNWI LPGCSTSSFFRI (SEQ ID NO: 182)

Toxin Sequence:

Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asp-Xaal-Lys-Xaa3-Cys-Xaal-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4- Ile-Leu-Xaa3-Gly-Cys-Ser-Thr-Ser-Ser-Phe-Phe-Lys-Ile-^Λ (SEQ ID NO: 183)

Name: Fill.3

Species : figulinus

Isolated: No

Cloned: Yes

DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC

TGGGCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAA GTCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTTTTGTAAGGCAGAC

GAAAAGCCATGCGAGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTGCACCAAGCACAA ATTGGATTTTACCTGGATGCTCGACGAGTTCGTTCTTCAAGATCCGACTTTCGGCCAGCTAGGCCATGCC TAGG (SEQ ID NO: 184)

Translation: MRLCLTFLLVLMILASVTGERSSRHTLSRAARVRNRGPSFCRADERPCEYHADCCNCCLSGICAPSTN I LPGCSTSSFFRIRLSAS (SEQ ID NO: 185)

Toxin Sequence :

Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asp-Xaal-Lys-Xaa3-Cys-Xaal-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4- Ile-Leu-Xaa3-Gly-Cys-Ser-Thr-Ser-Ser-Phe-Phe-Lys-Ile-Arg-Leu-Ser-Ala- Ser-^A (SEQ ID NO: 186)

Name: Fill.4

Species : figulinus

Isolated: No

Cloned: Yes DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC TGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAA GTCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAAAGGCCCTCGATGCTGGGTCGGCCGT GTCCATTGCACCTATCATAAAGACTGCTGTCCGTCGGTATGTTGCTTCΆAGGGAAGGTGTAAACCACAΆT CATGGGGATGCTGGTCGGGTCCGACCTAGGCGTGCTGGCCTTGAGGCAGCTAGGCCATGCCTAGG (SEQ

ID NO:187)

Translation:

MKLCLTFLLVLMILASVTGEKSSRHTLSRAARVRNRGPRC VGRVHCTYHRDCCPSVCCFRGRCRPQSWG C SGPT (SEQ ID NO: 188)

Toxin Sequence :

Gly-Xaa3-Arg-Cys-Xaa4-Val-Gly-Arg-Val-His-Cys-Thr-Xaa5-His-Lys-Asp- Cys-Cys-Xaa3-Ser-Val-Cys-Cys-Phe-Lys-Gly-Arg-Cys-Lys-Xaa3-Gln-Ser- Xaa4-Gly-Cys-Xaa4-Ser-Gly-Xaa3-Thr-^A (SEQ ID NO: 189)

Name: Fill.5

Species : figulinus

Isolated: No

Cloned: Yes

DNA Sequence:

CCGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGCT GGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAAG

TCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCTGTAAGAAAGACAGAAAGCCAT

GCTCGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTGCACCAAGCACAAATTGGATTTT

ACCTGGATGCTCGACGAGTACGTTCACTTGACGCGCTGACTTTCAGCCAGCTAGGCCATGCCTAGG

(SEQ ID NO:190)

Translation:

MKLCLTFLLVLMILASVTGERSSKHTLSRAARVKNRGCKKDRKPCSYHADCCNCCLSGICAPSTN ILPG

CSTSTFT (SEQ ID NO: 191) Toxin Sequence: Gly-Cys-Lys-Lys-Asp-Arg-Lys-Xaa3-Cys-Ser-Xaa5-His-Ala-Asp-Cys-Cys-Asn- Cys-Cys-Leu-Ser-Gly-Ile-Cys-Ala-Xaa3-Ser-T r-Asn-Xaa4-Ile-Leu-Xaa3- Gly-Cys-Ser-Thr-Ser-Thr-Phe-Thr-^A (SEQ ID NO: 192)

Name: Fill.6

Species : figulinus

Isolated: No

Cloned: Yes

DNA Sequence:

CCAGCTATCANCACTTCGCAGCNGNCGAGGCTTTGAAGTCCTAATCATAGAAGAAGGCAAAAATATCTGC TGGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGGGGAGAA GTCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCTGTAAGAAAGACAGAAAGCCA TGCTCGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTGCACCAAGCACAAATTGGATTT TACCTGGATGCTCGACGAGTTCGTTCTTCAAGATCTGACTTTCAGCCAGCTAGGCCATGCCTAGG (SEQ ID NO:193)

Translation: MRLCLTFLLVLMILASVTGERSSRHTLSRAARVKNRGCKRDRRPCSYHADCCNCCLSGICAPSTN ILPG CSTSSFFRI (SEQ ID NO: 194)

Toxin Sequence:

Gly-Cys-Lys-Lys-Asp-Arg-Lys-Xaa3-Cys-Ser-Xaa5-His-Ala-Asp~Cys-Cys-Asn- Cys-Cys-Leu-Ser-Gly-Ile-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4-Ile-Leu-Xaa3- Gly-Cys-Ser-Thr-Ser-Ser-Phe-Phe-Lys-Ile-^A (SEQ ID NO: 195)

Name: Fill.7

Species : figulinus

Isolated: No

Cloned: Yes

DNA Sequence: CCGCTATCAGCACTTCGCAGCAGNCGAGGCTTTGAAGTCCTAATCATAGAAGAAGGCAAAAATATCTGCT GGTCAATATGAAGCTGTGCCTGACGTTCCTTCTTGTTCTGATGATTCTGGCATCAGTGACTGgGgAGAAG TCAAGCAAGCATACACTGAGTCGTGCTGCTAGGGTAAAAAACAGAGGCCCTAGTTCTTGTAAGGCAGACG AAGAGCCATGCGAGTATCATGCAGATTGCTGTAATTGCTGTCTCAGTGGAATCTGTGCACCAAGCACAAA TTGGATTTTACCTGGATGCTCGACGAGTTCGTTCTTCAAGATCTGACTTTCAGCCAGCTAGGCCATGCCT AGG (SEQ ID NO: 196)

Translation:

MKLCLTFLLVLMILASVTGERSSRHTLSRAARVKNRGPSSCKADEEPCEYHADCCNCCLSGICAPSTNWI LPGCSTSSFFRI (SEQ ID NO: 197)

Toxin Sequence:

Gly-Xaa3-Ser-Ser-Cys-Lys-Ala-Asp-Xaal-Xaal-Xaa3-Cys-Xaal-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4- Ile-Leu-Xaa3-Gly-Cys-Ser-Thr-Ser-Ser-Phe-Phe-Lys-Ile-^A (SEQ ID NO: 198)

Name: Lll.l

Species : lynceus

Isolated: No

Cloned: Yes DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC TGGTCAATATGAAGCTGTGTGTGACGTTCCTTCTTGTTCTGATGATTCTGCCATCGGTGACTGGGGAGAA GTCTAGCAAGCGTACACTGAATGGTGCTCTTCTGAAACGCAATTGGAGCTGGTGCTTCAACGCTGGAGTA AAATGCGACAATCATTCCGACTGCTGTGAGGATACCTGTTGTTACGATAACACCTGTGTTGTGGCTGTCG CGGCGTGCTAGGTGCGATGGACCTAGGCGAGCTGGCCTTGAGCTAGCTAGGCCATGCCTAGG (SEQ ID NO:199) Translation:

MRLCVTFLLVLMILPSVTGERSSRRTLNGALLRRNWSWCFNAGVRCDNHSDCCEDTCCYDNTCVVAVAAC (SEQ ID NO:200)

Toxin Sequence :

Asn-Xaa4-Ser-Xaa4-Cys-Phe-Asn-Ala-Gly-Val-Lys-Cys-Asp-Asn-His-Ser-Asp- Cys-Cys-Xaal-Asp-Thr-Cys-Cys-Xaa5-Asp-Asn-Thr-Cys-Val-Val-Ala-Val-Ala-

Ala-Cys-^Λ (SEQ ID NO:201)

Name : L11 . 2

Species : lynceus

Isolated: No

Cloned: Yes DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGTAAAAATATCTGC TGGTCAGTATGAAGCTGAGTGTGACGTTCCTTCTTATTCTGATGATTCCGCCATCGGTGACTGGGGAAAA GTCAAGCAAGCATACACTGAGTCGTGCTCTTCTGACAGGCTATCGCGCTGGAAGAAGCACTGAAAAAAGA TGCTACTTCAATGGAGCACCATGCGACAGACATGAAGAGTGCTGTACGTGGCAAAGATGTTGTTTTTCGC AAAGGTGTGGCACAGCTACCTTTGGATGCTGGGTGGATCCGTACTAGGCGTGCTGGCCTTGAGCCAGCTA GGCCATGCCTAGG (SEQ ID NO: 202)

Translation :

MRLSVTFLLILMIPPSVTGERSSRHTLSRALLTGYRAGRSTERRCYFNGAPCDRHEECCTWQRCCFSQRC GTATFGC VDPY (SEQ ID NO: 203)

Toxin Sequence:

Cys-Xaa5-P e-Asn-Gly-Ala-Xaa3-Cys-Asp-Arg-His-Xaal-Xaal-Cys-Cys-Thr- Xaa4-Gln-Arg-Cys-Cys-Phe-Ser-Gln-Arg-Cys-Gly-Thr-Ala-Thr-Phe-Gly-Cys- Xaa4-Val-Asp-Xaa3-Xaa5-^A (SEQ ID NO:204)

Name : L11 . 3

Species : lynceus

Isolated: No

Cloned: Yes

DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC TGGTCAATATGAAGCTGTGTGTGACGTTCCTTCTTGTTCTGATGATTCTGCCATCGGTGACTGGGGAGAA GTCTAGCAAGCGTACACTGAATGGTGCTCTTCTGAAACGCAATTGGAGCTGGTGCTTCAACGCTGGAGTA GAATGCGACAATCATTCCGACTGCTGTGAGGATACCTGTTGTTACGATAACACCTGTGTTGTGGCTGTCG CGGCGTGCTAGGTGCGATGGACCTAGGCGAGCTGGCCTTGAGCTAGCTAGGCCATGCCTAGG (SEQ ID NO:205)

Translation: MRLCVTFLLVLMILPSVTGERSSRRTLNGALLRRN SWCFNAGVΞCDNHSDCCEDTCCYDNTCVVAVAAC (SEQ ID NO:206)

Toxin Sequence : Asn-Xaa4-Ser-Xaa4-Cys-Phe-Asn-Ala-Gly-Val-Xaal-Cys-Asp-Asn-His-Ser-

Asp-Cys-Cys-Xaal-Asp-Thr-Cys-Cys-Xaa5-Asp-Asn-Thr-Cys-Val-Val-Ala-Val- Ala-Ala-Cys-^Λ (SEQ ID NO: 207)

Name: L11.4

Species : lynceus

Isolated: No

Cloned: Yes DNA Sequence :

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC TGGCACGCCAATATGAAGCTGTGTGTGACGTTCCTTCTTGTTCTGATGATTCTGCCATCGGTGACTGGGG AGAAGTCTAGCAAGCGTACACTGAATGGTGCTCTTCTGAAACGCAATTGGAGCTGGTGCTTCAACGCTGG AGTAAAATGCGACAATCATTCCGACTGCTGTGCTGATACCTGTTGTTACGATAACACCTGTGTTGTGGCT GTCGCGGCGTGCTAGGTGCGATGGACCTAGGCGAGCTGGCCTTGAGCTAGCTAGGCCATGCCTAGG (SEQ ID NO:208)

Translation:

MRLCVTFLLVLMILPSVTGERSSRRTLNGALLRRN SWCFNAGVRCDNHSDCCADTCCYDNTCWAVAAC (SEQ ID NO:209)

Toxin Sequence:

Asn-Xaa4-Ser-Xaa4-Cys-Phe-Asn-Ala-Gly-Val-Lys-Cys-Asp-Asn-His-Ser-Asp- Cys-Cys-Ala-Asp-Thr-Cys-Cys-Xaa5-Asp-Asn-Thr-Cys-Val-Val-Ala-Val-Ala- Ala-Cys-^A (SEQ ID NO:210)

Name: L11.5

Species : lynceus

Isolated: No

Cloned: Yes

DNA Sequence:

CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC TGGTCAATATGAAGCTGTGTGTGACGTTCCTTCTTGTTCTGATGACTCTGCCATCGGTGACTGGGGAGAA GTCTAGCATGCGTACACTGAATCGTCTTCTGAAACGCAATTGGAGTTGGTGCTCAGGCTCTGGAGAAGGA TGCGACTATCATTCCGAGTGCTGTGGGGAGAGATGTTGTATCGAAAGCATGTGTATTGGGGATGGCGTGG CGTGCTGGCCTTGAGCCAGCTAGGCCATGCCTAGG (SEQ ID NO: 211) Translation:

MRLCVTFLLVL TLPSVTGEKSSMRTLNRLLRRNWSWCSGSGEGCDYHSECCGERCCIESMCIGDGVACW P (SEQ ID NO:212)

Toxin Sequence: Asn-Xaa4-Ser-Xaa4-Cys-Ser-Gly-Ser-Gly-Xaal-Gly-Cys-Asp-Xaa5-His -Ser- Xaal-Cys-Cys-Gly-Xaal-Arg-Cys-Cys-Ile-Xaal-Ser-Met-Cys-Ile-Gly-Asp- Gly-Val-Ala-Cys-Xaa4-Xaa3-^A ( SEQ ID NO : 213 )

Name : L11 . 6

Species : lynceus Isolated: No Cloned: Yes

DNA Sequence: CCAGCTATCAGCACTTCGCAGCAGTCGAGGCTTTGAAATCCTAATCATAGAAGAAGGCAAAAATATCTGC TGGTCAATATGAAGCTGTGTGTGACGTTCCTTCTTGTTCTGATGATTCTGCCATCGGTGACTGGGGAGAA GTCTAGCAAGCGTACACTGAATGGTGCTCTTCTGAAACGCAATTGGAGCTGGTGCTTCAACGCTGGAGTA AAATGCGACAATCATTCCGACTGCTGTGAGGATACCTGTTGTTACGATAGCACCTGTGTTGTGGCTGTCG CGGCGTGCTAGGTGCGATGGACCTAGGCGAGCCGGCCTTGAGCTAGCTAGGCCATGCCTAGG (SEQ ID NO:214)

Translation:

MRLCVTFLLVLMILPSVTGERSSRRTLNGALLRRNWSWCFNAGVRCDNHSDCCEDTCCYDSTCVVAVAAC (SEQ ID NO:215)

Toxin Sequence :

Asn-Xaa4-Ser-Xaa4-Cys-Phe-Asn-Ala-Gly-Val-Lys-Cys-Asp-Asn-His-Ser-Asp- Cys-Cys-Xaal-Asp-Thr-Cys-Cys-Xaa5-Asp-Ser-Thr-Cys-Val-Val-Ala-Val-Ala- Ala-Cys-^A (SEQ ID NO: 216)

Name: brlla

Species : brunneus

Isolated: Yes

Cloned: No

Toxin Sequence:

Cys-Gly-Xaa5-Val-Gly-Gln-Ala-Cys-Asp-Asp-Asp-Ser-Asp-Cys-Cys-Gly-Ser- Ile-Cys-Cys-Val-Ala-Gly-Xaal-Cys-Val-Ile-Thr-Gly-Arg-Arg-Cys-# (SEQ ID NO:217)

Name: Emll.l

Species : emaciatus

Isolated: No

Cloned: Yes

DNA Sequence:

GCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTGATCGTAGAAGGCTAAAACAACTGGTGGTCA GCATGAAACTGTGTTCGACGTCTCTTCTTATTCTGGTGATTCTGCCATCGGTGACTGGAGAGAAGTCTGG CAAGCATACACTGAGTGGTGCTGCTCTGAGAGGCAATCGGGGAGCGTGCTCAGACACAGGACAAGGATGC ATACATCATTTCAACTGCTGTTGGGATTTGTGCTGTTACGGCCGCACGTGTGGTGTGAATGTCATGGGGT GTCCTCCCTTCTAGTGCGATGGAGCCAGGCGTGCTGGCCTCGTGGCAGACTCGCTCAGTGTGCCTGATCT GTCCAAGTGGAACGACCTGACATGATCATCGTATTCCTTTGCCAAGAGCAAGCTAGGCCATGCCTAGGT (SEQ ID NO:218)

Translation :

MRLCSTSLLILVILPSVTGERSGRHTLSGAALRGNRGACSDTGQGCIHHFNCCWDLCCYGRTCGVNVMGC PPF (SEQ ID NO:219)

Toxin Sequence :

Gly-Ala-Cys-Ser-Asp-Thr-Gly-Gln-Gly-Cys-Ile-His-His-Phe-Asn-Cys-Cys- Xaa4-Asp-Leu-Cys-Cys-Xaa5-Gly-Arg-Thr-Cys-Gly-Val-Asn-Val-Met-Gly-Cys- Xaa3-Xaa3-Phe-^A (SEQ ID NO: 220) Name: Emll.2

Species : emaciatus

Isolated: No

Cloned: Yes

DNA Sequence:

GCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTGATCGTAGAAGGCTAAAACAACTGGTGGTCA GCATGAAACTGTGTTTGACGTTTCTTCTTATTCTGGTGATTCTGCCATCGGTGACTGGAGAGAAGTCTGG CAAGCATACACTGAGTGGTGCTGCTCTGAGAGGCGATCGGGGAGCGTGCTCAGACACAGGACAAGGATGC ATACATCATTCCAACTGCTGTTGGGATTTGTGCTGTTACGGCCGCACGTGTGGTGTGAATGTCATGGGGT GTCCTCCCTTCTAGTGCGATGGAGCCAGGCGTGCTGGCCTCGTGGCAGACTCGCTCAGTGTGCCTGATCT GTCCAAGTGGAACGACCTGACATGATCATCGTATTCCTTTGCCAAGAGCCAGCTAGGCCATGCCTAGGT (SEQ ID NO:221) Translation :

MRLCLTFLLILVILPSVTGERSGRHTLSGAALRGDRGACSDTGQGCIHHSNCCWDLCCYGRTCGVNVMGC PPF (SEQ ID NO:222)

Toxin Sequence : Gly-Ala-Cys-Ser-Asp-Thr-Gly-Gln-Gly-Cys-Ile-His-His-Ser-Asn-Cys-Cys-

Xaa4-Asp-Leu-Cys-Cys-Xaa5-Gly-Arg-Thr-Cys-Gly-Val-Asn-Val-Met-Gly-Cys- Xaa3-Xaa3-Phe-^A (SEQ ID NO: 223)

Name: Emll.3

Species : emaciatus

Isolated: No

Cloned: Yes DNA Sequence:

^■ GCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTGCTCGTAGAAGAAGGCAAAAACATCTGGTGG TCAGTATGGAGCTGTGTGTGGCGTTTCTTCTTATTCTGGTGATTCTGCCATCGGTGACTGGGGAGAAGTC TAGCAAGCGTACACTGAGTGGTGCTGCTCTGAGAGGCGATCGGGGAACGTGCTCAGGCATAGGACAAGGA TGCATACATCATTTGAACTGCTGTTGGGATATGTGCTGTTACGGCCACACGTGTGTTGTGAATATCATAG GGTGTCCTCCACACTAGTGCGATGGGGCTAGGCGTGCTGGCCTCGTGGCGGACTCGCTCACTATGCCTGA TCTGTCCAAGTGAAACGACCAGATGACATGATCGTCGTATTCCTTTGCCAGGAGCCAGCTAGGCCATGCC TAGGT (SEQ ID NO: 224)

Translation : MELCVAFLLILVILPSVTGERSSRRTLSGAALRGDRGTCSGIGQGCIHHLNCCWDMCCYGHTCWNIIGC PPH (SEQ ID NO:225)

Toxin Sequence :

Gly-Thr-Cys-Ser-Gly-Ile-Gly-Gln-Gly-Cys-Ile-His-His-Leu-Asn-Cys-Cys- Xaa4-Asp-Met-Cys-Cys-Xaa5-Gly-His-Thr-Cys-Val-Val-Asn-Ile-Ile-Gly-Cys- Xaa3-Xaa3-His-^A (SEQ ID NO: 226)

Name: Emll.4

Species : emaciatus

Isolated: No

Cloned: Yes

DNA Sequence: GCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTGATCGTAGAAGAAGGCTAAAACAACTGGTGG TCAGCATGAAACTGTGTTTGACGTTTCTTCTTATTCTGGTGGTTCTGCCATCGGTGACTGGAGAGAAGTC TGGCAAGCATACACTGAGTGGTGCTGCTCTGAGAGGCGATCGGGGAGCGTGCTCAGACACAGGACAAGGA TGCATACATCATTCCGACTGCTGTTGGGATTTGTGCTGTTACGGCCGCACGTGTGGTGTGAATGTCATGG GGTGTCCTCCCTTCTAGTGCGATGGAGCCAGGCGTGCTGGCCTCGTGGCAGACTCGCTCAGTGTGCCTGA TCTGTCCAAGTGGAACGACCTGACATGATCATCGTATTCCTTTGCCAAGAGCCAGCTAGGCCATGCCTAG GT (SEQ ID NO:227)

Translation:

MKLCLTFLLILVVLPSVTGERSGRHTLSGAALRGDRGACSDTGQGCIHHSDCCWDLCCYGRTCGVNVMGC PPF (SEQ ID NO:228)

Toxin Sequence:

Gly-Ala-Cys-Ser-Asp-Thr-Gly-Gln-Gly-Cys-Ile-His-His-Ser-Asp-Cys-Cys- Xaa4-Asp-Leu-Cys-Cys-Xaa5-Gly-Arg-Thr-Cys-Gly-Val-Asn-Val-Met-Gly-Cys- Xaa3-Xaa3-Phe-^Λ (SEQ ID NO: 229)

Type II

Name: U026

Species : episcopatus

Isolated: Yes

Cloned: No Toxin Sequence:

Cys-Ile-Arg-Xaal-Asp-Ala-Xaa3-Cys-Ser-Phe-Ser-Ala-His-Cys-Cys-Gly-Arg- Asn-Cys-Cys-Arg-Gly-Xaa5-Cys-Xaal-Arg-Xaa3-Cys-Arg-Xaa4-Ile-# (SEQ ID NO:230)

Name : Eml1.5

Species: emaciatus

Isolated: No

Cloned: Yes

DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCAGCTGTTTCCTGCTGGTCATCGTTTGTCTGAACTTGATTGTGCTTA CCAATGCCTGCCTCCATGAAACGTCGCCCTGCAGACGTAGTTTCCAATGCTGTCACGGAATTTGCTGTTT TCGGAGATGCAGTAATTCGTGTCGATTTGGAAAGAGGGCGACATTCCAAGAATTCATTCTACATCGCTGA TATGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 231)

Translation:

MMFRVTSVSCFLLVIVCLNLIVLTNACLHETSPCRRSFQCCHGICCFRRCSNSCRFGRRATFQEFILHR (SEQ ID NO:232)

Toxin Sequence:

Cys-Leu-His-Xaal-Thr-Ser-Xaa3-Cys-Arg-Arg-Ser-Phe-Gln-Cys-Cys-His-Gly- Ile-Cys-Cys-Phe-Arg-Arg-Cys-Ser-Asn-Ser-Cys-Arg-Phe-Gly-Lys-Arg-Ala- Thr-Phe-Gln-Xaal-P e-Ile-Leu-His-Arg-^Al (SEQ ID NO:233)

Name : Eml1.6

Species : emaciatus

Isolated: No Cloned: Yes DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCAGCTGTTTCCTGCTGGTCATCGCTTGTCTGAACTTGGTTGTGCTTA CCAATGCCTGCCTCCGTGACGGACAGTCCTGCAGATATCATTCCGATTGCTGTAGATACTCTTGCTGTTG GGGGTATTGCGATCAGAAGTGTCTAATTATTGGAAAGAGGGCGACATTCCAAGAACTCATCCTACATCGT TGAAATGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 234)

Translation:

MMFRVTSVSCFLLVIACLNLVVLTNACLRDGQSCRYHSDCCRYSCCWGYCDQRCL11GRRATFQELILHR (SEQ ID NO:235)

Toxin Sequence :

Cys-Leu-Arg-Asp-Gly-Gln-Ser-Cys-Arg-Xaa5-His-Ser-Asp-Cys-Cys-Arg-Xaa5- Ser-Cys-Cys-Xaa4-Gly-Xaa5-Cys-Asp-Gln-Lys-Cys-Leu-Ile-Ile-Gly-Lys-Arg- Ala-Thr-Phe-Gln-Xaal-Leu-Ile-Leu-His-Arg-^Al (SEQ ID NO:236)

Name: Emll.7

Species : emaciatus

Isolated: No

Cloned: Yes

DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCGGCTGTTTCCTGCTGGTCATCGTTTGTCTGAACTTGGTTGTGCTTA CCAATGCCTGCCGCCGTGAAGGATCGTCCTGCAGACGTTCTTACCAGTGCTGTCGTAAGAGTTGCTGTAT TGGGGAGTGCGAATTTCCGTGTCGATGGGTTGGAAAGAGGGCAACATTCCGAGAACTCATCCTACATCAT TGAAATGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 237)

Translation: MMFRVTSVGCFLLVIVCLNLVVLTNACRREGSSCRRSYQCCRRSCCIGECEFPCRWVGRRATFRELILHH (SEQ ID NO:238)

Toxin Sequence :

Cys-Arg-Arg-Xaal-Gly-Ser-Ser-Cys-Arg-Arg-Ser-Xaa5-Gln-Cys-Cys-Arg-Lys- Ser-Cys-Cys-Ile-Gly-Xaal-Cys-Xaal-Phe-Xaa3-Cys-Arg-Xaa4-Val-Gly-Lys- Arg-Ala-Thr-Phe-Arg-Xaal-Leu-Ile-Leu-His-His-^Al (SEQ ID NO:239)

Name: Eml1.8 Species: emaciatus

Isolated: No

Cloned: Yes

DNA Sequence: ATGATGTTTCGTGTGACGTCAGTCAGCTGTTTCCTACTGGTCATCGTTTGTCTGAACTTGATTGTGCTTA TCAATGCCTGCTACCAAGATGAAACGCCCTGCAGAGGTAGTATCTTCTGCTGTCGCAAAAAATGCTGTAT AGGGACATGCAGATTTCCGTGTTACGTTAAATTAGAGAGGGCGACTTTCCAAGAACTCATCCTACAACCT TGAAACGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 240) Translation:

MMFRVTSVSCFLLVIVCLNLIVLINACYQDETPCRGSIFCCRRRCCIGTCRFPCYVRLERATFQELILQP (SEQ ID NO:241)

Toxin Sequence : Cys-Xaa5-Gln-Asp-Xaal-Thr-Xaa3-Cys-Arg-Gly-Ser-Ile-Phe-Cys-Cys-Arg- Lys-Lys-Cys-Cys-Ile-Gly-Thr-Cys-Arg-Phe-Xaa3-Cys-Xaa5-Val-Lys-Leu- Xaal-Arg-Ala-Thr-Phe-Gln-Xaal-Leu-Ile-Leu-Gln-Xaa3-^Λ (SEQ ID NO: 242)

Name: Eml1.9

Species : emaciatus

Isolated: No

Cloned: Yes

DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCAGCTGTTTCCTGCTGGTCATCGCTTGTCTGAACCTGGTTGTGCTTA CCAATGCCTGCCTCCGTGACGGACAGTCCTGCGGATATGATTCCGATTGCTGTAGATACTCTTGCTGTTG GGGGTATTGCGATCTTACGTGTCTAATTATTGGAAAGAGGGCGACATTCCAAGAACTCATCCTACATCGT TGAAATGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 243)

Translation:

MMFRVTSVSCFLLVIACLNLVVLTNACLRDGQSCGYDSDCCRYSCCWGYCDLTCLIIGRRATFQELILHR (SEQ ID NO:244)

Toxin Sequence:

Cys-Leu-Arg-Asp-Gly-Gln-Ser-Cys-Gly-Xaa5-Asp-Ser-Asp-Cys-Cys-Arg-Xaa5- Ser-Cys-Cys-Xaa4-Gly-Xaa5-Cys-Asp-Leu-Thr-Cys-Leu-Ile-Ile-Gly-Lys-Arg- Ala-Thr-Phe-Gln-Xaal-Leu-Ile-Leu-His-Arg-^Al (SEQ ID NO:245)

Name: Eml1.10

Species : emaciatus

Isolated: No

Cloned: Yes

DNA Sequence :

ATGATGTTTCGTGTGACGTCAGTCAGCTGTTTCCTGCTGGTCATCGCTTGTCTGAACTCGTTTCAGGTTG TGCTTACCAGCCGCTGCTTCCCTCCAGGAATATACTGCACACCCTATCTCCCCTGCTGTTGGGGAATTTG CTGTGGGACGTGCAGAAATGTGTGTCATTTGAGGATTGGAAAGAGGGCGACATTCCAAGAATGAATTCAT TCTACATCGTTTATATGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 246)

Translation :

MMFRVTSVSCFLLVIACLNSFQVVLTSRCFPPGIYCTPYLPCCWGICCGTCRNVCHLRIGRRATFQE (SEQ ID NO:247)

Toxin Sequence:

Cys-P e-Xaa3-Xaa3-Gly-Ile-Xaa5-Cys-Thr-Xaa3-Xaa5-Leu-Xaa3-Cys-Cys- Xaa4-Gly-Ile-Cys-Cys-Gly-Thr-Cys-Arg-Asn-Val-Cys-His-Leu-Arg-Ile-Gly- Lys-Arg-Ala-Thr-Phe-Gln-Xaal-^Al (SEQ ID NO:248)

Name: Emll.11

Species : emaciatus

Isolated: No

Cloned: Yes

DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCAGCTGTTTCCTACTGGTCATCGTTTGTCTGAACTTGATTGTGCTTA TCAATGCCTGCTACCAAGATGAAACGCCCTGCAGAGGTAGTACCTTCTGCTGTCGCAAAAAATGCTGTAT AGGGACATGCAGATTTCCGTGTTACGTTAAATTAGAGAGGGCGACTTTCCAAGAACTCATCCTACAACCT TGAAACGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 249)

Translation: MMFRVTSVSCFLLVIVCLNLIVLINACYQDETPCRGSTFCCRRRCCIGTCRFPCYVRLERATFQELILQP (SEQ ID NO:250)

Toxin Sequence:

Cys-Xaa5-Gln-Asp-Xaal-Thr-Xaa3-Cys-Arg-Gly-Ser-T r-Phe-Cys-Cys-Arg- Lys-Lys-Cys-Cys-Ile-Gly-Thr-Cys-Arg-Phe-Xaa3-Cys-Xaa5-Val-Lys-Leu- Xaal-Arg-Ala-Thr-Phe-Gln-Xaal-Leu-Ile-Leu-Gln-Xaa3-^A (SEQ ID NO: 251)

Name : Emll . 12

Species : emaciatus

Isolated: No

Cloned : Yes

DNA Sequence: ATGATGTTTCGTGTGACGTCAGTCAGCTGTTTCCTGCTGGTCATCGCTTGTCTGAACTTGGTTGTGCTTA CCAATGCCTGCCTCCGTGACGGACAGTCCTGCGGATATCATTCCGATTGCTGTAGATACTCTTGCTGTTG GGGGTATTGCGATCAGAAGTGTCTAATTATTGGAAAGAGGGCGACATTCCAAGAACTCATCCTACATCCT TGAAATGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 252) Translation:

MMFRVTSVSCFLLVIACLNLVVLTNACLRDGQSCGYHSDCCRYSCCWGYCDQRCLIIGRRATFQELILHP (SEQ ID NO:253)

Toxin Sequence: Cys-Leu-Arg-Asp-Gly-Gln-Ser-Cys-Gly-Xaa5-His-Ser-Asp-Cys-Cys-Arg-Xaa5- Ser-Cys-Cys-Xaa4-Gly-Xaa5-Cys-Asp-Gln-Lys-Cys-Leu-Ile-Ile-Gly-Lys-Arg- Ala-Thr-Phe-Gln-Xaal-Leu-Ile-Leu-His-Xaa3- ^l (SEQ ID NO: 254)

Name: Vrll.l

Species : virgo

Isolated: No

Cloned: Yes DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCAGCTGTTTCCTGCTGGTCATCGCTTGTCTGAACTTGGTTGTGCTTA CCAATGCCTGCCTTCGTGACGGACAGTCCTGCGGATATGATTCCGATTGCTGTAGATACTCTTGCTGTTG GGGGTATTGCGATCTTACGTGTCTAATTATTGGAAAGAGGGCGACATTCCAAGAACTCATCCTACATCGT TGAAATGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 255)

Translation:

MMFRVTSVSCFLLVIACLNLVVLTNACLRDGQSCGYDSDCCRYSCCWGYCDLTCLIIGRRATFQELILHR (SEQ ID NO:256) Toxin Sequence:

Cys-Leu-Arg-Asp-Gly-Gln-Ser-Cys-Gly-Xaa5-Asp-Ser-Asp-Cys-Cys-Arg-Xaa5- Ser-Cys-Cys-Xaa4-Gly-Xaa5-Cys-Asp-Leu-Thr-Cys-Leu-Ile-Ile-Gly-Lys-Arg- Ala-Thr-Phe-Gln-Xaal-Leu-Ile-Leu-His-Arq-^Al (SEQ ID NO:257) Name: Vrll.2

Species : virgo

Isolated: No

Cloned: Yes

DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCGGCTGTTTCCTGCTGGCCATCGTTTGTCTGAACTTGATTGTGCTTA CCAATGCCTGCCTCCATGAAACGTCGCCCTGCAGACGTAGTTTCCAATGCTGTCACGGAATTTGCTGTTT TCGGAGATGCAGTAATTCGTGTCGATTTGGAAAGAGGGCGACATTCCAAGAATTCATTCTACATCGCTGA TATGTTGCCCAGAGGTCTGCTGCTTCTCGt (SEQ ID NO: 258)

Translation:

MMFRVTSVGCFLLAIVCLNLIVLTNACLHETSPCRRSFQCCHGICCFRRCSNSCRFGRRATFQEFILHR (SEQ ID NO:259)

Toxin Sequence:

Cys-Leu-His-Xaal-Thr-Ser-Xaa3-Cys-Arg-Arg-Ser-Phe-Gln-Cys-Cys-His-Gly- Ile-Cys-Cys-Phe-Arg-Arg-Cys-Ser-Asn-Ser-Cys-Arg-Phe-Gly-Lys-Arg-Ala- Thr-Phe-Gln-Xaal-P e-Ile-Leu-His~Arg- ^:L (SEQ ID NO: 260)

Name: Vrll.3

Species: virgo

Isolated: No Cloned: Yes

DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCAGCTGTTTCCTGCTGGTCATCGCTTGTCTGAACTTGGTTGTGCTTA CCAATGCCTGCCTCCGTGACGGACAGTCCTGCGGATATCATTCCGATTGCTGTAGGTACTCTTGCTGTTG GGGGTATTGCGATCAGAAGTGTCTAATTATTGGAAAGAGGGCGACATTCCAAGAACTCATCCTACATCGT TGAAATGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 261)

Translation:

MMFRVTSVSCFLLVIACLNLVVLTNACLRDGQSCGYHSDCCRYSCCWGYCDQRCLIIGRRATFQELILHR (SEQ ID NO:262)

Toxin Sequence:

Cys-Leu-Arg-Asp-Gly-Gln-Ser-Cys-Gly-Xaa5-His-Ser-Asp-Cys-Cys-Arg-Xaa5- Ser-Cys-Cys-Xaa4-Gly-Xaa5-Cys-Asp-Gln-Lys-Cys-Leu-Ile-Ile-Gly-Lys-Arq- Ala-Thr-Phe-Gln-Xaal-Leu-Ile-Leu-His-Arg-^Al (SEQ ID NO: 263)

Name: Vrll.4

Species: virgo Isolated: No

Cloned: Yes

DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCAGCTGTTTCCTGCTGGTCATCGTTTGTCTGAACTTGGTTGTGCTTA CCAATGCCTGCCTCCATGAAACGCCGCCCTGCAGACGTAGTTTCCAATGCTGTCACGGAAATTGCTGTTT TCGGAGATGCAGTAATTCGTGTCGATTTGGAAAGAGGGCGACATTCCAAGAATTCATTCTACATCGCTGA TATGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 264)

Translation: MMFRVTSVSCFLLVIVCLNLWLTNACLHETPPCRRSFQCCHGNCCFRRCSNSCRFGKRATFQEFILHR (SEQ ID NO:265) Toxin Sequence:

Cys-Leu-His-Xaal-Thr-Xaa3-Xaa3-Cys-Arg-Arg-Ser-Phe-Gln-Cys-Cys-His- Gly-Asn-Cys-Cys-Phe-Arg-Arg-Cys-Ser-Asn-Ser-Cys-Arg-Phe-Gly-Lys-Arg- Ala-Thr-Phe-Gln-Xaal-Phe-Ile-Leu-His-Arq-^Al (SEQ ID NO:266)

Name: Vrll.5

Species : virgo Isolated: No

Cloned: Yes

DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCGGCTGTTTCCTGCTGGTCATCGTTTGTCTGAACTTGGTTGTGCTTA CCAATGCCTGCCTCCATGAAACGTCGCCCTGCGGACGTAGTTTCCAATGCTGTCACGGAATTTGTTGTTT TCGGAGATGCAGTAATTCGTGTCGATTTGGAAAGAGGGCGACATTCCAAGAATTCATTCTACATCGCTGA TATGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 267)

Translation: MMFRVTSVGCFLLVIVCLNLWLTNACLHETSPCGRSFQCCHGICCFRRCSNSCRFGKRATFQEFILHR (SEQ ID NO:268)

Toxin Sequence:

Cys-Leu-His-Xaal-Thr-Ser-Xaa3-Cys-Gly-Arg-Ser-Phe-Gln-Cys-Cys-His-Gly- Ile-Cys-Cys-Phe-Arg-Arg-Cys-Ser-Asn-Ser-Cys-Arg-Phe-Gly-Lys-Arg-Ala- Thr-P e-Gin-Xaal-Phe-Ile-Leu-His-Arg-^Al (SEQ ID NO: 269)

Name: Vrll.6 Species: virgo

Isolated: No

Cloned: Yes

DNA Sequence: ATGATGTTTCGTGTGACGTCAGTCAGCTGTTTCCTGCTGGTCATCGTTTGTCTGAACTTGGTTGTGCTTA CCAATGCCTGCCTCTATGAAACGTCGCCCTGCAGACGTAGTTTCCAATGCTGTCACGGAATTTGCTGTTT TCGGAGATGCAGTAATTCGTGTCGATTTGGAAAGAGGGCGACATTCCAAGAATTCATTCTACATCGCTGA TATGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 270) Translation:

MMFRVTSVSCFLLVIVCLNLVVLTNACLYETSPCRRSFQCCHGICCFRRCSNSCRFGRRATFQEFILHR (SEQ ID NO:271)

Toxin Sequence : Cys-Leu-Xaa5-Xaal-Thr-Ser-Xaa3-Cys-Arg-Arg-Ser-Phe-Gln-Cys-Cys-His-

Gly-Ile-Cys-Cys-Phe-Arg-Arg-Cys-Ser-Asn-Ser-Cys-Arq-Phe-Gly-Lys-Arq- Ala-Thr-P e-Gln-Xaal-Phe-Ile-Leu-His-Arg-^Al (SEQ ID NO:272)

Name: Vrll.7

Species : virgo

Isolated: No

Cloned: Yes DNA Sequence: ATGATGTTTCGTGTGACGTCAGTCGGCTGTTTCCTGCTGGTCATCGCTTGTCTGAACTTGTTTCAGGTTG TGCTTACCAGACGCTGCTTCCCTCTAGGAACGTTCTGCTCAAGATATCTCCCCTGCTGTAGTGGAATGTG CTGTTCTGGGTGGTGCACACGAAGGTGTGCCCCAAGGTTTGGAAAGAGGGCGACATTCCAAGAATGAATT CATTCTACATCGTTGATATGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 273)

Translation:

MMFRVTSVGCFLLVIACLNLFQVVLTRRCFPLGTFCSRYLPCCSGMCCSGWCTRRCAPRFGRRATFQE (SEQ ID NO:274) Toxin Sequence:

Cys-Phe-Xaa3-Leu-Gly-Thr-Phe-Cys-Ser-Arg-Xaa5-Leu-Xaa3-Cys-Cys-Ser- Gly-Met-Cys-Cys-Ser-Gly-Xaa4-Cys-Thr-Arg-Arg-Cys-Ala-Xaa3-Arg-Phe-Gly- Lys-Arq-Ala-T r-Phe-Gln-Xaal-^Al (SEQ ID NO:275)

Name: Fill.8

Species: figulinus

Isolated: No

Cloned: Yes

DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCGGCTGTTTCCTGCTGGTCATCGTTTTTCTGAACTTGGTTGTGCTTA CCGATGCCTGTCACCATGAAGGATTGCCCTGCACAAGTGATGACGGTTGCTGTGGCATGGAATGCTGCGG CGGGGTTTGCTCATCACATTGTGGAAACGGGAGGCGACGCCAAGTTCCGTTGAAATCATTTGGCCAACGT TGATATGTTTGACCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 276)

Translation :

MMFRVTSVGCFLLVIVFLNLWLTDACHHEGLPCTSDDGCCGMECCGGVCSSHCGNGRRRQVPLRSFGQR (SEQ ID NO:277)

Toxin sequence :

Cys-His-His-Xaal-Gly-Leu-Xaa3-Cys-Thr-Ser-Asp-Asp-Gly-Cys-Cys-Gly-Met- Xaal-Cys-Cys-Gly-Gly-Val-Cys-Ser-Ser-His-Cys-Gly-Asn-Gly-Arg-Arg-Arg- Gln-Val-Xaa3-Leu-Lys-Ser-Phe-Gly-Gln-Arg-^Al (SEQ ID NO:278)

Name : Fill . 8A

Species : figulinus

Isolated: No

Cloned: Yes

DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCGGCTGTTTCCTGCTGGTCATCGTTTTTCTGAACTTGGTTGTGCTTA CCGATGCCTGTCACCATGAAGGATTGCCCTGCACAAGTGATGACGGTTGCTGTGGCATGGAATGCTGCGG CGGGGTTTGCTCATCACATTGTGGAAACGGGAGGCGACGCCGAGTTCCGTTGAAATCATTTGGCCAACGT TGATATGTTTGACCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 279)

Translation:

MMFRVTSVGCFLLVIVFLNLWLTDACHHEGLPCTSDDGCCGMECCGGVCSSHCGNGRRRRVPLRSFGQR (SEQ ID NO:280)

Toxin sequence :

Cys-His-His-Xaal-Gly-Leu-Xaa3-Cys-Thr-Ser-Asp-Asp-Gly-Cys-Cys-Gly-Met- Xaal-Cys-Cys-Gly-Gly-Val-Cys-Ser-Ser-His-Cys-Gly-Asn-Gly-Arg-Arq-Arg- Arq-Val-Xaa3-Leu-Lys-Ser-P e-Gly-Gln-Arg-^Al (SEQ ID NO:281) Name: Fill.8B

Species : figulinus

Isolated: No Cloned: Yes

DNA Sequence :

ATGATGTTTCGTGTGACGTCAGTCGGCTGTTTCCTGCTGGTCATCGTTTTTCTGAACTTGGTTGTGCTTA CCGATGCCTGTCACCATGAAGGATTGCCCTGCACAAGTGATGACGGTTGCTGTGGCATGGAATGCTGCGG CGGGGTTTGCTCATCACATTGTGGAAACGGGGGGCGACGCCGAGTTCCGTTGAAATCATTTGGCCAACGT TGATATGTTTGACCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 282)

Translation:

MMFRVTSVGCFLLVIVFLNLVVLTDACHHEGLPCTSDDGCCGMECCGGVCSSHCGNGGRRRVPLRSFGQR (SEQ ID NO:283)

Toxin sequence:

Cys-His-His-Xaal-Gly-Leu-Xaa3-Cys-Thr-Ser-Asp-Asp-Gly-Cys-Cys-Gly-Met- Xaal-Cys-Cys-Gly-Gly-Val-Cys-Ser-Ser-His-Cys-Gly-Asn-Gly-Gly-Arg-Arg- Arg-Val-Xaa3-Leu-Lys-Ser-Phe-Gly-Gln-Arg-^Al (SEQ ID NO:284)

Name: Fill.9

Species : figulinus

Isolated: No

Cloned: Yes

DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCGGCTGTTTCCTGCTGGTCATCGTTTTTCTGAACTTGATTGTGCCTT CCAGTTCCTGCCGCGCTGAAGGAGTGCGCTGCGAATTTGATTCCCAATGCTGTGAATCTGAATGCTGTAT GGGGAGTTGCGCAAATCCGTGTCGAATTCCTGGGAAGAGGGCGAGACTCTTTCGACAACGTTGATATGTT GCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 285)

Translation: MMFRVTSVGCFLLVIVFLNLIVPSSSCRAEGVRCEFDSQCCESECCMGSCANPCRIPGRRARLFRQR (SEQ ID NO:286)

Toxin sequence:

Cys-Arg-Ala-Xaal-Gly-Val-Arg-Cys-Xaal-Phe-Asp-Ser-Gln-Cys-Cys-Xaal- Ser-Xaal-Cys-Cys-Met-Gly-Ser-Cys-Ala-Asn-Xaa3-Cys-Arg-Ile-Xaa3-Gly- Lys-Arg-Ala-Arg-Leu-Phe-Arg-Gln-Arg-^Al (SEQ ID NO: 287)

Name: Fill.10

Species : figulinus

Isolated: No

Cloned: Yes

DNA Sequence: ATGATGTTTCGTGTGACGTCAGTCGGCTGTTTCCTGCTGGTCATCGTTTTTCTGAACTTGGTTGTGCCTA CCAGTGCCTGCCGCGCTGAAGGAGTGTACTGCGAATATGGTTCCCAATGCTGTCTATCTCAATGCTGTAT GGCGAGTTGCGCAAATCCGTGTCGCCATCCTGGAAAGAGGGCGAGACTCCAAGAATTCTTTCGACAACGT TGATACGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 288) Translation :

MMFRVTSVGCFLLVIWLNLVWTSACI^EGWCEY

( SEQ ID NO : 289 ) Toxin sequence :

Cys-Arg-Ala-Xaal-Gly-Val-Xaa5-Cys-Xaal-Xaa5-Gly-Ser-Gln-Cys-Cys-Leu- Ser-Gln-Cys-Cys-Met-Ala-Ser-Cys-Ala-Asn~Xaa3-Cys-Arg-His-Xaa3-Gly-Lys- Arg-Ala-Arg-Leu-Gln-Xaal-Phe-Phe-Arg-Gln-Arg-^Al (SEQ ID NO:290)

Name: Fill.lOA

Species : figulinus

Isolated: No

Cloned: Yes

DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCGGCTGTTTCCTGCTGGTCATCGTTTTTCTGAACTTGGTTGTGCCTA CCAGTGCCTGCCGCGCTGAAGGAGTGTACTGCGAATATGGTTCCCAATGCTGTCTATCTCAATGCTGTAT GGCGAGTTGCGCAAATCCGTGTCGCCATCCTGGAAAGAGGGCGAGACTCCAAGAATTCTTTCGACGACGT TGATACGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 291)

Translation:

MIVIFRVTSVGCFLLVIΛ LNL PTSACR^

( SEQ ID NO : 292 )

Toxin sequence :

Cys-Arg-Ala-Xaal-Gly-Val-Xaa5-Cys-Xaal-Xaa5-Gly-Ser-Gln-Cys-Cys-Leu- Ser-Gln-Cys-Cys-Met-Ala-Ser-Cys-Ala-Asn-Xaa3-Cys-Arg-His-Xaa3-Gly-Lys- Arg-Ala-Arg-Leu-Gln-Xaal-Phe-Phe-Arg-Arg-Arg-^Al (SEQ ID NO: 293)

Name: Fill.11

Species : figulinus

Isolated: No

Cloned: Yes

DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCGGCTGTTTCCTGCTGGTCATCGTTTTTCTGAACTTGGTTGTGCTTA CCGATGCCTGTCACCATGAAGGATTGCCCTGCACAAGTGGTGACGGTTGCTGTGGCATGGAATGCTGCGG CGGGGTTTGCTCATCACATTGTGGAAACGGGAGGCGACGCCAAGTTCCGTTGAAATCATTTGGCCAACGT TGATATGTTTGACCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 294)

Translation:

MIVLPRVTSVGCFLLVIVFLNLVVLTDACHHEGLPCTSGDGCCGMECCGGVCSSHCGNGRRRQVPLKSFGQR ( SEQ ID NO : 295 )

Toxin sequence:

Cys-His-His-Xaal-Gly-Leu-Xaa3-Cys-Thr-Ser-Gly-Asp-Gly-Cys-Cys-Gly-Met- Xaal-Cys-Cys-Gly-Gly-Val-Cys-Ser-Ser-His-Cys-Gly-Asn-Gly-Arg-Arg-Arg- Gln-Val-Xaa3-Leu-Lys-Ser-Phe-Gly-Gln-Arg-^Al (SEQ ID NO : 296)

Name: Fill.12 Species: figulinus Isolated: No Cloned: Yes

DNA Sequence: ATGATGTTTCGTGTGACGTCAGTCGGCTGTTTCCTGCTGGTCATCGTTTTTCTGAACTTGGTTGTGCTCA CCGATGCCTGTCACCATGAAGGATTGCCCTGCGCAAGTGATGACGGTTGCTGTGGCATGGAATGCTGCGG CGGGGTTTGCTCATCACATTGTGGAAACGGGAGGCGACGCCGAGTTCCGTTGAAATCATTTGGCCAACGT TGATATGTTTGACCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 297) Translation:

MFRVTSVGCFLLVIVFLNLVVLTDACHHEGLPCASDDGCCGMECCGGVCSSHCGNGRRRRVPLRSFGQR (SEQ ID NO:298)

Toxin sequence : Cys-His-His-Xaal-Gly-Leu-Xaa3-Cys-Ala-Ser-Asp-Asp-Gly-Cys-Cys-Gly-Met- Xaal-Cys-Cys-Gly-Gly-Val-Cys-Ser-Ser-His-Cys-Gly-Asn-Gly-Arg-Arg-Arg- Arg-Val-Xaa3-Leu-Lys-Ser-Phe-Gly-Gln-Arg-^Al (SEQ ID NO:299)

Name: J029 [02P; OllP]

Species: radiatus

Isolated: Yes

Cloned: Yes Toxin Sequence :

Gly-Xaa3-Ser-Phe-Cys-Lys-Ala-Asp-Xaal-Lys-Xaa3-Cys-Xaal-Xaa5-His-Ala- Asp-Cys-Cys-Asn-Cys-Cys-Leu-Ser-Gly-Ile-Cys-Ala-Xaa3-Ser-Thr-Asn-Xaa4- Ile-Leu-Xaa3-Gly-Cys-Ser-Thr-Ser-Ser-Phe-Phe-Lys-Ile-^A (SEQ ID NO: 300)

Name: Aull.l

Species : aulicus

Isolated: No

Cloned: Yes

DNA Sequence:

GCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGCAAAAACATCTGGTGG TCAGTATGAAGCTGTGTGTGACGTTTCTTCTTGTTCTGGTGATTCTGCCATCAGTAACTGGGGAGAAGTC TAGCGAGCGTACACTGAGTGGTGCTACTCTGAGAGGCGATTGGGGAACGTGCTCATGGCCAGGACAAGAA TGCAAACATGATTCCGACTGCTGTGGGAGTTTCTGTTGTGTCGGCAAAAGGTGCTTACACACTTACTTTC CATGTAACTTATCTCGCTCCTAGTGCGATGGACCTAGGCGTGCTGGCCTAGCGGTAGACTCGCTCAGTAT GCCTGATCTGTCCGAGTGAAACGACCTGACGCGATCCGTCGTATTCCTTTGCCAAGAGCCAGCTAGGCCA TGCCTAGGT (SEQ ID NO: 301) Translation:

MRLCVTFLLVLVILPSVTGEKSSERTLSGATLRGDWGTCS PGQECRHDSDCCGSFCCVGKRCLHTYFPC NLSRS (SEQ ID NO: 302)

Toxin Sequence: Gly-Asp-Xaa4-Gly-T r-Cys-Ser-Xaa4-Xaa3-Gly-Gln-Xaal-Cys-Lys-His-Asp- Ser-Asp-Cys-Cys-Gly-Ser-Phe-Cys-Cys-Val-Gly-Lys-Arg-Cys-Leu-His-Thr- Xaa5-Phe-Xaa3-Cys-Asn-Leu-Ser-Arg-Ser-^A (SEQ ID NO: 303)

Name: Aull-2 Species: aulicus Isolated: No Cloned: Yes

DNA Sequence : GCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGCAAAAACATCTGGTGG TCAGTATGAAGCTGTGTGTGACGTTTCTTCTTGTTCTGGTGATTCTGCCATCAGTAACTGGGGAGAAGTC TAGCGAGCGCACACTGAGTGGTGCTACTCTGAGAGGCGATTGGGGAACGTGCTCATGGTCAGGACAAGAA TGCAAACATGTTTCCGACTGCTGTGGGAGTTTCTGTTGTGTCGGCAAAAGGTGCTTACACATTTACTTTC CATGTAACTTATCTCGCTCCTAGTGCGATGGACCTAGGCGTGCTGGCCTAGTGGTAGACTCGCTCAGTAT GCCTGATCTGTCCGAGTGAAACGACCTGACGCGATCCGTCGTATTCCTTTGCCAAGAGCCAGCTAGGCCA TGCCTAGGT (SEQ ID NO: 304)

Translation:

MRLCVTFLLVLVILPSVTGEKSSERTLSGATLRGDWGTCSWSGQECKHVSDCCGSFCCVGKRCLHIYFPC NLSRS (SEQ ID NO: 305)

Toxin Sequence:

Gly-Asp-Xaa4-Gly-Thr-Cys-Ser-Xaa4-Ser-Gly-Gln-Xaal-Cys-Lys-His-Val- Ser-Asp-Cys-Cys-Gly-Ser-Phe-Cys-Cys-Val-Gly-Lys-Arg-Cys-Leu-His-Ile- Xaa5-P e-Xaa3-Cys-Asn-Leu~Ser-Arg-Ser-^A (SEQ ID NO: 306)

Name: Aull.3

Species : aulicus

Isolated: No

Cloned: Yes

DNA Sequence:

GCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGCAAAAACATCTGGTGG TCAGTATGAAGCTGTGTGTGACGTTTCTTCTTGTTCTGGTGATTCTGCCATCAGTAACTGGGGAGAAGTC TAGCGAGCGTACACTGAGTGGTGCTACTCTGAGAGGCGATTGGGGAACGTGCTCATGGTCAGGACAAGAA TGCAAACATGATTCCGACTGCTGTGGGAGTTTCTGTTGTGTCGGCAAAAGGTGCTTACACATTTACTTTC CATGTAACTTATCTCGCCCCTAGTGCGATGGACCTAGGCGTGCTGGCCTAGTGGTAGACTCGCTCAGTAT GCCTGATCTGTCCGAGTGAAACGACCTGACGCGATCCGTCGTATTCCTTTGCCAAGAGCCAGCTAGGCCA TGCCTAGGT (SEQ ID NO: 307)

Translation:

MRLCVTFLLVLVILPSVTGERSSERTLSGATLRGDWGTCSWSGQECRHDSDCCGSFCCVGRRCLHIYFPC NLSRP (SEQ ID NO: 308)

Toxin Sequence:

Gly-Asp-Xaa4-Gly-Thr-Cys-Ser-Xaa4-Ser-Gly-Gln-Xaal-Cys-Lys-His-Asp- Ser-Asp-Cys-Cys-Gly-Ser-Phe-Cys-Cys-Val-Gly-Lys-Arg-Cys-Leu-His-Ile- Xaa5-Phe-Xaa3-Cys-Asn-Leu-Ser-Arg-Xaa3-^A (SEQ ID NO: 309)

Name: Aull.4 Species: aulicus Isolated: No Cloned: Yes

DNA Sequence:

GCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGCAAAAACATCTGGTGG

TCAGTATGAAGCTGTGTGTGACGTTTCTTCTTGTTCTGGTGATTCTGCCATCAGTAACTGGGGAGAAGTC TAGCGAGCGTACACTGAGTGGTGCTACTCTGAGAGGCGATTGGGGAACGTGCTCATGGTCAGGACAAGAA

TGCAAACATGATTCCGACTGCTGTGGGAGTTTCTGTTGTGTCGGCAAAAGGTGCTTACACATTTACTTTC CATGTAACTTATCTCGCTCCTAGTGCGATGGACCTAGGCGTGCTGGCCTAGTGGTAGACTCGCTCAGTAT GCCTGATCTGTCCGAGTGAAACGACCTGACGCGATCCGTCGTATTCCTTTGCCAAGAGCCAGCTAGGCCA TGCCTAGGT (SEQ ID NO: 310) Translation:

MRLCVTFLLVLVILPSVTGERSSERTLSGATLRGDWGTCSWSGQECRHDSDCCGSFCCVGKRCLHIYFPC NLSRS (SEQ ID NO: 311)

Toxin Sequence: Gly-Asp-Xaa4-Gly-Thr-Cys-Ser-Xaa4-Ser-Gly-Gln-Xaal-Cys-Lys-His-Asp- Ser-Asp-Cys-Cys-Gly-Ser-Phe-Cys-Cys-Val-Gly-Lys-Arg-Cys-Leu-His-Ile- Xaa5-Phe-Xaa3-Cys-Asn-Leu-Ser-Arg-Ser-^A (SEQ ID NO: 312)

Name: Aull.5

Species : aulicus

Isolated: No

Cloned: Yes DNA Sequence:

GCTATCAGCACTTCGCAGCAGTCGAGGNTTTAAAATCCTAATCGTAGAAGAAGGCAAAAACATCTGGTGG TCAGTATGAAGCTGTGTGTGACGTTTCTTCTTGTTCTGGTGATTCTGCCATCAGTAACTGGGGAGAAGTC TAGCGAGCGTACACTGAGTGGTGCTACTCTGAGAGGCGATGGGGGAACGTGCTCATGGCCAGGACAAGAA TGCAAACATGATTCCGACTGCTGTGGGAGTTTCTGTTGTGTCGGCAAAAGGTGCTTACACACTTACTTTC CATGTAACTTATCTCGCTCCTAGTGCGATGGACCTAGGCGTGCTGGCCTAGCGGTAGACTCGCTCAGTAT GCCTGATCTGTCCGAGTGAAACGACCTGACGCGATCCGTCGTATTCCTTTGCCAAGAGCCAGCTAGGCCA TGCCTAGGT (SEQ ID NO: 313)

Translation: MRLCVTFLLVLVILPSVTGERSSERTLSGATLRGDGGTCSWPGQECRHDSDCCGSFCCVGKRCLHTYFPC NLSRS (SEQ ID NO: 314)

Toxin Sequence:

Gly-Asp-Gly-Gly-Thr-Cys-Ser-Xaa4-Xaa3-Gly-Gln-Xaal-Cys-Lys-His-Asp- Ser-Asp-Cys-Cys-Gly-Ser-Phe-Cys-Cys-Val-Gly-Lys-Arg-Cys-Leu-His-Thr- Xaa5-Phe-Xaa3-Cys-Asn-Leu-Ser-Arg-Ser- (SEQ ID NO: 315)

Name: Aull.6

Species : aulicus

Isolated: No

Cloned: Yes

DNA Sequence: GCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGCAAAAACATCTGGTGG TCAGTATGAAGCTGTGTGTGACGTTTCTTCTTGTTCTGGTGATTCTGCCATCAGTAACTGGGGAGAAGTC TAGCGAGCGTACACTGAGTGGTGCTACTCTGAGAGGCGATTGGGGAACGTGCTCATGGCCAGGACAAGAA TGCGAACATGATTCCGACTGCTGCGGGAGTTTCTGTTGTGTCGGCAGAAGGTGCTTACACATTTACTTTC CATGTAACTTATCTCGCTCCTAGTGCGATGGACCTAGGCGTGCTGGCCTAGTGGTAGACTCGCTCAGTAT GCCTGATCTGTCCGAGTGAAACGACCTGACGCGATCCGTCGTATTTCTTTGCCAAGAGCCAGCTAGGCCA TGCCTAGGT (SEQ ID NO: 316)

Translation:

MRLCVTFLLVLVILPSVTGERSSERTLSGATLRGD GTCSWPGQECEHDSDCCGSFCCVGRRCLHIYFPC NLSRS (SEQ ID NO: 317) Toxin Sequence:

Gly-Asp-Xaa4-Gly-Thr-Cys-Ser-Xaa4-Xaa3-Gly-Gln-Xaal-Cys-Xaal-His-Asp- Ser-Asp-Cys-Cys-Gly-Ser-Phe-Cys-Cys-Val-Gly-Arg-Arg-Cys-Leu-His-Ile- Xaa5-Phe-Xaa3-Cys-Asn-Leu-Ser-Arg-Ser-^A (SEQ ID NO: 318)

Name: Epll.l

Species : episcopatus

Isolated: No

Cloned: Yes

DNA Sequence:

GCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCAAATCGTAGAAGAAGGCAAAAACGTCTGGTGA CAGTATGAAGCTGTGTGTGACGTTTCTTCTTATTCTGGTGATTCTGCCATCGGTAACTGGGGAGAAGTCT AGCAAGCGTACACTGAGTGGTGCTGCTCTGAGAGGCGATTGGGGAATGTGCTCAGGCATAGGACAAGGAT GCGGACAAGATTCCAACTGCTGTGGGGATATGTGCTGTTATGGCCAAATATGCGCTATGACTTTCGCGGC ATGTGGTCCCTAACTTCTTTCCCTTCTAGTGCGATGGACCTAGGCGTGCTGGCCTAGCGGCCGACTCGCT CAGTATGCCTGATCTGTCCGAGTGAAACGACCTGACACGATCCGTCGTATTCCTTTGCCAAGAGCCAGTT AGGCCATGCCTAGGT (SEQ ID NO: 319)

Translation:

MKLCVTFLLILVILPSVTGERSSRRTLSGAALRGDWGMCSGIGQGCGQDSNCCGDMCCYGQICAMTFAAC GP (SEQ ID NO:320)

Toxin Sequence :

Gly-Asp-Xaa4-Gly-Met-Cys-Ser-Gly-Ile-Gly-Gln-Gly-Cys-Gly-Gln-Asp-Ser- Asn-Cys-Cys-Gly-Asp-Met-Cys-Cys-Xaa5-Gly-Gln-Ile-Cys-Ala-Met-Thr-Phe- Ala-Ala-Cys-Gly-Xaa3-^A (SEQ ID NO: 321)

Name: Epll.2

Species : episcopatus

Isolated: No

Cloned: Yes

DNA Sequence:

GCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGCAAAAACGTCTGGTGT CAGTATGAAGCTGTGTGTGACGTTTCTTCTTATTCTGGTGATTCTGCCATCAGTAACTGGGGAGAAGTCT AGCAAGCGTACACTGAGTGGTGCTGCTCTGAGAGGCGATCGGGGAATGTGCTCTCGCATAGGACAAGGAT GCGGACAAGATTCCGACTGCTGTGGGGATATGTGCTGTTACGGCCAAATATGCGCTATGACTTTCGCGGC ATGTGGTCCCTAACTTCTTTCCCTTCTAGTGCGATGGACCTAGGCGTGCTGGCCTAGCGGCCGACACGCT CAGTATGCCTGATCTGTCCGAGTGAAACGACCTGACACGATCCGTCGTATTCCTTTGCCAAGAGCCAGCT AGGCCATGCCTAGGT (SEQ ID NO: 322)

Translation:

MKLCVTFLLILVILPSVTGERSSRRTLSGAALRGDRGMCSRIGQGCGQDSDCCGDMCCYGQICAMTFAAC GP (SEQ ID NO: 323) Toxin Sequence:

Gly-Met-Cys-Ser-Arg-Ile-Gly-Gln-Gly-Cys-Gly-Gln-Asp-Ser-Asp-Cys-Cys- Gly-Asp-Met-Cys-Cys-Xaa5-Gly-Gln-Ile-Cys-Ala-Met-Thr-Phe-Ala-Ala-Cys- Gly-Xaa3-^A (SEQ ID NO: 324) Name: Epll.3

Species : episcopatus

Isolated: No

Cloned: Yes

DNA Sequence:

GCTATCAGCCTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGCAAAAACGTCTGGTGTC AGTATGAAGCTGTGTGTGACGTTTCTTCTTATTCTGGTGATTCTGCCATCGGTAACTGGGGAGAAGTCTA GCAAGCGTACACTGAGTGGTGCTGCTCTGAGAGGCGATTGGGGAATGTGCTCAGGCATAGGACAAGGATG CGGACAAGATTCCGGCTGCTGTGGGGATATGTGCTGTTATGGCCAAATATGCGCTATGACTTTCGCGGCA TGTGGTCCCTAACTTCTTTCCCTTCTAGTGCGATGGACCTAGGCGTGCTGGCCTAGCGGCCGACTCGCTC AGTATGCCTGATCTGTCCGAGTGAAACGACCTGACACGATCCGTCGTATTCCTTTGCCAAGAGCCAGCTA GGCCATGCCTAGGT (SEQ ID NO: 325) Translation:

MKLCVTFLLILVILPSVTGERSSKRTLSGAALRGDWGMCSGIGQGCGQDSGCCGDMCCYGQICAMTFAAC GP- (SEQ ID NO: 326)

Toxin Sequence: Gly-Asp-Xaa4-Gly-Met-Cys-Ser-Gly-Ile-Gly-Gln-Gly-Cys-Gly-Gln-Asp-Ser- Gly-Cys-Cys-Gly-Asp-Met-Cys-Cys-Xaa5-Gly-Gln-Ile-Cys-Ala-Met-Thr-Phe- Ala-Ala-Cys-Gly-Xaa3-^A (SEQ ID NO: 327)

Name: Epll.4

Species : episcopatus

Isolated: No

Cloned: Yes DNA Sequence:

GCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCAAATCGTAGAAGAAGGCAAAAACGTCTGGTGA CAGTATGAAGCTGTGTGTGACGTTTCTTCTTATTCTGGTGATTCTGCCATCGGTAACTGGGGAGAAGTCT AGCAAGCGTACACTGAGTGGTGCTGCTCTAAGAGGCGATTGGGGAATGTGCTCAGGCATAGGACAAGGAT GCGGACAAGATTCCAACTGCTGTGGGGATAAGTGCTGTTATGGCCAAATATGCGCTATGACTTTCGCGGC ATGTGGTCCCTAACTTCTTTCCCTTCTAGTGCGATGGACCTAGGCGTGCTGGCCTAGCGGCCGACTCGCC CAGTATGCCTGATCTGTCCGAGTGAAACGACCTGACACGATCCGTCGTATTCCTTTGCCAAGAGCCAGCT AGGCCATGCCTAGGT (SEQ ID NO: 328)

Translation: MRLCVTFLLILVILPSVTGERSSRRTLSGAALRGD GMCSGIGQGCGQDSNCCGDRCCYGQICAMTFAAC GP (SEQ ID NO:329)

Toxin Sequence:

Gly-Asp-Xaa4-Gly-Met-Cys-Ser-Gly-Ile-Gly-Gln-Gly-Cys-Gly-Gln-Asp-Ser- Asn-Cys-Cys-Gly-Asp-Lys-Cys-Cys-Xaa5-Gly-Gln-Ile~Cys-Ala-Met-Thr-Phe- Ala-Ala-Cys-Gly-Xaa3-^A (SEQ ID NO: 330)

Name: Epll.5

Species : episcopatus

Isolated: No

Cloned: Yes

DNA Sequence:

GCTATAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCAAATCGTAGAAGAGGGCAAAAACGTCTGGTGTC AGTATGAAGCTGTGTGTGACGTTTCTTCTTATTCTGGTGATTCTGCCATCAGTAACTGGGGAGAAGTCTA GCAAGCGTACACTGAGTGGTGCTGCTCTGAGAGGCGATCGGGGAATGTGCTCTCGCATAGGACAAGGATG CGGACAAGATTCCAACTGCTGTGGGGATATGTGCTGTTATGGCCAAATATGCGCTATGACTTTCGCGGCA TGTGGTCCCTAACTTCTTTCCCTTCTAGTGCGATGGACCTAGGCGTGCTGGCCTAGCGGCCGACTCGCTC AGTATGCCTGATCTGTCCGAGTGAAACGACCTGACACGATCCGTCGTATTCCTTTGCCAAGAGCAAGCTA GGCCATGCCTAGGT (SEQ ID NO: 331)

Translation:

MRLCVTFLLILVILPSVTGERSSRRTLSGAALRGDRGMCSRIGQGCGQDSNCCGDMCCYGQICAMTFAAC GP (SEQ ID NO: 332)

Toxin Sequence:

Gly-Met-Cys-Ser-Arg-Ile-Gly-Gln-Gly-Cys-Gly-Gln-Asp-Ser-Asn-Cys-Cys- Gly-Asp-Met-Cys-Cys-Xaa5-Gly-Gln-Ile-Cys-Ala-Met-Thr-Phe-Ala-Ala-Cys- Gly-Xaa3-^A ( SEQ ID NO : 333 )

Name: Epll.6

Species : episcopatus

Isolated: No

Cloned: Yes

DNA Sequence: GCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCAAATCGCAGAAGAAGGCAAAAACGTCTGGTGT CAGTATGAAGCTGTGTGTGTCGTTTCTTCTTATTCTGGTGATTCTGCCATCGGTAACTGGGGAGAAGTCT AGCAAGCGTACACTGAGTGGTGCTGCTCTGAGAGGCGATCGGGGAATGTGCTCAGGCATAGGACAAGGAT GCGGACAAGATTCCGGCTGCTGTGGGGATATGTGCTGTTATGGCCAAATATGCGCTATGACTTTCGCGGC ATGTGGTCCCTAACTTCTTTCCCTTCTAGTGCGATGGACCTAGGCGTGCTGGCCTAGCGGCCGACTCGCT CAGTATGCCTGATCTGTCCGAGTGAAACGACCTGACACGATCCGTCGTATTCCTTTGCCAAGAGCCAGCT AGGCCATGCCTAGGT (SEQ ID NO: 334)

Translation: MRLCVSFLLILVILPSVTGERSSRRTLSGAALRGDRGMCSGIGQGCGQDSGCCGDMCCYGQICAMTFAAC GP (SEQ ID NO: 335)

Toxin Sequence :

Gly-Met-Cys-Ser-Gly-Ile-Gly-Gln-Gly-Cys-Gly-Gln-Asp-Ser-Gly-Cys-Cys- Gly-Asp-Met-Cys-Cys-Xaa5-Gly-Gln-Ile-Cys-Ala-Met-Thr-Phe-Ala-Ala-Cys- Gly-Xaa3-^A ( SEQ ID NO : 336)

Name: Epll.7

Species : episcopatus

Isolated: No

Cloned: Yes DNA Sequence:

GCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCTAATCGTAGAAGAAGGCAAAAACGTCTGGTGT CAGTATGAAGCTGTGTGTGACGTTTCTTCTTATTCTGGTGATTCTGCCATCAGTAACTGGGGAGAAGTCT AGCAAGCGTACACTGAGTGGTGCTGCTCTGAGAGGCGATCGGGGAATGTGCTCTCGCATAGGACAAGGAT GCGGACAAGATTCCGACTGCTGTGGGGATATGTGCTGTCACGGCCAAATATGCGCTATGACTTTCGCGGC ATGTGGTCCCTAACTTCCTTCCCTTCTAGTGCGATGGACCTAGGCGTGCTGGCCTAGCGGCCGACACGCT CAGTATGCCTGATCTGCCCGAGTGAAACGACCTGACACGATCCGTCGTATTCCTTTGCCAAGAGCCAGCT AGGCCATGCCTAGGT (SEQ ID NO: 337)

Translation: MRLCVTFLLILVILPSVTGERSSRRTLSGAALRGDRGMCSRIGQGCGQDSDCCGDMCCHGQICAMTFAAC GP (SEQ ID NO:338)

Toxin Sequence:

Gly-Met-Cys-Ser-Arg-Ile-Gly-Gln-Gly-Cys-Gly-Gln-Asp-Ser-Asp-Cys-Cys- Gly-Asp-Met-Cys-Cys-His-Gly-Gln-Ile-Cys-Ala-Met-Thr-Phe-Ala-Ala-Cys- Gly-Xaa3-^Λ (SEQ ID NO: 339)

Name: Epll.8

Species : episcopatus

Isolated: No

Cloned: Yes

DNA Sequence: GCTATCAGCACTTCGCAGCAGTCGAGGCTTTAAAATCCAAATCGTAGAAGAAGGCAAAAACGTCTGGTGA CAGTATGAAGCTGTGTGTGACGTTTCTTCTTATTCTGGTGATTCTGCCATCGGTAACTGGGGAGAAGTCT AGCAAGCGTACACTGAGTGGTGCTGCTCTGAGAGGCGATTGGGGAATGTGCTCAGGCATAGGACAAGGAT GCGGACAAGATTCCAACTGCTGTGGGGATATGTGCTGTCATGGCCAAATATGCGCTATGACTTTCGCGGC ATGTGGTCCCTAACTTCTTTCCCTTCTAGTGCGATGGACCTAGGCGTGCTGGCCTAGCGGCCGACTCGCT CAGTATGCCTGATCTGTCCGAGTGAAACGACCTGACACGATCCGTCGTATTCCTTTGCCAAGAGCAAGCT AGGCCATGCCTAGGT (SEQ ID NO: 340)

Translation:

MRLCVTFLLILVILPSVTGEKSSRRTLSGAALRGD GMCSGIGQGCGQDSNCCGDMCCHGQICAMTFAAC GP (SEQ ID NO:341)

Toxin Sequence :

Gly-Asp-Xaa4-Gly-Met-Cys-Ser-Gly-Ile-Gly-Gln-Gly-Cys-Gly-Gln-Asp-Ser- Asn-Cys-Cys-Gly-Asp-Met-Cys-Cys-His-Gly-Gln-Ile-Cys-Ala-Met-Thr-Phe- Ala-Ala-Cys-Gly-Xaa3-^Λ (SEQ ID NO: 342)

Name: Sxll.l

Species : striolatus

Isolated: No

Cloned: Yes

DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCAGCTGTTTCTTGCTGGTCATTGTTCTTCTGAACTTGGTTGTGCTTA CCGATGCCTGTCACCATGAAGGGTTGCCCTGCTCAAGTGATGACGGTTGCTGTGGCATGGAATGCTGCAA TGGGGTTTGCTCATCAAGTTGTGGAAACGGGAGGCGACGCCAAGTTCCGTTGAAATCATTTGGCCAACGT CGATATGTTTGACCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 343)

Translation: MMFRVTSVSCFLLVIVLLNLWLTDACHHEGLPCSSDDGCCGMECCNGVCSSSCGNGRRRQVPLRSFGQR RYV (SEQ ID NO: 344)

Toxin Sequence:

Cys-His-His-Xaal-Gly-Leu-Xaa3-Cys-Ser-Ser-Asp-Asp-Gly-Cys-Cys-Gly-Met- Xaal-Cys-Cys-Asn-Gly-Val-Cys-Ser-Ser-Ser-Cys-Gly-Asn-# (SEQ ID NO: 345) Name: Sxll.3

Species : striolatus

Isolated: No

Cloned: Yes

DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCCTGCTGGTCATCGTTCTTCTGAATTTGGTTGTGCTTACCAATGCCT GCCACATGGATTGCTCAAAGATGACTTGCTGTAGCGGTATATGCTGTTTTTACTGCGGACGTCCTATGTG TCCTGGCACTAGGAGGGCGCTACTCCAAAGATTAGTGGGACATCAACGTTGATATGTTGCCCAGAGGTCT GCTGCTTCTCGT (SEQ ID NO: 346)

Translation : MMFRVTSVLLVIVLLNLWLTNACHMDCSRMTCCSGICCFYCGRPMCPGTRRALLQRLVGHQR (SEQ ID NO:347)

Toxin Sequence :

Cys-His-Met-Asp-Cys-Ser-Lys-Met-Thr-Cys-Cys-Ser-Gly-Ile-Cys-Cys-P e- Xaa5-Cys-Gly-Arg-Xaa3-Met-Cys-Xaa3-Gly-Thr-Arg-Arg-Ala-Leu-Leu-Gln- Arg-Leu-Val-Gly-His-Gln-Arg-^A (SEQ ID NO: 348)

Name: Epll.9

Species : episcopatus

Isolated: No

Cloned: Yes

DNA Sequence: ATGATGTTTCGTGTGACGTCAGTCGGCTGTTTACTGCTGGTCATCGTTTTCCTGAACTTGGTTGTGCCTA CCAATGCCTGCGCTGGTCAAGAAGAGCCCTGCAGTTCACGTAGCGATTGCTGTGGTTCAGTTGGTTGCTG TTTTGGGCAGTGCGAAAGTCCGTGCCGAATGCCTGGGAAGAGGAAACTCCGACAATTCTTTCGACAACGT TGATATGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 349) Translation:

MMFRVTSVGCLLLVIVFLNLVVPTNACAGQEEPCSSRSDCCGSVGCCFGQCESPCRMPGRRKLRQFFRQR (SEQ ID NO:350)

Toxin Sequence : Cys-Ala-Gly-Gln-Xaal-Xaal-Xaa3-Cys-Ser-Ser-Arg-Ser-Asp-Cys-Cys-Gly- Ser-Val-Gly-Cys-Cys-Phe-Gly-Gln-Cys-Xaal-Ser-Xaa3-Cys-Arg-Met-Xaa3-# (SEQ ID NO:351)

Name: Epll.10

Species : episcopatus

Isolated: No

Cloned: Yes DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCGGCTGTTTACTGCTGGCCATCGTTTTCCTGAACTTGGTTGTGCCTA CCAATGCCTGCGCTGGTCAAGAAGAGCCCTGCAGTTCACGTGACGATTGCTGTGGTTCAGTTGGTTGCTG TTTTGGGCAGTGCGAAACTCCGTGCCGAATGCCTGGGAAAAGGAAACTCCGACAATTCTTTCGACAACGT TGATATGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 352)

Translation: MMFRVTSVGCLLLAIVFLNLVVPTNACAGQEEPCSSRDDCCGSVGCCFGQCETPCRMPGRRRLRQFFRQR (SEQ ID NO:353)

Toxin Sequence:

Cys-Ala-Gly-Gln-Xaal-Xaal-Xaa3-Cys-Ser-Ser-Arg-Asp-Asp-Cys-Cys-Gly- Ser-Val-Gly-Cys-Cys-P e-Gly-Gln-Cys-Xaal-Thr-Xaa3-Cys-Arg-Met-Xaa3-# (SEQ ID NO:354)

Name: Epll.ll

Species : episcopatus

Isolated: No

Cloned: Yes DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCGGCTGTTTCCTGCTGGCCATCGTTTTCCTGAACTTGATTGTGCCTA CCAATGCCTGCGCAGGTCAAGAAGAGCCCTGCAGTTCACGTAGTGATTGCTGTGGTTCAGTTGGTTGCTG TTTTGGGCAGTGCGAAAGTCCGTGCCGAATGATTGGGAAGAGGAAACTCCGACAATTCTTTCGACAACGT TGATATGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 355)

Translation:

MMFRVTSVGCFLLAIVFLNLIVPTNACAGQEEPCSSRSDCCGSVGCCFGQCESPCRMIGRRKLRQFFRQR (SEQ ID NO:356) Toxin Sequence :

Cys-Ala-Gly-Gln-Xaal-Xaal-Xaa3-Cys-Ser-Ser-Arg-Ser-Asp-Cys-Cys-Gly- Ser-Val-Gly-Cys-Cys-P e-Gly-Gln-Cys-Xaal-Ser-Xaa3-Cys-Arg-Met-Ile-# (SEQ ID NO:357)

Name: Epll.12

Species : episcopatus

Isolated: No

Cloned: Yes

DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCGGCTGTTTCCTGCTGGTCATCCTTTCTCTGAACTTGGTTGTGCTTA CCAATGCCTGCCTTTCTGAAGGATCTCCCTGCAGTATGAGTGGCAGTTGCTGTCACAAGAGTTGCTGTCG TTCGACTTGCACTTTTCCGTGTCTAATTCCTGGGAAGAGGGCGAAACTCCGAGAATTCTTTCGACAACGT TGATATGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 350)

Translation:

MMFRVTSVGCFLLVILSLNLVVLTNACLSEGSPCSMSGSCCHRSCCRSTCTFPCLIPGRRARLREFFRQR (SEQ ID NO:359)

Toxin Sequence:

Cys-Leu-Ser-Xaal-Gly-Ser-Xaa3-Cys-Ser-Met-Ser-Gly-Ser-Cys-Cys-His-Lys- Ser-Cys-Cys-Arg-Ser-T r-Cys-Thr-P e-Xaa3-Cys-Leu-Ile-Xaa3-# (SEQ ID NO:360)

Name: Epll.13

Species: episcopatus

Isolated: No Cloned: Yes DNA Sequence:

ATGATGTTTCGTGTGACGTCAGTCGGCTGTTTCCTGCTGGTCATCCTTTCTCTGAACTTGGTTATGCTTA CCAATGCCTGCCCTTCTGAAGGATCTCCCTGCAGTATGAGTGGCAGTTGCTGTCACAAGAGTTGCTGTCG TTCGACTTGCACTTTTCCGTGTCTAATTCCTGGGAAGAGGGCGAAACTCCGAGAATTCTTTCGACAACGT TGATATGTTGCCCAGAGGTCTGCTGCTTCTCGT (SEQ ID NO: 361)

Translation:

MMFRVTSVGCFLLVILSLNLVMLTNACPSEGSPCSMSGSCCHRSCCRSTCTFPCLIPGRRARLREFFRQR (SEQ ID NO:362)

Toxin Sequence:

Cys-Xaa3-Ser-Xaal-Gly-Ser-Xaa3-Cys-Ser-Met-Ser-Gly-Ser-Cys-Cys-His- Lys-Ser-Cys-Cys-Arg-Ser-Trιr-Cys-Thr-Phe-Xaa3-Cys-Leu-Ile-Xaa3-# (SEQ ID NO:363)

Where :

Xaal = Glu or γ-Carboxy Glu Xaa2 = Gin or pyroglu

Xaa3 = Pro or Hydroxy Pro

Xaa4 = Trp or Bromo Trp

Xaa5 = Tyr or ¹²⁵I-Tyr or Mono-Iodo Tyr or Di-Iodo Tyr or O-sulpho-Tyr or O-Phospho-Tyr = Free-carboxyl C-term or Amidated C-term, preferably Free-carboxyl

# = Free-carboxyl C-term or Amidated C-term, preferably Amidated

¹ underlined C-terminus may optionally be processed to remove underlined residues, leaving an amidated C-term.

TABLE2

Alignment of I-Superfamily Conotoxins - Type I (SEQ ID NO:) brlla CGYVGQA-CDDDSDCCG-SICCVAGECVITGR RC# (364)

Btll. .1 CLSLGQR-CERHSNCCG-YLCCFYDKCVVTAI GCGHY^A (365) B Bttllll.. .22 MCSF GQR-CERHFNCCG-DLCCFDDMCLVAAI GCGY^A (366)

Btll. .3 I-CSFLG CERHFNCCG-DLCCFDDMCVVTAI GCGH^A (367)

Btll. .4 MCLSLGQR-CGRHSNCCG-YLCCFYDKCVVTAI GCGHY^Λ (368)

Btll. .5 MCLSLGQR-CERHSDCCG-YLCCFYDKCVVTAI GCGHY^A (369)

Btll. .6 G-HVPCG-KDGRKCGYHTHCCN CC SGICKPSTS I—GCSTSSFT^Λ (370) B Bttllll.. .77 CLSLGQR-CERHSNCCG-YLCCFYDKCVVTAV GCGHY^Λ (371)

Btll. .8 MCLSLGQR-CERHSNCCG-YLCCFYDKCVMTAI GCGHY^Λ (372)

Call. .1 G--H CGYPGERGCRYHSQCCG-DMCCYDRKCVATAM PCDFPY^Λ (373)

Call. .10 G-PSFCK-ADEKPCKYHADCCN CCLGGICKPSTS I—GCSTNVFLTR^A (374)

Call. .11 G-P-RC- VGRVHCTYHKDCCP-SVCCFKGRCKPQSW GCWSGPT^A (375) C Caallll.. .1122 G-PSFCK-ADEKPCEYHADCCN CCLSGICAPSTNWILPGCSTSSFFKI^A (376)

Call. .14 G-PSFCK-ANGKPCSYHADCCN CC SGICKPSTNVILPGCSTSSFFRI^Λ (377)

Call. .2 G—HWCGY GERGCRYHSQCCG-DMCCYDRKCVVTAM PCDFPY^Λ (378)

Call. .3 G—HWCGYPGERGCRYHSQCCG-D CCYDRKCVVTA PCDFPY^A (379)

Call. .4 G—H CGY GERGCRYHSQCCG-D CCYDRKCAVTAM PCDFPY^A (380) C Caallll.. .55 G—HWCGYPGERGCRYHSQCCG-DMCCYDRMCVVTAM PCDFPY^Λ (381)

Call. .6 G—H CGYLGERGCRYHGQCCG-DMCCYDRKCVVTAM PCDFPY^A (382 )

Call. .7 G-PSFCK-ANGKPCSYHADCCN CCLSGICEPSTNVILPGCSTSSFFRI^Λ (383)

Call, .8 G-PSFCK-ADEKPCEYHADCCN CF SGICAPSTNWILPGCSTSSFFKI^A (384)

Call. .9 G-PSFCK-ADEKPCKYHADCCN CCLGGICKPSTSWI—GCSTNVFLTR^A (385) E Emmll1l.. .11 G— -CSDTGQG-CIHHFNCC -DLCCYGRTCGVNVM GCPPF^A (386)

Emll. .2 G—A-CSDTGQG-CIHHSNCCW-DLCCYGRTCGVNVM GCPPF^A (387)

Emll. .3 G—T-CSGIGQG-CIHH NCCW-DMCCYGHTCVVNII GCPPH^A (388) Emll.4 G—A-CSDTGQG-CIHHSDCCW-DLCCYGRTCGVNVM GCPPF^A (389)

Fill.l G-HVSCG-KDGRACDYHADCCN CCLGGICKPSTSWI—GCSTNVFLTR^A (390)

Fill.2 G-PSFCK-ADEKPCEYHADCCN CCLSGICAPSTNWILPGCSTSSFFKI^A (391)

Fill.3 G-PSFCK-ADEKPCEYHADCCN CCLSGICAPSTNWILPGCSTSSFFKIRLSAS^A (392)

Fill.4 G-P-RC-WVGRVHCTYHKDCCP-SVCCFKGRCKPQSW GCWSGPT^Λ (393)

Fill.5 G CK-KDRKPCSYHADCCN CCLSGICAPSTNWILPGCSTSTFT^Λ (394)

Fill.6 G CK-KDRKPCSYHADCCN CCLSGICAPSTNWILPGCSTSSFFKI^A (395)

Fill.7 G-PSSCK-ADEEPCEYHADCCN CCLSGICAPSTNWILPGCSTSSFFKI^A (396)

GH-015 G CK-KDRKOCSYHADCCN CC SGICAOSTNUILPGCSTSTFT^A (397 )

J029 G-OSFCK-ADEKOCEYHADCCN CC SGICAOSTNWI PGCSTSSFFKI^Λ (398)

J029[OllP] G-OSFCK-ADEKPCEYHADCCN CCLSGICAOSTNWILPGCSTSSFFKI^A (399)

J029[O2p, OllP] G-PSFCK-ADEKPCEYHADCCN CCLSGICAOSTNWILPGCSTSSFFKI^A (400)

Lll.l -NWSWCFNAGVK-CDNHSDCCE-DTCCYDNTCVVAVA AC^A (401)

L11.2 C-YFNGAPCDRHEECCTWQRCCFSQRCGTATF GCWVDPY^Λ (402)

Lll.3 -NWSWCFNAGVE-CDNHSDCCE-DTCCYDNTCVVAVA AC^A (403)

L11.4 -NWSWCFNAGVK-CDNHSDCCA-DTCCYDNTCVVAVA AC^A (404)

L11.5 -NWSWCSGSGEG-CDYHSECCG-ERCCIESMCIGDGV ACWP^A (405) 11.6 -NWSWCFNAGVK-CDNHSDCCE-DTCCYDSTCVVAVA AC^Λ (406)

Mll.l G—AVPCG-KDGRQCRNHADCCN CCPIGTCAPSTNWILPGCSTGQFMTR^A (407)

Mil.13 G-HVSCG-KDGRACDYHADCCN CCLGGICKPSTSWI—GCSTNVFLTR^A (408)

Mil.2 T-CSNKGQQ-CGDDSDCCW-HLCCVNNKCAHLIL LCNL^A (409)

Mil.3 G-PSFCK-ADEKPCEYHADCCN CCLSGICAPSTNWILPGCSTSSFFEI^A (410)

Mil.4 G-PSFCK-ADEKPCEYHADCCN CCLSGICAPSTNWILPGCSTSSFFKT^A (411)

Mil.5 G-HVPCG-KDGRKCGYHADCCN CCLSGICKPSTSWT—GCSTSTFD^Λ (412)

Mil.6 G MCSLLGQR-CGDHSDCCW-DMCCASEMCVVTFL PCK^A (413)

Mil.7 G-PSFCK-ANGKPCSYHADCCN CCLSGICKPSTNVILPGCSTSSLFRI^Λ (414)

Mil.8 G—T-CSGRGQE-CKHDSDCCG-HLCCAGITCQFTYI PCK^A (415)

Mil.9 G CK-KDRKPCSYHADCCN CCLSGICAPSTNWILPGCSTSTFT^Λ (416)

Rll.l G-HVPCG-KDGRKCGYHADCCN CCLSGICKPSTSWT—GCSTSTVRLTR^Λ ( 417 )

R11.10 G-HVPCG-KDGRKCGYHADCCN CCLSGICKPSTSWT—GCSTSTVQLTR^Λ (418)

Rll.ll G-HVSCG-KDGRACDYHADCCN CCLGGICKPSTSWI—GCSTNVFLTR^A (419)

R11.12 G-HVPCG-KDRRKCGYHADCCN CCLSGICKPSTSWT—GCSTSTFLLTR^A (420)

R11.13 G-HVPCG-KDGRKCGYHADCCN CCLSGICKPSTSWT—GCSTSTFLLTR^Λ ( 421 )

R11.14 G-OSFCK-ANGKOCSYHADCCN CCLSGICKOSTNVILPGCSTSSFFRI^Λ (422)

R11.15 G-HVPCG-KDGRKCGYHADCCN CCLSGICKPSTSWT—GCSTSTFN^Λ (423)

R11.16 G-HVPCG-KDGRKCGYHTHCCN CCLSGICKPSTSLI—GCSTSSFT^Λ (424)

R11.17 G-PSFCK-ANGKPCSYHADCCN CCLSGICAPSTNWILPGCSTSSFFKI^Λ (425)

R11.18 G-AVPCG-KDGRQCRNHADCCN CCPFGTCAPSTNRILPGCSTGMFLTR^Λ (426)

R11.19 -E C-KTNKMSCSLHXXCCR-FRCCFHGKCQTSVF GCUVDP^Λ (427 )

R11.2 G-AVPCG-KDGRQCRNHADCCN CCPIGTCAPSTNWILPGCSTGPFMTR^A (428)

R11.3 G-P-RC-WVGRVHCTYHKDCCP-SVCCFKGRCKPQSW GCWSGPT^Λ (429)

R11.4 G-PSFCK-ADEKPCKYHADCCN CCLGGICKPSTSWI—GCSTNVFLTR^A (430)

R11.5 G-AVPCG-KDGRQCRNHADCCN CCPIGTCAPSTNWILPGCSTGQFMTADF^Λ (431)

R11.7 G-PSFCK-ADEKPCEYHSDCCN CCLSGICAPSTNWILPGCSTSSFFKI^Λ (432)

Sll.l G—T-CSFLGQG-CGDHSDCCW-NMCCASEMCVVTLL QCK^A (433)

S11.2 G CK-KDRKPCSYQADCCN CCPIGTCAPSTNWILPGCSTGPFMAR^A (434)

S11.3 G-PSFCK-ADEKPCKYHADCCN CCLGGICKPSTSWI—GCSTNVFLTR^A (435)

S11.4 G-PSFCK-ADEKPCKYHAGCCN CCLGGICKPSTSWI—GCSTNVFLTR^A (436)

S11.5 G-PSFCK-ANGKPCSYHADCCN CCLSGICKPSTNVILPGCSTSSFFRI^A (437)

S11.6 G-PSFCK-ADEKPCEYHADCCN CCLSGICAPSTNWILPGCSTSSFFKI^Λ (438)

S11.7 G CK-KDRKPCSYHADCCN CCLSGICAPSTNWILPGCSTSTFT^Λ (439)

S11.8 G-PSFCK-ADEKPCKYHADCCN CCLGGICKPSTSWI—GCSTNVFLTR^Λ (440)

Ξpll.2 GMCSRIGQG-CGQDSDCCG-DMCCYGQICAM TFAACGP (441)

Epll.5 GMCSRIGQG-CGQDSNCCG-DMCCYGQICAM TFAACGP (442 )

Epll.7 GMCSRIGQG-CGQDSDCCG-DMCCHGQICAM TFAACGP (443 )

Epll.3 GDWGMCSGIGQG-CGQDSGCCG-DMCCYGQICAM TFAACGP (44 )

Epll.6 GMCSGIGQG-CGQDSGCCG-DMCCYGQICAM TFAACGP (445)

Epll.l GDWGMCSGIGQG-CGQDSNCCG-DMCCYGQICAM TFAACGP (446)

Epll.4 GD GMCSGIGQG-CGQDSNCCG-DKCCYGQICAM TFAACGP (447)

Epll.8 GD GMCSGIGQG-CGQDSNCCG-DMCCHGQICAM TFAACGP (448)

Aull.3 GDWGTCSWSGQE-CKHDSDCCG-SFCCVGKRCLH IYFPCNLSRP (449)

Aull.4 GDWGTCSWSGQE-CKHDSDCCG-SFCCVGKRCLH IYFPCNLSRS (450)

A ll .1 GD GTCSWPGQE-CKHDSDCCG-SFCCVGKRCLH TYFPCNLSRS (451) Aull.2 GDWGTCSWSGQE-CKHVSDCCG-SFCCVGKRCLH- •IYFPCNLSRS (452) Aull.6 GDWGTCSWPGQE-CEHDSDCCG-SFCCVGRRCLH- -IYFPCNLSRS (453) Aull.5 GDGGTCSWPGQE-CKHDSDCCG-SFCCVGKRCLH- -TYFPCNLSRS (454)

X is Gla, O is Hyp and U is Br-Trp

TABLE 3 Alignment of I-Superfamily Conotoxins - Type II

U026 CIRXDAPCSFSAHCCGRN-CCRGYCXR-PCRWI# (455) Emll.5 CLHETSPCRRSFQCCHGI-CCFRRCSN-SCRF# (456) Emll.6 CLRDGQSCRYHSDCCRYS-CC GYCDQ-KCLII# (457) Emll.7 CRREGSSCRRSYQCCRKS-CCIGECEF-PCRWV# ( 458 ) Emll.8 CYQDETPCRGSIFCCRKK-CCIGTCRF-PCYVKLERATFQELILQP^A (459) Emll.9 CLRDGQSCGYDSDCCRYS-CCWGYCDL-TCLIIt (460) Emll.10 CFPPGIYCTPYLPCCWGI-CC-GTCRN-VCHLRI# (461) Emll.11 CYQDETPCRGSTFCCRKK-CCIGTCRF-PCYVKLERATFQELILQP^A ( 462 ) Emll.12 CLRDGQSCGYHSDCCRYS-CC GYCDQ-KCLII# (463) Vrll. .1 CLRDGQSCGYDSDCCRYS-CCWGYCDL-TCLII# (464) Vrll..2 CLHETSPCRRSFQCCHGI-CCFRRCSN-SCRF# (465) Vrll..3 CLRDGQSCGYHSDCCRYS-CCWGYCDQ-KCLII# (466) Vrll..4 CLHETPPCRRSFQCCHGN-CCFRRCSN-SCRF# (467) Vrll..5 CLHETSPCGRSFQCCHGI-CCFRRCSN-SCRF# ( 68) Vrll..6 CLYETSPCRRSFQCCHGI-CCFRRCSN-SCRF# (469) Vrll..7 CFPLGTFCSRYLPCCSGM-CCSG CTR-RCAPRF# (470) Fill.8 CHHEGLPCTSDDGCCG-MECCGGVCSS-HCGN# (471) Fill.9 CRAΞGVRCΞFDSQCCES-ECCMGSCAN-PCRIP# (472) Fill.10 CRAEGVYCEYGSQCCLS-QCCMASCAN-PCRHP# (473 ) Fill.11 CHHEGLPCTSGDGCCG-MECCGGVCSS-HCGN# (474) Fill.12 CHHEGLPCASDDGCCG-MECCGGVCSS-HCGN# (475 ) Epll.9 CAGQEΞPCSSRSDCCGSVGCCFGQCESP-CRMP# (476) Epll.10 CAGQEEPCSSRDDCCGSVGCCFGQCETP-CRMP# (477) Epll.ll CAGQEΞPCSSRSDCCGSVGCCFGQCESP-CRMI# (478) Epll.12 CLSEGSPCSMSGSCCHK-SCCRSTCTFP-CLIP# (479) Ξpll.13 CPSEGSPCSMSGSCCHK-SCCRSTCTFP-CLIP# (480) Sxll.l CHHEGLPCSSDDGCCG-MECCNGVCSS-SCGN# (481) Sxll.3 CHMD CSK-MTCCSGI-CC-FYCGRPMCPGTRRALLQRLVGHQR^A (482)

X is Gla

TABLE 4 Alignment of Alternatively Processed I-Superfamily Conotoxins- Type II

Emll CLHETSPCRRSFQCCHGICCFRRCSNSCRFGKRATFQEFILHR (483) Vrll CLHETSPCRRSFQCCHGICCFRRCSNSCRFGKRATFQEFILHR (484) Vrll CLHETPPCRRSFQCCHGNCCFRRCSNSCRFGKRATFQEFILHR (485) Vrll CLHETSPCGRSFQCCHGICCFRRCSNSCRFGKRATFQEFILHR (486) Vrll CLYETSPCRRSFQCCHGICCFRRCSNSCRFGKRATFQEFILHR (487 ) Emll CYQDETPCRGSIFCCRKKCCIGTCRFPCYVKLERATFQELILQP (488) Emll.11 CYQDETPCRGSTFCCRKKCCIGTCRFPCYVKLERATFQELILQP (489) Emll.6 CLRDGQSCRYHSDCCRYSCCWGYCDQKCLIIGKRATFQELILHR (490) Emll.9 CLRDGQSCGYDSDCCRYSCC GYCDLTCLIIGKRATFQELILHR (491) Vrll.l CLRDGQSCGYDSDCCRYSCCWGYCDLTCLIIGKRATFQELILHR (492) Emll.9A CLRDGQSCGYDSDCCRYSCC GYCDLTCLIIGKRATFQELILHP (493) Emll.12 CLRDGQSCGYHSDCCRYSCC GYCDQKCLIIGKRATFQELILHP (494) Vrll.3: CLRDGQSCGYHSDCCRYSCCWGYCDQKCLIIGKRATFQELILHR (495) Emll.7: CRREGSSCRRSYQCCRKSCCIGECEFPCR VGKRATFRELILHH (496) Emll.10 CFPPGIYCTPYLPCCWGICC-GTCRNVCHLRIGKRATFQE (497) Vrll.7: CFPLGTFCSRYLPCCSGMCCSG CTRRCAPRFGKRATFQE (498) Fill.8: CHHEGLPCTSDDGCCGMECCGGVCSSHCGNGRRRQVPLKSFGQR (499) Fill.8A CHHEGLPCTSDDGCCGMECCGGVCSSHCGNGRRRRVPLKSFGQR (500) Fill.8B CHHEGLPCTSDDGCCGMECCGGVCSSHCGNGGRRRVPLKSFGQR (501) Fill.11 CHHEGLPCTSGDGCCGMECCGGVCSSHCGNGRRRQVPLKSFGQR (502) Fill.12 CHHEGLPCASDDGCCGMECCGGVCSSHCGNGRRRRVPLKSFGQR (503) Fill.9: CRAEGVRCEFDSQCCESECCMGSCANPCRIPGKRARLFRQR ( 504 ) Fill.10: CRAEGVYCEYGSQCCLSQCCMASCANPCRHPGKRARLQEFFRQR (505) Fill.lOA CRAEGVYCEYGSQCCLSQCCMASCANPCRHPGKRARLQEFFRRR (506)

EXAMPLE 4

Biological Activity of I-Conotoxins [0101] The biological activity of I-conotoxin peptides were tested in mice and goldfish as exemplified by R11.19. Briefly, approximately 0.5 - 1.0 nmol of R11.19 was injected i.e. into 13-15 day-old mice weighing approximately 6 g. Shortly after injection, the mice began running and jumping in short duration immediately followed by convulsion with back legs kicking, copius urination, coma and death. The other conotoxins describe herein also produced death in mice at higher doses.

[0102] Approximately 0.1 nmol of R11.19 was injected into goldfish weighing aproximately 1 g. Shortly after injection, the goldfish began gasping (gills opening widely), followed by swimming backward or in circular and/or vertical motion, imbalanced swimming (body tilting), lying almost flat near the bottom and death.

EXAMPLE 5 Effect of I-Conotoxins on Skeletal Neomuscular Junction [0103] The motor nerve of a cutaneus pectoris muscle of frog was electrically stimulated every minute while the muscle's response was recorded extracellularly. Traces were acquired sequentially from bottom to top and aare shown in Figures 1 and 2. The peptide (1 μM) was introduced just before the 8^th trace from the bottom was acquired in Figure 1. Thus, traces below the 8^th trace are control responses, and those above the 8th trace are those in the presence of peptide. The control biphasic response is that of a muscle action potential initiated in the middle of the muscle (i.e. at the neuromuscular junction). The repetitive responses induced by the peptide have a similar shape as the control response, indicating that these (repetitive) responses are also initiated at the neuromuscular junction. [0104] Extracellular recording shows that I-conotoxin Rl 1.19 from C. radiatus produces repetitive action potentials in motor nerve. It is thought that the peptide exerts its action by blocking potassium channels in the presynaptic nerve terminal. Hyperactivity of the nerve is evident by recording from the neuromuscular junction (Figure 1 & 2) and the motor nerve itself (Figure 2).

EXAMPLE 6

Effect of I-Conotoxins in a Pain Model

[0105] Analgesic activity of Λ-conotoxins is also tested in pain models as follows. [0106] Persistent pain (^"formalin test). Intrathecal (i.t.) drug injections are performed as described by Hylden and Wilcox (1980). A I-conotoxin, e.g., R11.14, or vehicle is administered in a volume of 5 μl. Fifteen minutes after the i.t. injection, the right hindpaw is injected with 20 μl of 5% formalin. Animals are placed in clear plexiglass cylinders backed by mirrors to facilitate observation. Animals are closely observed for 2 minutes per 5 minute period, and the amount of time the animal spent licking the injected paw is recorded in this manner for a total of 45-50 minutes. Results are expressed as licking time in seconds per five minutes. At the end ofthe experiment, all animals are placed on an accelerating rotorod and the latency to first fall was recorded. Rl 1.14 is found to be active in this model which is predictive of efficacy for treating neuropathic pain. [0107] Acute pain (fail-flick . A I-conotoxin, e.g., R11.14, or saline is administered intrathecally (i.t.) according to the method of Hylden and Wilcox (1980) in a constant volume of 5 μl. Mice are gently wrapped in a towel with the tail exposed. At various time-points following the i.t. injection, the tail is dipped in a water bath maintained at 54 C. and the time to a vigorous tail withdrawal is recorded. If there is no withdrawal by 8 seconds, the tail is removed to avoid tissue damage.

[0108] Neuropathic pain. The partial sciatic nerve ligation model is used to assess the efficacy of I-conotoxin R11.14 in neuropathic pain. Nerve injury is produced according to the methods of Mafmberg and Basbaum (1998). Animals are anesthetized with a ketamine/xylazine solution, the sciatic nerve is exposed and tightly ligated with 8-0 silk suture around 1/3 to 1/2 of the nerve. In sham-operated mice the nerve is exposed, but not ligated. Animals are allowed to recover for at least 1 week before testing is performed. On the testing day, mice are placed in plexiglass cylinders on a wire mesh frame and allowed to habituate for at least 60 minutes. Mechanical allodynia is assessed with calibrated von Frey filaments using the up-down method as described by Chaplan et al. (1994), and the 50% withdrawal threshold is calculated. Animals that did not respond to any of the filaments in the series are assigned a maximal value of 3.6 grams, which is the filament that typically lifted the hindlimb without bending, and corresponds to approximately 1/10 the animal's body weight.

[0109] The data obtained demonstrate that I-conotoxins have potent analgesic properties in three commonly used models of pain: acute, persistent/inflammatory and neuropathic pain models.

EXAMPLE 7

Calcium-Channel Antagonist Activity: Inhibition of Ionic Currents [0110] Ionic currents through calcium channels are examined in cells that are voltage-clamped by a single patch-clamp electrode. These whole-cell patch-clamp studies are performed mainly on N1E115 mouse neuroblastoma cells, although a variety of cell types, including human neuroblastoma cell line IMR-32, are also examined.

[0111] Most measurements are obtained using a bath saline that allowed examination of the calcium currents in the absence of other ionic currents. These solutions contained 80 mM NMDG (as a sodium replacement), 30 mM TEAC1 (to block potassium currents), 10 mM BaCl₂ (as a charge-carrier through the calcium channels), and 10 mM HEPES at pH 7.3. Some solutions also contained 2 mM quinidine (to block potassium currents) and 3 μM tetrodotoxin (to block sodium currents). Normal bath saline is (mM): 140 NaCl, 10 glucose, 3 KC1, 2 CaCl₂, 1 MgCl₂, 10 mM HEPES pH 7.3. Intracellular solutions contained (mM): 150 CsCl, 0.5 CaCl₂, 5 EGTA, 5 MgCl₂, 2 K₂ATP at pH 7.3-7.4. Bath saline and all internal solutions are filtered before use. [0112] Pipets are made from Corning 7052 glass (Garner Glass Company, Claremont,

Calif. 91711), coated with Sylgard (Dow Corning, Midland, Mich. 48640) and fire-polished before use. Bubble numbers are typically 5 to 6, with pipet resistances typically 2-5 MOhms. Corning 8161, Kimble, and other glasses are also used without noticeable effect on the calcium currents observed. [0113] Recordings are carried out at room temperature with an Axopatch 1-C amplifier

(Axon Instruments, Foster City, Calif. 94404) and analyzed with pCLAMP software (Axon Instruments). Data are filtered at 1000 Hz for a typical sampling rate of 0.1 kHz; in all cases data are filtered at a frequency at most 1/5 of the sampling rate to avoid biasing. Data are collected on-line by the software. Analysis is performed on-screen with print-out via a Hewlett-Packard LaserJet Printer (Hewlett-Packard, Palo Alto, Calif. 94306).

[0114] The typical experiment is conducted as follows: after seal formation followed by series resistance compensation and capacitative transient cancellation, a voltage clamp protocol is performed wherein the cell potential is stepped from the holding potential (typically -100 mV) to test potentials that ranged from -60 mV to +20 mV in 10 mV increments. The cell is held at the holding potential for 5 seconds between pulses. Protocols starting from other holding potentials usually covered the same range of test potentials. I-conotoxins are found to have calcium channel blocking activity in such cell lines.

[0115] It will be appreciated that the methods and compositions of the instant invention can be incorporated in the form of a variety of embodiments, only a few of which are disclosed herein. It will be apparent to the artisan that other embodiments exist and do not depart from the spirit of the invention. Thus, the described embodiments are illustrative and should not be construed as restrictive.

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Claims (42)

WHAT IS CLAIMED IS:

1. A substantially pure I-conotoxin peptide having the generic formula I: Xaa₁-Xaa₂-Xaa₃- Xaa₄-Cys-Xaa₅-Xaa₆-Xaa₇-Xaa₈-Xaa₉-Xaa₁o-Cys-Xaa₁₁-Xaa₁₂-Xaa₁₃-Xaa₁₄-Xaa₁₅-Cys- Cys-Xaaι₆-Xaa₁₇-Xaa₁₈-Cys-Cys-Xaa₁₉-Xaa₂₀-Gly-Xaa_2]-Cys-Xaa₂₂-Xaa₂₃-Xaa₂₄-Xaa₂₅-

Xaa₂₆-Xaa₂₇-Xaa₂₈-Xaa₂₉-Xaa₃₀-Xaa₃₁-Cys-Xaa₃₂-Xaa₃₃-Xaa₃₄-Xaa₃₅-Xaa₃₆-Xaa₃₇-Xaa₃₈- Xaa₃₉-Xaa₄₀-Xaa₄₁ (SEQ ID NO:l), wherein Xaa_x is des-Xaa_! or Gly; Xaa_j is des-Xaa^ Pro, hydroxy-Pro (Hyp), Ala, His or Gly; Xaa^ is des-Xaa₃, Ser, Val, Pro, Hyp, Thr, g- Ser, g-Thr, g-Hyp or any synthetic hydroxylated amino acid; Xaa₄ is des-Xaa₄, Gly, Glu, γ-carboxy-Glu (Gla), Phe, Pro, Hyp, Arg, Lys, ornithine, homo-Lys, homoarginine, nor-

Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa₅ is an aliphatic amino acids bearing linear or branched saturated hydrocarbon chains such as Leu (D or L), He and Val or non-natural derivatives of the aliphatic amino acid, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl- Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys, any synthetic basic amino acid, Gly,

Trp (D or L), neo-Trp, halo-Trp (D or L), or any aromatic synthetic amino acid; Xaa₆ is Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl- Lys, N,N',N"-trimethyl-Lys, any synthetic basic amino acid, Ala, an aliphatic amino acids bearing linear or branched saturated hydrocarbon chains such as Leu (D or L), He and Val or non-natural derivatives of the aliphatic amino acid, Thr, Ser, g-Thr or g-Ser;

Xaa_? is Gly, Asp, Glu, Gla, Asn, Gin or any synthetic acidic amino acid; Xaa₈ is Gly, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl- Lys, N,N',N"-trimethyl-Lys, any synthetic basic amino acid, Asp, Glu, Gla, Asn, Gin or any synthetic acidic amino acid; Xaag is Ala, Val, Met, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa₁₀ is Ala, His, Ser, Thr, Pro, Hyp, g-Ser, g-Thr, g-Hyp, any synthetic hydroxylated amino acid, Asp, Glu, Gla, Asn, Gin, any synthetic acidic amino acid, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa_n is Gly, Ser, Thr, g-Ser, g-Thr, Asp, Glu, Gla, any synthetic acidic amino acid, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa₁₂ is Asn, Phe, Tyr, meta- Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, any synthetic aromatic amino acid, Gin or Leu (D or L); Xaa₁₃ is Ser, Thr, g- Ser, g-Thr or His; Xaa₁₄ is Ala, Gla, Ser, Thr, g-Ser, g-Thr, His, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"- trimethyl-Lys or any synthetic basic amino acid; Xaa₁₅ is Asp, Glu, His or Gla; Xaa₁₅ is des-Xaa₁₆, Gly, His, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any synthetic hyrdroxylated amino acid, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa₁₇ is des-Xaa₁₇, His, Ser, Thr, g-Ser, g-Thr, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys, any synthetic basic amino acid, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O- sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic aromatic amino acid; Xaa₁₈ is Val, Asn, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'- dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa₁₉ is des- Xaa_j9, Leu (D or L), Pro, Hyp, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic aromatic amino acid; Xaa^ is Gly, He, Ser, Thr, g-Ser, g-Thr, His, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys, any synthetic basic amino acid, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di- halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic aromatic amino acid;

Xaa^ is Ser, Thr, g-Ser, g-Thr, an aliphatic amino acids bearing linear or branched saturated hydrocarbon chains such as Leu (D or L), He and Val or non-natural derivatives of the aliphatic amino acid, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N- methyl-Lys, N,N'-dmiethyl-Lys, N,N',N"-trimethyl-Lys, any synthetic basic amino acid, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O- phospho-Tyr, nitro-Tyr or any synthetic aromatic amino acid; Xaa^ is Ala, Gin, Gla, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl- Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa^ is Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any synthetic hyrdroxylated amino acid, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"- trimethyl-Lys or any synthetic basic amino acid; Xaa^ is Gin, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp or any synthetic hyrdroxylated amino acid; Xaa^ is des-Xaa^, Ser, Thr, g- Ser or g-Thr; Xaa^ is des-Xaa^, Asn, Gin, Ser, Thr, g-Asn, g-Ser or g-Thr; Xaa^ is des- Xaa^, Val, Gla, Trp (D or L), neo-Trp, halo-Trp (D or L), any aromatic synthetic amino acid, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'- dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa^ is des- Xaa^, an aliphatic amino acids bearing linear or branched saturated hydrocarbon chains such as Leu (D or L), He and Val or non-natural derivatives of the aliphatic amino acid; Xaa₂₉ is des-Xaa^, an aliphatic amino acids bearing linear or branched saturated hydrocarbon chains such as Leu (D or L), He and Val or non-natural derivatives of the aliphatic amino acid; Xaa₃₀ is des-Xaa₃₀, He, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any synthetic hyrdroxylated amino acid, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-

Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic aromatic amino acid; Xaag_j is des-Xaaaj or Gly; Xaa₃₂ is Ser, Thr, g-Ser, g-Thr, Trp (D or L), neo- Trp, halo-Trp (D or L), any aromatic synthetic amino acid, Lys, Arg, ornithine, homo- Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa₃₃ is Val, Ser, Thr, g-Ser, g-Thr, Trp (D or L), neo-

Trp, halo-Trp (D or L) or any aromatic synthetic amino acid; Xaa₃₄ is Gly, He, Asp, Glu, Gla, Asn, Ser, Thr, g-Asn, g-Ser or g-Thr; Xaa₃₅ is des-Xaa₃₅, Val, Met, Gin, Pro, Hyp, Ser, Thr, g-Ser, g-Thr, g-Hyp or any synthetic hydroxylated amino acid; Xaagg is des- Xaagg, Val, Thr, Ser, g-Thr, g-Ser, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo- Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic aromatic amino acid; Xaa₃₇ is des-Xaa₃₇, Gin, Asn, Thr, Ser, g-Ser, g-Ser, g-Asn, Met, Leu, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O- phospho-Tyr, nitro-Tyr, any synthetic aromatic amino acid, Lys, Arg, ornithine, homo- Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaajg is des-Xaa₃₈, Leu, Ser, Thr, g-Ser, g-Thr, Lys,

Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaajg is des-Xaa₃₉, He, Ala, Thr, Ser, g-Ser, g-Thr, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N- methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; Xaa₄₀ is des-Xaa₄₀, Asp, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N- methyl-Lys, N,N'-dimethyl-Lys, N,N',N"-trimethyl-Lys or any synthetic basic amino acid; and Xaa₄₁ is des-Xaa₄₁, Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di- halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic aromatic amino acid.Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any synthetic aromatic amino acid, with the proviso that the peptide is not J029 (SEQ JD NO:2).

2. A substantially pure I-conotoxin peptide selected from the group consisting ofthe mature toxins set forth in Table 1 with the proviso that the peptide is not J029 (SEQ ID NO:2).

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

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

5. A substantially pure I-conotoxin peptide derivative comprising a derivative of the conotoxin peptide of claim 2.

6. The substantially pure I-conotoxin peptide derivative of claim 5, wherein the Arg residues may be substituted by Lys, ornithine, homoargine, nor-Lys, N-methyl-Lys, N,N- dimethyl-Lys, N,N,N-trimethyl-Lys or any synthetic basic amino acid; the Lys residues may be substituted by Arg, ornithine, homoargine, nor-Lys, or any synthetic basic amino acid; the Tyr residues may be substituted with any synthetic hydroxy containing amino acid; the Ser residues may be substituted with Thr or any synthetic hydroxylated amino acid; the Thr residues may be substituted with Ser or any synthetic hydroxylated amino acid; the Phe and Trp residues may be substituted with any synthetic aromatic amino acid; and the Asn, Ser, Thr or Hyp residues may be glycosylated; the Cys residues may be in D or L configuration; the Cys residues may be substituted with homocysteine (D or L); the Tyr residues may also be substituted with the 3-hydroxyl or 2-hydroxyl isomers (meta-Tyr or ortho-Tyr, respectively) and corresponding O-sulpho- and O-phospho- derivatives; the acidic amino acid residues may be substituted with any synthetic acidic amino acid, e.g., tetrazolyl derivatives of Gly and Ala; pairs of Cys residues may be replaced pairwise with isoteric lactam or ester-thioether replacements, such as Ser/(Glu or Asp), Lys/(Glu or Asp), Cys(Glu or Asp) or Cys/Ala combinations; the aliphatic amino acids may be substituted by synthetic derivatives bearing non-natural aliphatic branched or linear side chains C_nH_2n+2 up to and including n=8; the Leu residues may be substituted with Leu (D); the Glu residues may be substituted with Gla; the Gla residues may be substituted with Glu; the N-terminal Gin residues may be substituted with pyroGlu; and the Met residues may be substituted with norleucine.

7. The substantially pure I-conotoxin peptide derivative of claim 5 which is modified to contain an O-glycan, an S-glycan or an N-glycan.

8. The substantially pure I-conotoxin peptide derivative of claim 6 which is modified to contain an O-glycan, an S-glycan or an N-glycan.

9. An isolated nucleic acid comprising a nucleic acid coding for a I-conotoxin precursor comprising an amino acid sequence selected from the group of amino acid sequences set forth in Table 1.

10. The nucleic acid of claim 9 wherein the nucleic acid comprises a nucleotide sequence selected from the group of nucleotide sequences set forth in Table 1 or their complements.

11. A substantially pure I-conotoxin protein precursor comprising an amino acid sequence selected from the group of amino acid sequences set forth in Table 1.

12. A pharmaceutical composition comprising a I-conotoxin peptide of claim 1 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12, wherein said I-conotoxin peptide is modified to contain an O-glycan, an S-glycan or an N-glycan.

14. A pharmaceutical composition comprising a I-conotoxin peptide of claim 2 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition of claim 14, wherein the Arg residues may be substituted by Lys, ornithine, homoargine, nor-Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any synthetic basic amino acid; the Lys residues may be substituted by Arg, ornithine, homoargine, nor-Lys, or any synthetic basic amino acid; the Tyr residues may be substituted with any synthetic hydroxy containing amino acid; the Ser residues may be substituted with Thr or any synthetic hydroxylated amino acid; the Thr residues may be substituted with Ser or any synthetic hydroxylated amino acid; the Phe and Trp residues may be substituted with any synthetic aromatic amino acid; and the Asn, Ser, Thr or Hyp residues may be glycosylated; the Cys residues may be in D or L configuration; the Cys residues may be substituted with homocysteine (D or L); the Tyr residues may also be substituted with the 3 -hydroxyl or 2-hydroxyl isomers (meta-

Tyr or ortho-Tyr, respectively) and corresponding O-sulpho- and O-phospho-derivatives; the acidic amino acid residues may be substituted with any synthetic acidic amino acid, e.g., tetrazolyl derivatives of Gly and Ala; pairs of Cys residues may be replaced pairwise with isoteric lactam or ester-thioether replacements, such as Ser/(Glu or Asp), Lys/(Glu or Asp), Cys/(Glu or Asp) or Cys/Ala combinations; the aliphatic amino acids may be substituted by synthetic derivatives bearing non-natural aliphatic branched or linear side chains C_nH_2n+2 up to and including n=8; the Leu residues may be substituted with Leu (D); the Glu residues may be substituted with Gla; the Gla residues may be substituted with Glu; the N-teπninal Gin residues may be substituted with pyroGlu; and the Met residues may be substitued with norleucine.

16. The pharmaceutical composition of claim 14 wherein said I-conotoxin peptide is modified to contain an O-glycan, an S-glycan or an N-glycan.

17. The pharmaceutical composition of claim 15 said I-conotoxin peptide is modified to contain an O-glycan, an S-glycan or an N-glycan.

18. A method for regulating the flow of potassium through potassium channels in an individual in need thereof which comprises administering a therapeutically effective amount ofthe pharmaceutical composition of any one of claims 12-17.

19. The method of claim 18, wherein said individual in need thereof suffers from a disorder selected from the group consisting of multiple sclerosis, other demyelinating diseases (such as acute dissenmiated encephalomyelitis, optic neuromyelitis, adrenoleukodystrophy, acute transverse myelitis, progressive multifocal leukoencephalopathy), sub-acute sclerosing panencephalomyelitis (SSPE), metachromatic leukodystrophy, Pelizaeus-Merzbacher disease, spinal cord injury, botulinum toxin poisoning, Huntington's chorea, compression and entrapment neuropathies (such as carpal tunnel syndrome, ulnar nerve palsy), cardiovascular disorders (such as cardiac arrhythmias, congestive heart failure), reactive gliosis, hyperglycemia, immunosuppression, ***e addiction, cancer, cognitive dysfunction, disorders resulting from defects in neurotransmitter release (such as Eaton-Lambert syndrome), and reversal ofthe actions of curare and other neuromuscular blocking drugs.

20. The method of claim 18, wherein said disorder is a demyelinating disease.

21. A method for treating disorders associated with radical depolarization of excitable membranes by activating a K_ATP channel which comprises administering to an individual in need thereof an effective amount of the pharmaceutical composition of any one of claims 12-17.

22. The method of claim 21 , wherein said disorder is cardiac ischemia.

23. The method of claim 21 , wherein said disorder is cerebral ischemia.

24. The method of claim 21 , wherein said disorder is asthma.

25. The method of claim 21 , wherein said disorder is ocular ischemia.

26. A method for treating or preventing disorders associated with voltage gated ion channel disorders in which comprises administering to a patient in need thereof a therapeutically effective amount ofthe pharmaceutical composition of any one of claims 12-17.

27. The method of claim 26, wherein said disorder is a neurologic disorder.

28. The method of claim 27, wherein said neurologic disorder is a neurotoxic injury associated with conditions of hypoxia, anoxia or ischemia.

29. The method of claim 28, wherein said neurotoxic injury is associated with stroke, cerebrovascular accident, brain or spinal cord trauma, myocardial infarct, physical trauma, drownings, suffocation, perinatal asphyxia, or hypoglycemic events.

30. The method of claim 27, wherein said neurologic disorder is a seizure.

31. The method of claim 30, wherein said seizure is associated with epilepsy.

32. The method of claim 26, wherein said disorder is pain.

33. The method of claim 32, wherein said pain is migraine, acute pain, persistent pain, neuropathic pain or nociceptive pain.

34. The method of claim 26, wherein said disorder is a neuromuscular disorder.

35. The method of claim 34, wherein said neuromuscular disorder is myofacial pain syndrome, chronic muscle spasm, dystonias or spasticity.

36. A method for providing musculoskeletal relaxation in a patient undergoing a surgical procedure requiring anesthesia which comprises administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of claims 12-17.

37. A method of alleviating pain which comprises administering to a mammal that is either exhibiting pain or is about to be subjected to a pain-causing event a pain-alleviating amount ofthe pharmaceutical composition of any one of claims 12-17.

38. A method of identifying compounds that mimic the therapeutic activity of a I-conotoxin, comprising the steps of: (a) conducting a biological assay on a test compound to determine the therapeutic activity; and (b) comparing the results obtained from the biological assay ofthe test compound to the results obtained from the biological assay of a I-conotoxin.

39. A substantially pure I-conotoxin peptide derivative comprising a permutant of the peptide of claim 2.

40. A substantially pure I-conotoxin peptide derivative comprising a permutant of the peptide of claim 4.

41. A substantially pure I-conotoxin peptide derivative comprising a permutant of the peptide of claim 6.

42. A substantially pure I-conotoxin peptide derivative comprising a permutant of the peptide of claim 8.