US2005096270A1PendingUtilityA1
I-superfamily conotoxins
Est. expiryJun 30, 2020(expired)· nominal 20-yr term from priority
Inventors:Craig WalkerReshma ShettyElsie JimenezJ. Michael McintoshBaldomero M. OliveraMaren WatkinsRobert M. JonesGregory Shen
C07K 14/43504
59
PatentIndex Score
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Claims
Abstract
The invention relates to relatively short peptides (termed 1-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.
Claims
exact text as granted — not AI-modified1 . An isolated I-conotoxin peptide selected from the group consisting of the mature toxins set forth in Table 1 with the proviso that the peptide is not J029 (SEQ ID NO:2).
2 . The isolated I-conotoxin peptide of claim 1 , which is modified to contain an O-glycan, an S-glycan or an N-glycan.
3 . An isolated I-conotoxin peptide derivative comprising a derivative of the conotoxin peptide of claim 1 .
4 . The isolated I-conotoxin peptide derivative of claim 3 , wherein the Arg residues may be substituted by Lys, omithine, 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, omithine, 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 n H 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 Gln residues may be substituted with pyroGlu; and the Met residues may be substituted with norleucine.
5 . The isolated I-conotoxin peptide derivative of claim 3 which is modified to contain an O-glycan, an S-glycan or an N-glycan.
6 . The isolated I-conotoxin peptide derivative of claim 4 which is modified to contain an O-glycan, an S-glycan or an N-glycan.
7 . 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.
8 . The nucleic acid of claim 7 wherein the nucleic acid comprises a nucleotide sequence selected from the group of nucleotide sequences set forth in Table 1 or their complements.
9 . A isolated I-conotoxin protein precursor comprising an amino acid sequence selected from the group of amino acid sequences set forth in Table 1.
10 . A pharmaceutical composition comprising a I-conotoxin peptide of claim 1 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.
11 . The pharmaceutical composition of claim 10 , wherein said I-conotoxin peptide is modified to contain an O-glycan, an S-glycan or an N-glycan.
12 . The pharmaceutical composition of claim 10 , wherein the Arg residues may be substituted by Lys, omithine, 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, omithine, 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 n H 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 Gln residues may be substituted with pyroGlu; and the Met residues may be substitued with norleucine.
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 method for regulating the flow of potassium through potassium channels in an individual in need thereof which comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an I-conotoxin peptide or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier, said I-conotoxin peptide having the generic formula I:
Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Cys-Xaa 5 -Xaa 6 -
(SEQ ID NO:1)
Xaa 7 -Xaa 8 -Xaa 9 -Xaa 10 -Cys-Xaa 11 -
Xaa 12 -Xaa 13 -Xaa 14 -Xaa 15 -Cys-Cys-
Xaa 16 -Xaa 17 -Xaa 18 -Cys-Cys-Xaa 19 -
Xaa 20 -Gly-Xaa 21 -Cys-Xaa 22 -Xaa 23 -
Xaa 24 -Xaa 25 -Xaa 26 -Xaa 27 -Xaa 28 -Xaa 29 -
Xaa 30 -Xaa 31 -Cys-Xaa 32 -Xaa 33 -Xaa 34 -
Xaa 35 -Xaa 36 -Xaa 37 -Xaa 38 -Xaa 39 -Xaa 40 -
Xaa 41 ,
wherein Xaa, is des-Xaa 1 or Gly;
Xaa 2 is des-Xaa 2 , Pro, hydroxy-Pro (Hyp), Ala, His or Gly;
Xaa 3 is des-Xaa 3 , Ser, Val, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp or any non-natural hydroxylated amino acid;
Xaa 4 is des-Xaa 4 , Gly, Glu, γ-carboxy-Glu (Gla), Phe, Pro, Hyp, Arg, Lys, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 5 is an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural basic amino acid, Gly, Trp (D or L), neo-Trp, halo-Trp (D or L), or any non-natural aromatic amino acid;
Xaa 6 is Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural basic amino acid, Ala, an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid, Thr, Ser, g-Thr or g-Ser;
Xaa 7 is Gly, Asp, Glu, Gla, Asn, Gln or any non-natural acidic amino acid;
Xaa 8 is Gly, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural basic amino acid, Asp, Glu, Gla, Asn, Gln or any non-natural acidic amino acid;
Xaa 9 is Ala, Val, Met, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 10 is Ala, His, Ser, Thr, Pro, Hyp, g-Ser, g-Thr, g-Hyp, any non-natural hydroxylated amino acid, Asp, Glu, Gla, Asn, Gln, any non-natural 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 non-natural basic amino acid;
Xaa 11 is Gly, Ser, Thr, g-Ser, g-Thr, Asp, Glu, Gla, any non-natural acidic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 12 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 non-natural aromatic amino acid, Gln or Leu (D or L);
Xaa 13 is Ser, Thr, g-Ser, g-Thr or His;
Xaa 14 is Ala, Gla, Ser, Thr, g-Ser, g-Thr, His, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 15 is Asp, Glu, His or Gla; Xaa 16 is des-Xaa 16 , Gly, His, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any non-natural hydroxylated amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 17 is des-Xaa 17 , His, Ser, Thr, g-Ser, g-Thr, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural 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 non-natural aromatic amino acid;
Xaa 18 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 non-natural basic amino acid;
Xaa 19 is des-Xaalg, 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 non-natural aromatic amino acid;
Xaa 20 is Gly, Ile, 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 non-natural 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 non-natural aromatic amino acid;
Xaa 21 is Ser, Thr, g-Ser, g-Thr, an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural 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 non-natural aromatic amino acid;
Xaa 22 is Ala, Gln, Gla, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 23 is Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any non-natural hydroxylated amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 24 is Gln, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp or any non-natural hydroxylated amino acid;
Xaa 25 is des-Xaa 25 , Ser, Thr, g-Ser or g-Thr;
Xaa 26 is des-Xaa 26 , Asn, Gln, Ser, Thr, g-Asn, g-Ser or g-Thr;
Xaa 27 is des-Xaa 27 , Val, Gla, Trp (D or L), neo-Trp, halo-Trp (D or L), any non-natural aromatic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 28 is des-Xaa 28 , an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), He and Val and non-natural derivatives of the aliphatic amino acid;
Xaa 29 is des-Xaa 29 , an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid;
Xaa 30 is des-Xaa 30 , Ile, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any non-natural 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 non-natural aromatic amino acid;
Xaa 31 is des-Xaa 31 or Gly;
Xaa 32 is Ser, Thr, g-Ser, g-Thr, Trp (D or L), neo-Trp, halo-Trp (D or L), any non-natural aromatic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 33 is Val, Ser, Thr, g-Ser, g-Thr, Trp (D or L), neo-Trp, halo-Trp (D or L) or any non-natural aromatic amino acid;
Xaa 34 is Gly, Ile, Asp, Glu, Gla, Asn, Ser, Thr, g-Asn, g-Ser or g-Thr;
Xaa 35 is des-Xaa 35 , Val, Met, Gln, Pro, Hyp, Ser, Thr, g-Ser, g-Thr, g-Hyp or any non-natural hydroxylated amino acid;
Xaa 36 is des-Xaa 36 , 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 non-natural aromatic amino acid;
Xaa 37 is des-Xaa 37 , Gln, 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 non-natural aromatic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 38 is des-Xaa 38 , 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 non-natural basic amino acid;
Xaa 39 is des-Xaa 39 , Ile, 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 non-natural basic amino acid;
Xaa 40 is des-Xaa 40 , Asp, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid; and
Xaa 41 is des-Xaa 41 , Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any non-natural aromatic amino acid.
15 . The method of claim 14 , 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, cocaine 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.
16 . The method of claim 14 , wherein said disorder is a demyelinating disease.
17 . 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 comprising an I-conotoxin peptide or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier, said I-conotoxin peptide having the generic formula I:
Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Cys-Xaa 5 -Xaa 6 -
(SEQ ID NO:1)
Xaa 7 -Xaa 8 -Xaa 9 -Xaa 10 -Cys-Xaa 11 -
Xaa 12 -Xaa 13 -Xaa 14 -Xaa 15 -Cys-Cys-
Xaa 16 -Xaa 17 -Xaa 18 -Cys-Cys-Xaa 19 -
Xaa 20 -Gly-Xaa 21 -Cys-Xaa 22 -Xaa 23 -
Xaa 24 -Xaa 25 -Xaa 26 -Xaa 27 -Xaa 28 -Xaa 29 -
Xaa 30 -Xaa 31 -Cys-Xaa 32 -Xaa 33 -Xaa 34 -
Xaa 35 -Xaa 36 -Xaa 37 -Xaa 38 -Xaa 39 -Xaa 40 -
Xaa 41 ,
wherein Xaa 1 is des-Xaa 1 or Gly;
Xaa 2 is des-Xaa 2 , Pro, hydroxy-Pro (Hyp), Ala, His or Gly;
Xaa 3 is des-Xaa 3 , Ser, Val, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp or any non-natural hydroxylated amino acid;
Xaa 4 is des-Xaa 4 , Gly, Glu, γ-carboxy-Glu (Gla), Phe, Pro, Hyp, Arg, Lys, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 5 is an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural basic amino acid, Gly, Trp (D or L), neo-Trp, halo-Trp (D or L), or any non-natural aromatic amino acid;
Xaa 6 is Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural basic amino acid, Ala, an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid, Thr, Ser, g-Thr or g-Ser;
Xaa 7 is Gly, Asp, Glu, Gla, Asn, Gln or any non-natural acidic amino acid;
Xaa 8 is Gly, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural basic amino acid, Asp, Glu, Gla, Asn, Gln or any non-natural acidic amino acid;
Xaa 9 is Ala, Val, Met, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 10 is Ala, His, Ser, Thr, Pro, Hyp, g-Ser, g-Thr, g-Hyp, any non-natural hydroxylated amino acid, Asp, Glu, Gla, Asn, Gln, any non-natural acidic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 11 is Gly, Ser, Thr, g-Ser, g-Thr, Asp, Glu, Gla, any non-natural acidic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 12 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 non-natural aromatic amino acid, Gln or Leu (D or L);
Xaa 13 is Ser, Thr, g-Ser, g-Thr or His;
Xaa 14 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 non-natural basic amino acid;
Xaa 15 is Asp, Glu, His or Gla; Xaa 16 is des-Xaa 16 , Gly, His, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any non-natural hydroxylated amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 17 is des-Xaa 17 , His, Ser, Thr, g-Ser, g-Thr, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural 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 non-natural aromatic amino acid;
Xaa 18 is Val, Asn, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid,
Xaa 19 is des-Xaalg, 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 non-natural aromatic amino acid;
Xaa 20 is Gly, Ile, Ser, Thr, g-Ser, g-Thr, His, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural 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 non-natural aromatic amino acid;
Xaa 21 is Ser, Thr, g-Ser, g-Thr, an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural 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 non-natural aromatic amino acid;
Xaa 22 is Ala, Gln, Gla, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 23 is Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any non-natural hydroxylated amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 24 is Gln, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp or any non-natural hydroxylated amino acid;
Xaa 25 is des-Xaa 25 , Ser, Thr,,g-Ser or g-Thr;
Xaa 26 is des-Xaa 26 , Asn, Gln, Ser, Thr, g-Asn, g-Ser or g-Thr;
Xaa 27 is des-Xaa 27 , Val, Gla, Trp (D or L), neo-Trp, halo-Trp (D or L), any non-natural aromatic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 28 is des-Xaa 28 , an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), He and Val and non-natural derivatives of the aliphatic amino acid;
Xaa 29 is des-Xaa 29 , an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid;
Xaa 30 is des-Xaa 30 , Ile, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any non-natural 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 non-natural aromatic amino acid;
Xaa 31 is des-Xaa 31 or Gly;
Xaa 32 is Ser, Thr, g-Ser, g-Thr, Trp (D or L), neo-Trp, halo-Trp (D or L), any non-natural 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 non-natural basic amino acid;
Xaa 33 is Val, Ser, Thr, g-Ser, g-Thr, Trp (D or L), neo-Trp, halo-Trp (D or L) or any non-natural aromatic amino acid;
Xaa 34 is Gly, Ile, Asp, Glu, Gla, Asn, Ser, Thr, g-Asn, g-Ser or g-Thr;
Xaa 35 is des-Xaa 35 , Val, Met, Gln, Pro, Hyp, Ser, Thr, g-Ser, g-Thr, g-Hyp or any non-natural hydroxylated amino acid;
Xaa 36 is des-Xaa 36 , 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 non-natural aromatic amino acid;
Xaa 37 is des-Xaa 37 , Gln, 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 non-natural 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 non-natural basic amino acid;
Xaa 38 is des-Xaa 38 , 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 non-natural basic amino acid;
Xaa 39 is des-Xaa 39 , Ile, 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 non-natural basic amino acid;
Xaa 40 is des-Xaa 40 , Asp, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid; and
Xaa 41 is des-Xaa 41 , Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any non-natural aromatic amino acid.
18 . The method of claim 17 , wherein said disorder is cardiac ischemia.
19 . The method of claim 17 , wherein said disorder is cerebral ischemia.
20 . The method of claim 17 , wherein said disorder is asthma.
21 . The method of claim 17 , wherein said disorder is ocular ischemia.
22 . 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 of the pharmaceutical composition comprising an I-conotoxin peptide or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier, said I-conotoxin peptide having the generic formula I:
Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Cys-Xaa 5 -Xaa 6 -
(SEQ ID NO:1)
Xaa 7 -Xaa 8 -Xaa 9 -Xaa 10 -Cys-Xaa 11 -
Xaa 12 -Xaa 13 -Xaa 14 -Xaa 15 -Cys-Cys-
Xaa 16 -Xaa 17 -Xaa 18 -Cys-Cys-Xaa 19 -
Xaa 20 -Gly-Xaa 21 -Cys-Xaa 22 -Xaa 23 -
Xaa 24 -Xaa 25 -Xaa 26 -Xaa 27 -Xaa 28 -Xaa 29 -
Xaa 30 -Xaa 31 -Cys-Xaa 32 -Xaa 33 -Xaa 34 -
Xaa 35 -Xaa 36 -Xaa 37 -Xaa 38 -Xaa 39 -Xaa 40 -
Xaa 41 ,
wherein Xaa 1 is des-Xaa 1 or Gly;
Xaa 2 is des-Xaa 2 , Pro, hydroxy-Pro (Hyp), Ala, His or Gly;
Xaa 3 is des-Xaa 3 , Ser, Val, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp or any non-natural hydroxylated amino acid;
Xaa 4 is des-Xaa 4 , Gly, Glu, γ-carboxy-Glu (Gla), Phe, Pro, Hyp, Arg, Lys, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 5 is an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural basic amino acid, Gly, Trp (D or L), neo-Trp, halo-Trp (D or L), or any non-natural aromatic amino acid;
Xaa 6 is Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural basic amino acid, Ala, an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid, Thr, Ser, g-Thr or g-Ser;
Xaa 7 is Gly, Asp, Glu, Gla, Asn, Gln or any non-natural acidic amino acid;
Xaa 8 is Gly, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural basic amino acid, Asp, Glu, Gla, Asn, Gln or any non-natural acidic amino acid;
Xaa 9 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 non-natural basic amino acid;
Xaalo is Ala, His, Ser, Thr, Pro, Hyp, g-Ser, g-Thr, g-Hyp, any non-natural hydroxylated amino acid, Asp, Glu, Gla, Asn, Gln, any non-natural 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 non-natural basic amino acid;
Xaa 1 is Gly, Ser, Thr, g-Ser, g-Thr, Asp, Glu, Gla, any non-natural 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 non-natural basic amino acid;
Xaa 12 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 non-natural aromatic amino acid, Gln or Leu (D or L);
Xaa 13 is Ser, Thr, g-Ser, g-Thr or His;
Xaa 14 is Ala, Gla, Ser, Thr, g-Ser, g-Thr, His, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 15 is Asp, Glu, His or Gla; Xaa 16 is des-Xaa 16 , Gly, His, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any non-natural hydroxylated amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 17 is des-Xaa 17 , His, Ser, Thr, g-Ser, g-Thr, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural 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 non-natural aromatic amino acid;
Xaa 18 is Val, Asn, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 19 is des-Xaalg, 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 non-natural aromatic amino acid;
Xaa 20 is Gly, Ile, Ser, Thr, g-Ser, g-Thr, His, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural 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 non-natural aromatic amino acid;
Xaa 21 is Ser, Thr, g-Ser, g-Thr, an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural 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 non-natural aromatic amino acid;
Xaa 22 is Ala, Gln, Gla, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 23 is Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any non-natural hydroxylated amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 24 is Gln, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp or any non-natural hydroxylated amino acid;
Xaa 25 is des-Xaa 2 S, Ser, Thr, g-Ser or g-Thr;
Xaa 26 is des-Xaa 26 , Asn, Gln, Ser, Thr, g-Asn, g-Ser or g-Thr;
Xaa 27 is des-Xaa 27 , Val, Gla, Trp (D or L), neo-Trp, halo-Trp (D or L), any non-natural 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 non-natural basic amino acid;
Xaa 28 is des-Xaa 28 , an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid;
Xaa 29 is des-Xaa 29 , an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid;
Xaa 30 is des-Xaa 30 , Ile, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any non-natural 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 non-natural aromatic amino acid;
Xaa 31 is des-Xaa 31 or Gly;
Xaa 32 is Ser, Thr, g-Ser, g-Thr, Trp (D or L), neo-Trp, halo-Trp (D or L), any non-natural 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 non-natural basic amino acid;
Xaa 33 is Val, Ser, Thr, g-Ser, g-Thr, Trp (D or L), neo-Trp, halo-Trp (D or L) or any non-natural aromatic amino acid;
Xaa 34 is Gly, Ile, Asp, Glu, Gla, Asn, Ser, Thr, g-Asn, g-Ser or g-Thr;
Xaa 35 is des-Xaa 35 , Val, Met, Gln, Pro, Hyp, Ser, Thr, g-Ser, g-Thr, g-Hyp or any non-natural hydroxylated amino acid;
Xaa 36 is des-Xaa 36 , 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 non-natural aromatic amino acid;
Xaa 37 is des-Xaa 37 , Gln, 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 non-natural aromatic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 38 is des-Xaa 38 , Leu, Ser, Thr, g-Ser, g-Thr, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 39 is des-Xaa 39 , Ile, Ala, Thr, Ser, g-Ser, g-Thr, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 40 is des-Xaa 40 , Asp, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid; and
Xaa 41 is des-Xaa 41 , Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any non-natural aromatic amino acid.
23 . The method of claim 22 , wherein said disorder is a neurologic disorder.
24 . The method of claim 23 , wherein said neurologic disorder is a neurotoxic injury associated with conditions of hypoxia, anoxia or ischemia.
25 . The method of claim 24 , 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.
26 . The method of claim 24 , wherein said neurologic disorder is a seizure.
27 . The method of claim 22 , wherein said seizure is associated with epilepsy.
28 . The method of claim 22 , wherein said disorder is pain.
29 . The method of claim 28 , wherein said pain is migraine, acute pain, persistent pain, neuropathic pain or nociceptive pain.
30 . The method of claim 22 , wherein said disorder is a neuromuscular disorder.
31 . The method of claim 30 , wherein said neuromuscular disorder is myofacial pain syndrome, chronic muscle spasm, dystonias or spasticity.
32 . 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 comprising an I-conotoxin peptide or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier, said I-conotoxin peptide having the generic formula I:
Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Cys-Xaa 5 -Xaa 6 -
(SEQ ID NO:1)
Xaa 7 -Xaa 8 -Xaa 9 -Xaa 10 -Cys-Xaa 11 -
Xaa 12 -Xaa 13 -Xaa 14 -Xaa 15 -Cys-Cys-
Xaa 16 -Xaa 17 -Xaa 18 -Cys-Cys-Xaa 19 -
Xaa 20 -Gly-Xaa 21 -Cys-Xaa 22 -Xaa 23 -
Xaa 24 -Xaa 25 -Xaa 26 -Xaa 27 -Xaa 28 -Xaa 29 -
Xaa 30 -Xaa 31 -Cys-Xaa 32 -Xaa 33 -Xaa 34 -
Xaa 35 -Xaa 36 -Xaa 37 -Xaa 38 -Xaa 39 -Xaa 40 -
Xaa 41 ,
wherein Xaa 1 is des-Xaa 1 or Gly;
Xaa 2 is des-Xaa 2 , Pro, hydroxy-Pro (Hyp), Ala, His or Gly;
Xaa 3 is des-Xaa 3 , Ser, Val, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp or any non-natural hydroxylated amino acid;
Xaa 4 is des-Xaa 4 , 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 non-natural basic amino acid;
Xaa 5 is an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural basic amino acid, Gly, Trp (D or L), neo-Trp, halo-Trp (D or L), or any non-natural aromatic amino acid;
Xaa 6 is Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural basic amino acid, Ala, an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid, Thr, Ser, g-Thr or g-Ser;
Xaa 7 is Gly, Asp, Glu, Gla, Asn, Gln or any non-natural acidic amino acid;
Xaa 8 is Gly, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural basic amino acid, Asp, Glu, Gla, Asn, Gln or any non-natural acidic amino acid;
Xaa 9 is Ala, Val, Met, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 10 is Ala, His, Ser, Thr, Pro, Hyp, g-Ser, g-Thr, g-Hyp, any non-natural hydroxylated amino acid, Asp, Glu, Gla, Asn, Gln, any non-natural 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 non-natural basic amino acid;
Xaa 11 is Gly, Ser, Thr, g-Ser, g-Thr, Asp, Glu, Gla, any non-natural 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 non-natural basic amino acid;
Xaa 12 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 non-natural aromatic amino acid, Gln or Leu (D or L);
Xaa 13 is Ser, Thr, g-Ser, g-Thr or His;
Xaa 14 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 non-natural basic amino acid;
Xaa 15 is Asp, Glu, His or Gla; Xaa 16 is des-Xaa 16 , Gly, His, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any non-natural 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 non-natural basic amino acid;
Xaa 17 is des-Xaa 17 , His, Ser, Thr, g-Ser, g-Thr, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural 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 non-natural aromatic amino acid;
Xaa 18 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 non-natural basic amino acid;
Xaa 19 is des-Xaalg, 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 non-natural aromatic amino acid;
Xaa 20 is Gly, Ile, 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 non-natural 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 non-natural aromatic amino acid;
Xaa 21 is Ser, Thr, g-Ser, g-Thr, an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and 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 non-natural 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 non-natural aromatic amino acid;
Xaa 22 is Ala, Gln, Gla, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 23 is Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any non-natural 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 non-natural basic amino acid;
Xaa 24 is Gin, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp or any non-natural hydroxylated amino acid;
Xaa 25 is des-Xaa 25 , Ser, Thr, g-Ser or g-Thr;
Xaa 26 is des-Xaa 26 , Asn, Gin, Ser, Thr, g-Asn, g-Ser or g-Thr;
Xaa 27 is des-Xaa 27 , Val, Gla, Trp (D or L), neo-Trp, halo-Trp (D or L), any non-natural 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 non-natural basic amino acid;
Xaa 28 is des-Xaa 28 , an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid;
Xaa 29 is des-Xaa 29 , an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid;
Xaa 30 is des-Xaa 30 , Ile, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any non-natural 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 non-natural aromatic amino acid;
Xaa 31 is des-Xaa 31 or Gly;
Xaa 32 is Ser, Thr, g-Ser, g-Thr, Trp (D or L), neo-Trp, halo-Trp (D or L), any non-natural 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 non-natural basic amino acid;
Xaa 33 is Val, Ser, Thr, g-Ser, g-Thr, Trp (D or L), neo-Trp, halo-Trp (D or L) or any non-natural aromatic amino acid;
Xaa 34 is Gly, Ile, Asp, Glu, Gla, Asn, Ser, Thr, g-Asn, g-Ser or g-Thr;
Xaa 35 is des-Xaa 35 , Val, Met, Gin, Pro, Hyp, Ser, Thr, g-Ser, g-Thr, g-Hyp or any non-natural hydroxylated amino acid;
Xaa 36 is des-Xaa 36 , 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 non-natural aromatic amino acid;
Xaa 37 is des-Xaa 37 , Gln, 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 non-natural 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 non-natural basic amino acid;
Xaa 38 is des-Xaa 38 , 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 non-natural basic amino acid;
Xaa 39 is des-Xaa 39 , Ile, 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 non-natural basic amino acid;
Xaa 40 is des-Xaa 40 , Asp, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid; and
Xaa 41 is des-Xaa 41 , Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any non-natural aromatic amino acid.
33 . 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 of the pharmaceutical composition comprising an I-conotoxin peptide or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier, said I-conotoxin peptide having the generic formula I:
Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Cys-Xaa 5 -Xaa 6 -
(SEQ ID NO:1)
Xaa 7 -Xaa 8 -Xaa 9 -Xaa 10 -Cys-Xaa 11 -
Xaa 12 -Xaa 13 -Xaa 14 -Xaa 15 -Cys-Cys-
Xaa 16 -Xaa 17 -Xaa 18 -Cys-Cys-Xaa 19 -
Xaa 20 -Gly-Xaa 21 -Cys-Xaa 22 -Xaa 23 -
Xaa 24 -Xaa 25 -Xaa 26 -Xaa 27 -Xaa 28 -Xaa 29 -
Xaa 30 -Xaa 31 -Cys-Xaa 32 -Xaa 33 -Xaa 34 -
Xaa 35 -Xaa 36 -Xaa 37 -Xaa 38 -Xaa 39 -Xaa 40 -
Xaa 41 ,
wherein Xaa 1 is des-Xaa 1 or Gly;
Xaa 2 is des-Xaa 2 , Pro, hydroxy-Pro (Hyp), Ala, His or Gly;
Xaa 3 is des-Xaa 3 , Ser, Val, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp or any non-natural hydroxylated amino acid;
Xaa 4 is des-Xaa 4 , Gly, Glu, γ-carboxy-Glu (Gla), Phe, Pro, Hyp, Arg, Lys, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 5 is an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural basic amino acid, Gly, Trp (D or L), neo-Trp, halo-Trp (D or L), or any non-natural aromatic amino acid;
Xaa 6 is Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural basic amino acid, Ala, an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), Ile and Val and non-natural derivatives of the aliphatic amino acid, Thr, Ser, g-Thr or g-Ser;
Xaa 7 is Gly, Asp, Glu, Gla, Asn, Gin or any non-natural acidic amino acid;
Xaa 8 is Gly, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural basic amino acid, Asp, Glu, Gla, Asn, Gin or any non-natural acidic amino acid;
Xaa 9 is Ala, Val, Met, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 10 is Ala, His, Ser, Thr, Pro, Hyp, g-Ser, g-Thr, g-Hyp, any non-natural hydroxylated amino acid, Asp, Glu, Gla, Asn, Gln, any non-natural 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 non-natural basic amino acid;
Xaa 11 is Gly, Ser, Thr, g-Ser, g-Thr, Asp, Glu, Gla, any non-natural acidic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 12 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 non-natural aromatic amino acid, Gln or Leu (D or L);
Xaa 13 is Ser, Thr, g-Ser, g-Thr or His;
Xaa 14 is Ala, Gla, Ser, Thr, g-Ser, g-Thr, His, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 15 is Asp, Glu, His or Gla; Xaa 16 is des-Xaa 16 , Gly, His, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any non-natural hydroxylated amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 17 is des-Xaa 17 , His, Ser, Thr, g-Ser, g-Thr, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural 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 non-natural aromatic amino acid;
Xaa 18 is Val, Asn, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 19 is des-Xaalg, 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 non-natural aromatic amino acid;
Xaa 20 is Gly, Hle, Ser, Thr, g-Ser, g-Thr, His, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural 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 non-natural aromatic amino acid;
Xaa 21 is Ser, Thr, g-Ser, g-Thr, an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), lle and Val and non-natural derivatives of the aliphatic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys, any non-natural 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 non-natural aromatic amino acid;
Xaa 22 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 non-natural basic amino acid;
Xaa 23 is Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any non-natural 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 non-natural basic amino acid;
Xaa 24 is Gin, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp or any non-natural hydroxylated amino acid;
Xaa 25 is des-Xaa 25 , Ser, Thr, g-Ser or g-Thr;
Xaa 26 is des-Xaa 26 , Asn, Gin, Ser, Thr, g-Asn, g-Ser or g-Thr;
Xaa 27 is des-Xaa 27 , Val, Gla, Trp (D or L), neo-Trp, halo-Trp (D or L), any non-natural 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 non-natural basic amino acid;
Xaa 28 is des-Xaa 28 , an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), lie and Val and non-natural derivatives of the aliphatic amino acid;
Xaa 29 is des-Xaa 29 , an aliphatic amino acid bearing linear or branched saturated hydrocarbon chains selected from the group consisting of Leu (D or L), He and Val and non-natural derivatives of the aliphatic amino acid;
Xaa 30 is des-Xaa 30 , Ile, Ser, Pro, Hyp, Thr, g-Ser, g-Thr, g-Hyp, any non-natural 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 non-natural aromatic amino acid;
Xaa 31 is des-Xaa 31 or Gly;
Xaa 32 is Ser, Thr, g-Ser, g-Thr, Trp (D or L), neo-Trp, halo-Trp (D or L), any non-natural 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 non-natural basic amino acid;
Xaa 33 is Val, Ser, Thr, g-Ser, g-Thr, Trp (D or L), neo-Trp, halo-Trp (D or L) or any non-natural aromatic amino acid;
Xaa 34 is Gly, Ile, Asp, Glu, Gla, Asn, Ser, Thr, g-Asn, g-Ser or g-Thr;
Xaa 35 is des-Xaa 35 , Val, Met, Gln, Pro, Hyp, Ser, Thr, g-Ser, g-Thr, g-Hyp or any non-natural hydroxylated amino acid;
Xaa 36 is des-Xaa 36 , 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 non-natural aromatic amino acid;
Xaa 37 is des-Xaa 37 , Gln, 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 non-natural aromatic amino acid, Lys, Arg, omithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid;
Xaa 38 is des-Xaa 38 , 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 non-natural basic amino acid;
Xaa 39 is des-Xaa 39 , Ile, 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 non-natural basic amino acid;
Xaa 40 is des-Xaa 40 , Asp, Lys, Arg, ornithine, homo-Lys, homoarginine, nor-Lys, N-methyl-Lys, N,N′-dimethyl-Lys, N,N′,N″-trimethyl-Lys or any non-natural basic amino acid; and
Xaa 41 is des-Xaa 41 , Phe, Tyr, meta-Tyr, ortho-Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any non-natural aromatic amino acid.
34 . 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 of the test compound to the results obtained from the biological assay of an I-conotoxin.
35 . A substantially pure I-conotoxin peptide derivative comprising a permutant of the peptide of claim 1 .
36 . A substantially pure I-conotoxin peptide derivative comprising a permutant of the peptide of claim 2 .
37 . A substantially pure I-conotoxin peptide derivative comprising a permutant of the peptide of claim 3 .
38 . A substantially pure I-conotoxin peptide derivative comprising a permutant of the peptide of claim 4 .
39 . A substantially pure I-conotoxin peptide derivative comprising a permutant of the peptide of claim 5 .
40 . A substantially pure I-conotoxin peptide derivative comprising a permutant of the peptide of claim 6.Join the waitlist — get patent alerts
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