US2014350218A1PendingUtilityA1
Alpha-conotoxin peptides
Est. expiryJan 29, 2019(expired)· nominal 20-yr term from priority
A61P 25/04A61P 25/14C07K 9/00Y10S530/855Y10S530/857C07K 14/43504A61P 21/02C07K 7/08A61K 38/00
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Claims
Abstract
The invention relates to relatively short peptides (termed α-conotoxins herein), about 10-30 residues in length, which are naturally available in minute amounts in the venom of the cone snails or analogous to the naturally available peptides, and which preferably include two disulfide bonds.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A substantially pure α-conotoxin peptide selected from the group consisting of:
(SEQ ID NO: 4)
Asp-Xaa 1 -Cys-Cys-Ser-Asp-Ser-Arg-Cys-
Gly-Xaa 2 -Asn-Cys-Leu;
(SEQ ID NO: 5)
Ala-Cys-Cys-Ser-Asp-Arg-Arg-Cys-Arg-
Xaa 3 -Arg-Cys;
(SEQ ID NO: 6)
Phe-Thr-Cys-Cys-Arg-Arg-Gly-Thr-Cys-
Ser-Gln-His-Cys;
(SEQ ID NO: 7)
Asp-Xaa 4 -Cys-Cys-Arg-Arg-His-Ala-Cys-
Thr-Leu-Ile-Cys;
(SEQ ID NO: 8)
Asp-Xaa 4 -Cys-Cys-Arg-Xaa 5 -Xaa 5 -Cys-Thr-
Leu-Ile-Cys;
(SEQ ID NO: 10)
Gly-Gly-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-
Ala-Xaa 3 -Arg-Cys;
(SEQ ID NO: 11)
Ile-Ala-Xaa 3 -Asp-Ile-Cys-Cys-Ser-Xaa 1 -
Xaa 5 -Asp-Cys-Asn-His-Xaa 2 -Cys-Val;
and
(SEQ ID NO: 12)
Gly-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Xaa 2 -
His-Gln-Cys,
wherein Xaa 1 is Glu or γ-carboxy-Glu (Gla); Xaa 2 is Lys, N-methyl-Lys, N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa 3 is Trp (D or L), halo-Trp or neo-Trp; Xaa 4 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa 5 is Pro or hydroxy-Pro; and the C-terminus contains a carboxyl or amide group, or derivatives thereof.
2 . The substantially pure α-conotoxin peptide of claim 1 , which is modified to contain an O-glycan, an S-glycan or an N-glycan.
3 . A substantially pure α-conotoxin peptide having the generic formula II: Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Cys-Cys-Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Cys-Xaa 9 -Xaa 10 -Xaa 11 -Xaa 12 -Xaa 13 -Xaa 14 -Cys-Xaa 15 -Xaa 16 -Xaa 17 (SEQ ID NO:2), wherein Xaa 1 is des-Xaa 1 , Asp, Glu or γ-carboxy-Glu (Gla); Xaa 2 is des-Xaa 2 , Gln, Ala, Asp, Glu, Gla; Xaa 3 is des-Xaa 3 , Gly, Ala, Asp, Glu, Gla, Pro or hydroxy-Pro; Xaa 4 is des-Xaa 4 , Gly, Glu, Gla, Gln, Asp, Asn, Pro or hydroxy-Pro; Xaa 5 is Ser, Thr, Gly, Glu, Gla, Asn, Trp (D or L), neo-Trp, halo-Trp, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 6 is Asp, Asn, His, halo-His, Thr, Ser, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 7 is Pro or hydroxy-Pro; Xaa 8 is Ala, Ser, Thr, Asp, Val, Ile, Pro, hydroxy-Pro, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 9 is Gly, Ile, Leu, Val, Ala, Thr, Ser, Pro, hydroxy-Pro, Phe, Trp (D or L), neo-Trp, halo-Trp, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid or any unnatural aromatic amino acid; Xaa 10 is Ala, Asn, Phe, Pro, hydroxy-Pro, Glu, Gla, Gln, His, halo-His, Val, Ser, Thr, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 11 is Thr, Ser, His, halo-His, Leu, Ile, Val, Asn, Met, Pro, hydroxy-Pro, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 12 is Asn, Pro, hydroxy-Pro, Gln, Ser, Thr, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 13 is des-Xaa 13 , Gly, Thr, Ser, Pro, hydroxy-Pro, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; Xaa 14 is des-Xaa 14 , Ile, Val, Asp, Leu, Phe, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural hydroxy containing amino acid; and Xaa 15 is des-Xaa 15 , Gly, Ala, Met, Ser, Thr, Trp (D or L), neo-Trp, halo-Trp, any unnatural aromatic amino acid, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 16 is des-Xaa 16 , Trp (D or L), neo-Trp, halo-Trp, any unnatural aromatic amino acid, Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 17 is des-Xaa 17 , Arg, ornithine, homoarginine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; and the C-terminus contains a free carboxyl group or an amide group.
4 . A substantially pure α-conotoxin peptide of generic formula II of claim 3 selected from the group consisting of:
(SEQ ID NO: 13)
Cys-Cys-Ser-Asp-Xaa 5 -Ala-Cys-Xaa 2 -Gln-Thr-Xaa 5 -Gly-Cys-Arg;
(SEQ ID NO: 14)
Cys-Cys-Xaa 1 -Asn-Xaa 5 -Ala-Cys-Arg-His-Thr-Gln-Gly-Cys;
(SEQ ID NO: 15)
Gly-Cys-Cys-Xaa 3 -His-Xaa 5 -Ala-Cys-Gly-Arg-His-Xaa 4 -Cys;
(SEQ ID NO: 16)
Ala-Xaa 5 -Cys-Cys-Asn-Asn-Xaa 5 -Ala-Cys-Val-Xaa 2 -His-Arg-Cys;
(SEQ ID NO: 17)
Ala-Xaa 5 -Gly-Cys-Cys-Asn-Asn-Xaa 5 -Ala-Cys-Val-Xaa 2 -His-Arg-Cys;
(SEQ ID NO: 18)
Xaa 5 -Xaa 5 -Cys-Cys-Asn-Asn-Xaa 5 -Ala-Cys-Val-Xaa 2 -His-Arg-Cys;
(SEQ ID NO: 19)
Asp-Xaa 1 -Asn-Cys-Cys-Xaa 3 -Asn-Xaa 5 -Ser-Cys-Xaa 5 -Arg-Xaa 5 -Arg-Cys-Thr;
(SEQ ID NO: 20)
Gly-Cys-Cys-Ser-Thr-Xaa 5 -Xaa 5 -Cys-Ala-Val-Leu-Xaa 4 -Cys;
(SEQ ID NO: 21)
Gly-Cys-Cys-Gly-Asn-Xaa 5 -Asp-Cys-Thr-Ser-His-Ser-Cys;
(SEQ ID NO: 42)
Gly-Cys-Cys-Ser-Asn-Xaa 5 -Xaa 5 -Cys-Ala-His-Asn-Asn-Xaa 5 -Asp-Cys-Arg;
(SEQ ID NO: 154)
Gly-Cys-Cys-Xaa 4 -Asn-Xaa 5 -Val-Cys-Xaa 2 -Xaa 2 -Xaa 4 -Xaa 4 -Cys-Xaa 3 -Xaa 2 ;
(SEQ ID NO: 155)
Xaa 6 -Xaa 1 -Xaa 5 -Gly-Cys-Cys-Arg-His-Xaa 5 -Ala-Cys-Gly-Xaa 2 -Asn-Arg-Cys;
(SEQ ID NO: 156)
Cys-Cys-Ala-Asp-Xaa 5 -Asp-Cys-Arg-Phe-Arg-Xaa 5 -Gly-Cys;
(SEQ ID NO: 157)
Gly-Cys-Cys-Xaa 4 -Asn-Xaa 5 -Ser-Cys-Xaa 3 -Xaa 5 -Xaa 2 -Thr-Xaa 4 -Cys-Ser-Xaa 3 -
Xaa 2 ;
(SEQ ID NO: 158)
Cys-Cys-Ser-Asn-Xaa 5 -Thr-Cys-Xaa 2 -Xaa 1 -Thr-Xaa 4 -Gly-Cys;
(SEQ ID NO: 159)
Cys-Cys-Ala-Asn-Xaa 5 -Ile-Cys-Xaa 2 -Asn-Thr-Xaa 5 -Gly-Cys;
(SEQ ID NO: 160)
Cys-Cys-Asn-Asn-Xaa 5 -Thr-Cys-Xaa 2 -Xaa 1 -Thr-Xaa 4 -Gly-Cys;
(SEQ ID NO: 161)
Cys-Cys-Ser-Asn-Xaa 5 -Val-Cys-Xaa 2 -Xaa 1 -Thr-Xaa 4 -Gly-Cys;
(SEQ ID NO: 162)
Gly-Gly-Cys-Cys-Ser-Xaa 4 -Xaa 5 -Xaa 5 -Cys-Ile-Ala-Ser-Asn-Xaa 5 -Xaa 2 -Cys-Gly;
(SEQ ID NO: 163)
Gly-Cys-Cys-Ser-His-Xaa 5 -Val-Cys-Ser-Ala-Met-Ser-Xaa 5 -Ile-Cys;
(SEQ ID NO: 164)
Gly-Cys-Cys-Xaa 2 -Asn-Xaa 5 -Xaa 4 -Cys-Gly-Ala-Ser-Xaa 2 -Thr-Xaa 4 -Cys;
(SEQ ID NO: 165)
Gly-Cys-Cys-Ser-Xaa 4 -Xaa 5 -Xaa 5 -Cys-Phe-Ala-Thr-Asn-Xaa 5 -Asp-Cys;
(SEQ ID NO: 166)
Gly-Gly-Cys-Cys-Ser-Xaa 4 -Xaa 5 -Xaa 5 -Cys-Ile-Ala-Asn-Asn-Xaa 5 -Leu-Cys-Ala;
(SEQ ID NO: 167)
Gly-Gly-Cys-Cys-Ser-Xaa 4 -Xaa 5 -Xaa 5 -Cys-Ile-Ala-Asn-Asn-Xaa 5 -Phe-Cys-Ala;
(SEQ ID NO: 168)
Asp-Cys-Cys-Ser-Asn-Xaa 5 -Xaa 5 -Cys-Ser-Gln-Asn-Asn-Xaa 5 -Asp-Cys-Met;
and
(SEQ ID NO: 169)
Asp-Cys-Cys-Ser-Asn-Xaa 5 -Xaa 5 -Cys-Ala-His-Asn-Asn-Xaa 5 -Asp-Cys-Arg,
wherein Xaa 1 is Glu or γ-carboxy-Glu (Gla); Xaa 2 is Lys, N-methyl-Lys, N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa 3 is Trp (D or L), halo-Trp or neo-Trp; Xaa 4 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa 5 is Pro or hydroxy-Pro; and the C-terminus contains a carboxyl or amide group, or derivatives thereof.
5 . The substantially pure α-conotoxin peptide of claim 3 , which is modified to contain an O-glycan, an S-glycan or an N-glycan.
6 . The substantially pure α-conotoxin peptide of claim 4 which is modified to contain an O-glycan, an S-glycan or an N-glycan.
7 . A substantially pure α-conotoxin peptide selected from the group consisting of:
(SEQ ID NO: 22)
Gly-Cys-Cys-Ser-Asn-Xaa 5 -Val-Cys-His-Leu-Xaa 1 -His-Ser-Asn-Met-Cys;
(SEQ ID NO: 23)
Gly-Cys-Cys-Ser-Asn-Xaa 5 -Val-Cys-Arg-Gln-Asn-Asn-Ala-Xaa 1 -Xaa 4 -Cys-Arg;
(SEQ ID NO: 24)
Xaa 5 -Gln-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Xaa 1 -Ile-Cys-
Arg;
(SEQ ID NO: 25)
Xaa 5 -Xaa 1 -Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Xaa 1 -Ile-
Cys-Arg;
(SEQ ID NO: 26)
Xaa 5 -Gln-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Xaa 1 -Ile-Cys-
Asp;
(SEQ ID NO: 27)
Xaa 5 -Arg-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Xaa 1 -Ile-Cys-
Arg;
(SEQ ID NO: 28)
Xaa 5 -Gln-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Gly-Ile-Cys-
Arg;
(SEQ ID NO: 29)
Xaa 5 -Gln-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Xaa 1 -Thr-
Cys-Arg;
(SEQ ID NO: 30)
Xaa 5 -Gln-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Xaa 1 -Val-
Cys-Arg;
(SEQ ID NO: 31)
Xaa 5 -Gln-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Ile-Asp-His-Xaa 5 -Xaa 1 -Ile-Cys-
Arg;
(SEQ ID NO: 32)
Xaa 5 -Gln-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Xaa 1 -Ile-Cys-
Arg-Arg-Arg-Arg;
(SEQ ID NO: 33)
Gly-Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ala-Val-Asn-His-Xaa 5 -Xaa 1 -Leu-Cys;
(SEQ ID NO: 35)
Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Xaa 1 -Ile-Cys;
(SEQ ID NO: 36)
Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ser-Gly-Xaa 2 -Thr-Gln-Xaa 1 -Xaa 5 -Cys-Arg-
Xaa 1 -Ser;
(SEQ ID NO: 37)
Xaa 5 -Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ser-Gly-Asn-Asn-Xaa 5 -Xaa 1 -Phe-Cys-
Arg-Gln;
(SEQ ID NO: 38)
Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ser-Gly-Asn-Asn-Xaa 5 -Xaa 1 -Phe-Cys-Arg-
Gln;
(SEQ ID NO: 39)
Gly-Cys-Cys-Ser-His-Xaa 5 -Xaa 5 -Cys-Ala-Met-Asn-Asn-Xaa 5 -Asp-Xaa 4 -Cys;
(SEQ ID NO: 40)
Gly-Cys-Cys-Ser-His-Xaa 5 -Xaa 5 -Cys-Phe-Leu-Asn-Asn-Xaa 5 -Asp-Xaa 4 -Cys;
(SEQ ID NO: 41)
Gly-Cys-Cys-Ser-Asn-Xaa 5 -Xaa 5 -Cys-Ile-Ala-Xaa 2 -Asn-Xaa 5 -His-Met-Cys-Gly;
(SEQ ID NO: 43)
Gly-Cys-Cys-Ser-Asn-Xaa 5 -Ala-Cys-Ala-Gly-Asn-Asn-Xaa 5 -His-Val-Cys-Arg-
Gln;
(SEQ ID NO: 44)
Gly-Cys-Cys-Ser-Arg-Xaa 5 -Ala-Cys-Ile-Ala-Asn-Asn-Xaa 5 -Asp-Leu-Cys;
(SEQ ID NO: 45)
Gly-Cys-Cys-Ser-Asn-Xaa 5 -Val-Cys-His-Val-Xaa 1 -His-Xaa 5 -Xaa 1 -Leu-Cys-
Arg-Arg-Arg-Arg;
(SEQ ID NO: 46)
Gly-Gly-Cys-Cys-Ser-Phe-Xaa 5 -Ala-Cys-Arg-Xaa 2 -Xaa 5 -Arg-Xaa 5 -Xaa 1 -Met-
Cys-Gly;
(SEQ ID NO: 47)
Xaa 5 -Xaa 1 -Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Asn-Ser-Ser-His-Xaa 5 -Xaa 1 -Leu-
Cys-Gly;
(SEQ ID NO: 48)
Xaa 5 -Gln-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Asn-Val-Gly-His-Xaa 5 -Xaa 1 -Leu-
Cys-Gly;
(SEQ ID NO: 49)
Xaa 6 -Val-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Asn-Val-Gly-His-Xaa 5 -Xaa 1 -Ile-Cys-
Gly;
(SEQ ID NO: 50)
Gly-Cys-Cys-Ser-Arg-Xaa 5 -Xaa 5 -Cys-Ile-Ala-Asn-Asn-Xaa 5 -Asp-Leu-Cys;
(SEQ ID NO: 51)
Xaa 5 -Gln-Cys-Cys-Ser-His-Leu-Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Xaa 1 -Ile-Cys-
Arg;
(SEQ ID NO: 52)
Gly-Cys-Cys-Ser-Xaa 4 -Phe-Asp-Cys-Arg-Met-Met-Phe-Xaa 5 -Xaa 1 -Met-Cys-
Gly-Xaa 3 -Arg;
(SEQ ID NO: 53)
Gly-Gly-Cys-Cys-Ser-Phe-Ala-Ala-Cys-Arg-Xaa 2 -Xaa 4 -Arg-Xaa 5 -Xaa 1 -Met-
Cys-Gly;
(SEQ ID NO: 54)
Gly-Gly-Cys-Cys-Phe-His-Xaa 5 -Val-Cys-Xaa 4 -Ile-Asn-Leu-Leu-Xaa 1 -Met-Cys-
Arg-Gln-Arg;
(SEQ ID NO: 55)
Ser-Ala-Thr-Cys-Cys-Asn-Xaa 4 -Xaa 5 -Xaa 5 -Cys-Xaa 4 -Xaa 1 -Thr-Xaa 4 -Xaa 5 -
Xaa 1 -Ser-Cys-Leu;
(SEQ ID NO: 56)
Ala-Cys-Cys-Ala-Xaa 4 -Xaa 5 -Xaa 5 -Cys-Phe-Xaa 1 -Ala-Xaa 4 -Xaa 5 -Xaa 1 -Arg-Cys-
Leu;
(SEQ ID NO: 57)
Asn-Ala-Xaa 1 -Cys-Cys-Xaa 4 -Xaa 4 -Xaa 5 -Xaa 5 -Cys-Xaa 4 -Xaa 1 -Ala-Xaa 4 -Xaa 5 -
Xaa 1 -Ile-Cys-Leu;
(SEQ ID NO: 170)
Xaa 1 -Cys-Cys-Thr-Asn-Xaa 5 -Val-Cys-His-Ala-Xaa 1 -His-Gln-Xaa 1 -Leu-Cys-
Ala-Arg-Arg-Arg;
(SEQ ID NO: 171)
Gly-Cys-Cys-Ser-Asn-Xaa 5 -Val-Cys-His-Leu-Xaa 1 -His-Ser-Asn-Leu-Cys;
(SEQ ID NO: 172)
Xaa 1 -Cys-Cys-Thr-Asn-Xaa 5 -Val-Cys-His-Val-Xaa 1 -His-Gln-Xaa 1 -Leu-Cys-
Ala-Arg-Arg-Arg;
(SEQ ID NO: 173)
Xaa 6 -Xaa 1 -Cys-Cys-Ser-Xaa 4 -Xaa 5 -Ala-Cys-Asn-Leu-Asp-His-Xaa 5 -Xaa 1 -Leu-
Cys;
(SEQ ID NO: 174)
Xaa 5 -Xaa 1 -Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Asn-Ser-Thr-His-Xaa 5 -Xaa 1 -Leu-
Cys-Gly;
(SEQ ID NO: 175)
Leu-Asn-Cys-Cys-Met-Ile-Xaa 5 -Xaa 5 -Cys-Xaa 3 -Xaa 2 -Xaa 2 -Xaa 4 -Gly-Asp-Arg-
Cys-Ser-Xaa 1 -Val-Arg;
(SEQ ID NO: 176)
Ala-Phe-Gly-Cys-Cys-Asp-Leu-Ile-Xaa 5 -Cys-Leu-Xaa 1 -Arg-Xaa 4 -Gly-Asn-Arg-
Cys-Asn-Xaa 1 -Val-His;
(SEQ ID NO: 177)
Leu-Gly-Cys-Cys-Asn-Val-Thr-Xaa 5 -Cys-Xaa 3 -Xaa 1 -Xaa 2 -Xaa 4 -Gly-Asp-Xaa 2 -
Cys-Asn-Xaa 1 -Val-Arg;
(SEQ ID NO: 179)
Leu-Asn-Cys-Cys-Ser-Ile-Xaa 5 -Gly-Cys-Xaa 3 -Asn-Xaa 1 -Xaa 4 -Xaa 2 -Asp-Arg-
Cys-Ser-Xaa 2 -Val-Arg;
(SEQ ID NO: 180)
Gly-Gly-Cys-Cys-Ser-His-Xaa 5 -Val-Cys-Xaa 4 -Phe-Asn-Asn-Xaa 5 -Gln-Met-Cys-
Arg;
(SEQ ID NO: 181)
Gly-Gly-Cys-Cys-Ser-His-Xaa 5 -Val-Cys-Asn-Leu-Asn-Asn-Xaa 5 -Gln-Met-Cys-
Arg;
(SEQ ID NO: 182)
Gly-Cys-Cys-Ser-His-Xaa 5 -Xaa 5 -Cys-Xaa 4 -Ala-Asn-Asn-Gln-Ala-Xaa 4 -Cys-Asn;
(SEQ ID NO: 183)
Gly-Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ser-Val-Thr-His-Xaa 5 -Xaa 1 -Leu-Cys;
(SEQ ID NO: 184)
Gly-Gly-Cys-Cys-Ser-Xaa 4 -Xaa 5 -Ala-Cys-Ser-Val-Xaa 1 -His-Gln-Asp-Leu-Cys-
Asp;
(SEQ ID NO: 185)
Val-Ser-Cys-Cys-Val-Val-Arg-Xaa 5 -Cys-Xaa 3 -Ile-Arg-Xaa 4 -Gln-Xaa 1 -Xaa 1 -
Cys-Leu-Xaa 1 -Ala-Asp-Xaa 5 -Arg-Thr-Leu;
(SEQ ID NO: 186)
Xaa 6 -Asn-Cys-Cys-Ser-Ile-Xaa 5 -Gly-Cys-Xaa 3 -Xaa 1 -Xaa 2 -Xaa 4 -Gly-Asp-Xaa 2 -
Cys-Ser-Xaa 1 -Val-Arg;
(SEQ ID NO: 187)
Gly-Cys-Cys-Ser-Asn-Xaa 5 -Val-Cys-His-Leu-Xaa 1 -His-Xaa 5 -Asn-Ala-Cys;
(SEQ ID NO: 188)
Gly-Cys-Cys-Ser-Asn-Xaa 5 -Ile-Cys-Xaa 4 -Phe-Asn-Asn-Xaa 5 -Arg-Ile-Cys-Arg;
(SEQ ID NO: 189)
Xaa 1 -Cys-Cys-Ser-Gln-Xaa 5 -Xaa 5 -Cys-Arg-Xaa 3 -Xaa 2 -His-Xaa 5 -Xaa 1 -Leu-Cys-
Ser;
(SEQ ID NO: 190)
Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ala-Gly-Asn-Asn-Gln-His-Ile-Cys;
(SEQ ID NO: 191)
Gly-Cys-Cys-Ala-Val-Xaa 5 -Ser-Cys-Arg-Leu-Arg-Asn-Xaa 5 -Asp-Leu-Cys-Gly-
Gly;
(SEQ ID NO: 192)
Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asn-Asn-Xaa 5 -His-Ile-Cys;
(SEQ ID NO: 193)
Thr-Xaa 5 -Xaa 1 -Xaa 1 -Cys-Cys-Xaa 5 -Asn-Xaa 5 -Xaa 5 -Cys-Phe-Ala-Thr-Asn-Ser-
Asp-Ile-Cys-Gly;
(SEQ ID NO: 194)
Asp-Ala-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Ser-Gly-Xaa 2 -His-Gln-Asp-Leu-Cys;
(SEQ ID NO: 195)
Xaa 1 -Asp-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Leu-Cys;
(SEQ ID NO: 196)
Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ala-Gly-Ser-Asn-Ala-His-Ile-Cys;
(SEQ ID NO: 197)
Xaa 1 -Asp-Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Met-Cys;
(SEQ ID NO: 198)
Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ala-Gly-Asn-Asn-Xaa 5 -His-Ile-Cys;
(SEQ ID NO: 199)
Gly-Cys-Cys-Gly-Asn-Xaa 5 -Ser-Cys-Ser-Ile-His-Ile-Xaa 5 -Xaa 4 -Val-Cys-Asn;
(SEQ ID NO: 200)
Thr-Asp-Ser-Xaa 1 -Xaa 1 -Cys-Cys-Leu-Asp-Ser-Arg-Cys-Ala-Gly-Gln-His-Gln-
Asp-Leu-Cys-Gly;
(SEQ ID NO: 201)
Gly-Cys-Cys-Ser-Asn-Xaa 5 -Xaa 5 -Cys-Xaa 4 -Ala-Asn-Asn-Gln-Ala-Xaa 4 -Cys-
Asn;
(SEQ ID NO: 202)
Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ser-Val-Asn-Asn-Xaa 5 -Asp-Ile-Cys;
(SEQ ID NO: 203)
Gly-Xaa 2 -Cys-Cys-Ile-Asn-Asp-Ala-Cys-Arg-Ser-Xaa 2 -His-Xaa 5 -Gln-Xaa 4 -Cys-
Ser;
(SEQ ID NO: 204)
Gly-Cys-Cys-Xaa 4 -Asn-Ile-Ala-Cys-Arg-Ile-Asn-Asn-Xaa 5 -Arg-Xaa 4 -Cys-Arg;
(SEQ ID NO: 205)
Gly-Cys-Cys-Ser-His-Xaa 5 -Val-Cys-Arg-Phe-Asn-Xaa 4 -Xaa 5 -Xaa 2 -Xaa 4 -Cys-
Gly;
(SEQ ID NO: 206)
Asp-Xaa 1 -Cys-Cys-Ala-Ser-Xaa 5 -Xaa 5 -Cys-Arg-Leu-Asn-Asn-Xaa 5 -Xaa 4 -Val-
Cys-His;
(SEQ ID NO: 207)
Gly-Cys-Cys-Ser-Asn-Xaa 5 -Val-Cys-Xaa 3 -Gln-Asn-Asn-Ala-Xaa 1 -Xaa 4 -Cys-
Arg-Xaa 1 -Ser;
(SEQ ID NO: 208)
Gly-Cys-Cys-Ser-His-Xaa 5 -Xaa 5 -Cys-Ala-Gln-Asn-Asn-Gln-Asp-Xaa 4 -Cys;
(SEQ ID NO: 209)
Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ser-Gly-Asn-Asn-Arg-Xaa 1 -Xaa 4 -Cys-Arg-
Xaa 1 -Ser;
(SEQ ID NO: 210)
Asp-Xaa 5 -Cys-Cys-Ser-Xaa 4 -Xaa 5 -Asp-Cys-Gly-Ala-Asn-His-Xaa 5 -Xaa 1 -Ile-
Cys-Gly;
(SEQ ID NO: 211)
Xaa 1 -Cys-Cys-Ser-Gln-Xaa 5 -Xaa 5 -Cys-Arg-Xaa 3 -Xaa 2 -His-Xaa 5 -Xaa 1 -Leu-Cys-
Ser;
(SEQ ID NO: 212)
Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Ala-Gly-Asn-Asn-Xaa 5 -His-Ile-Cys;
(SEQ ID NO: 213)
Gly-Cys-Cys-Ser-Asp-Xaa 5 -Ser-Cys-Asn-Val-Asn-Asn-Xaa 5 -Asp-Xaa 4 -Cys;
(SEQ ID NO: 214)
Xaa 1 -Xaa 1 -Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-Ser-Val-Gly-His-Gln-Asp-Met-Cys-
Arg;
(SEQ ID NO: 215)
Gly-Gly-Cys-Cys-Ser-Asn-Xaa 5 -Ala-Cys-Leu-Val-Asn-His-Leu-Xaa 1 -Met-Cys;
(SEQ ID NO: 216)
Arg-Asp-Xaa 5 -Cys-Cys-Phe-Asn-Xaa 5 -Ala-Cys-Asn-Val-Asn-Asn-Xaa 5 -Gln-Ile-
Cys;
(SEQ ID NO: 217)
Cys-Cys-Ser-Asp-Xaa 5 -Ser-Cys-Xaa 3 -Arg-Leu-His-Ser-Leu-Ala-Cys-Thr-Gly-
Ile-Val-Asn-Arg;
(SEQ ID NO: 218)
Cys-Cys-Thr-Asn-Xaa 5 -Ala-Cys-Leu-Val-Asn-Asn-Ile-Arg-Phe-Cys-Gly;
(SEQ ID NO: 219)
Asp-Xaa 1 -Cys-Cys-Ser-Asp-Xaa 5 -Arg-Cys-His-Gly-Asn-Asn-Arg-Asp-His-Cys-
Ala;
(SEQ ID NO: 220)
Asp-Cys-Cys-Ser-His-Xaa 5 -Leu-Cys-Arg-Leu-Phe-Val-Xaa 5 -Gly-Leu-Cys-Ile;
(SEQ ID NO: 221)
Gly-Cys-Cys-Ser-His-Xaa 5 -Val-Cys-Xaa 2 -Val-Arg-Xaa 4 -Xaa 5 -Asp-Leu-Cys-Arg;
(SEQ ID NO: 222)
Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asn-Asn-Xaa 5 -His-Ile-Cys;
(SEQ ID NO: 223)
Gly-Cys-Cys-Ser-His-Xaa 5 -Val-Cys-Xaa 2 -Val-Arg-Xaa 4 -Ser-Asp-Met-Cys;
(SEQ ID NO: 224)
Gly-Gly-Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Xaa 2 -Val-His-Phe-Xaa 5 -His-Ser-Cys;
(SEQ ID NO: 225)
Val-Cys-Cys-Ser-Asn-Xaa 5 -Val-Cys-His-Val-Asp-His-Xaa 5 -Xaa 1 -Leu-Cys-Arg-
Arg-Arg-Arg;
(SEQ ID NO: 226)
Gly-Cys-Cys-Ser-His-Xaa 5 -Val-Cys-Asn-Leu-Ser-Asn-Xaa 5 -Gln-Ile-Cys-Arg;
(SEQ ID NO: 227)
Xaa 6 -Xaa 1 -Cys-Cys-Ser-His-Xaa 5 -Ala-Cys-Asn-Val-Asp-His-Xaa 5 -Xaa 1 -Ile-
Cys-Arg;
(SEQ ID NO: 228)
Gly-Cys-Cys-Ser-Asn-Xaa 5 -Ala-Cys-Leu-Val-Asn-His-Ile-Arg-Phe-Cys-Gly;
(SEQ ID NO: 229)
Asp-Cys-Cys-Asp-Asp-Xaa 5 -Ala-Cys-Thr-Val-Asn-Asn-Xaa 5 -Gly-Leu-Cys-Thr;
and
(SEQ ID NO: 230)
Gly-Cys-Cys-Ser-Asn-Xaa 5 -Xaa 5 -Cys-Ile-Ala-Xaa 2 -Asn-Xaa 5 -His-Met-Cys-Gly-
Gly-Arg-Arg,
wherein Xaa 1 is Glu or γ-carboxy-Glu (Gla); Xaa 2 is Lys, N-methyl-Lys, N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa 3 is Trp (D or L), halo-Trp or neo-Trp; Xaa 4 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa 5 is Pro or hydroxy-Pro; Xaa 6 is Gln or pyro-Glu; and the C-terminus contains a carboxyl or amide group, or derivatives thereof.
8 . The substantially pure α-conotoxin peptide of claim 7 , which is modified to contain an O-glycan, an S-glycan or an N-glycan.
9 . A substantially pure α-conotoxin peptide selected from the group consisting of:
(SEQ ID NO: 231)
Cys-Cys-Thr-Ile-Xaa 5 -Ser-Cys-Xaa 4 -Xaa 1 -
Xaa 2 -Xaa 2 -Xaa 2 -Ile-Xaa 2 -Ala-Cys-Val-Phe
and
(SEQ ID NO: 232)
Gly-Cys-Cys-Gly-Asn-Xaa 5 -Ala-Cys-Ser-
Gly-Ser-Ser-Xaa 2 -Asp-Ala-Xaa 5 -Ser-Cys,
wherein Xaa 1 is Glu or γ-carboxy-Glu (Gla); Xaa 2 is Lys, N-methyl-Lys, N,N-dimethyl-Lys or N,N,N-trimethyl-Lys; Xaa 4 is Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; and Xaa 5 is Pro or hydroxy-Pro; and the C-terminus contains a carboxyl or amide group, or derivatives thereof.
10 . The substantially pure α-conotoxin peptide of claim 9 , which is modified to contain an O-glycan, an S-glycan or an N-glycan.Join the waitlist — get patent alerts
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