Gamma-conopeptides

A substantially pure conopeptide or pharmaceutically acceptable salt thereof, said conopeptide having the general formula II:

• Xaa1-Cys-Xaa2-Cys-Xaa3-Xaa4-Cys-Cys-Xaa5-Xaa6-Cys-Xaa7-Cys-Xaa8 (SEQ ID NO:2), wherein Xaa1 is des-Xaa1 or a peptide having 1-6 amino acids;
• Xaa2 is a peptide having 5-6 amino acids;
• Xaa3 is a peptide having 4 amino acids;
• Xaa4 is Glu, γ-carboxyglutamic acid (γ-Glu) or Gln;
• Xaa5 is Ser or Thr;
• Xaa6 is a peptide having 2-3 amino acids;
• Xaa7 is a peptide having 3-6 amino acids;
• and Xaa8 is des-Xaa8 or a peptide having 2-9 amino acids, with the proviso that when Xaa1 is des-Xaa1 and Xaa5 is Ser, then Xaa6 is not the dipeptide Asp-Asn.

A substantially pure conopeptide or pharmaceutically acceptable salt thereof, said conopeptide having the general formula III:

• Xaa1-Cys-Xaa2-Cys-Xaa3-Xaa4-Cys-Cys-Ser-Asn-Ser-Cys-Asp-Xaa5-Cys-Xaa6 (SEQ ID NO:3), wherein Xaa1 is a peptide having 1-6 amino acids;
• Xaa2 is a hexapeptide;
• Xaa3 is a peptide having 4 amino acids;
• Xaa4 is Glu or γ-carboxyglutamic acid (γ-Glu);
• Xaa5 is a tripeptide;
• and Xaa6 is a peptide having 7-9 amino acids.

A substantially pure conopeptide or pharmaceutically acceptable salt thereof, said conopeptide having the general formula IV:

• Xaa1-Cys-Xaa2-Cys-Xaa3-Xaa4-Xaa5-Cys-Cys-Ser-Asn-Ser-Cys-Asp-Xaa6-Cys-Xaa7 (SEQ ID NO:4), wherein Xaa1 is a peptide having 1-6 amino acids;
• Xaa2 is a hexapeptide;
• Xaa3 is Ser or Thr;
• Xaa4 is a tripeptide;
• Xaa5 is Glu or γ-carboxyglutamic acid (γ-Glu);
• Xaa6 is a tripeptide;
• and Xaa7 is a peptide having 7-9 amino acids.

A substantially pure conopeptide or pharmaceutically acceptable salt thereof, said conopeptide having the general formula V:

• Xaa1-Xaa2-Cys-Xaa3-Xaa4-Phe-Xaa5-Cys-Thr-Xaa6-Ser-Xaa7-Cys-Cys-Ser-Asn-Ser-Cys-Asp-Gln-Thr-Tyr-Cys-Xaa8-Leu-Xaa9 (SEQ ID NO:5), wherein Xaa1 is des-Xaa1 or a dipeptide;
• Xaa2 is Asp, Glu or γ-carboxyglutamic acid (γ-Glu);
• Xaa3 is a dipeptide;
• Xaa4 is Trp or 6-bromo-Trp;
• Xaa5 is a dipeptide;
• Xaa6 is a dipeptide;
• Xaa7 is Glu or γ-Glu;
• Xaa8 is any amino acid;
• and, Xaa9 is a pentapeptide.

A substantially pure conopeptide selected from the group consisting of:

• (a) PnVIIA:
• Asp-Cys-Thr-Ser-Xaa1-Phe-Gly-Arg-Cys-Thr-Val-Asn-Ser-Xaa2-Cys-Cys-Ser-Asn-Ser-Cys-Asp-Gln-Thr-Tyr-Cys-Xaa2-Leu-Tyr-Ala-Phe-Xaa3-Ser (SEQ ID NO:6);
• (b) Tx6.4:
• Xaa1-Leu-Xaa2-Cys-Ser-Val-Xaa1-Phe-Ser-His-Cys-Thr-Lys-Asp-Ser-Xaa2-Cys-Cys-Ser-Asn-Ser-Cys-Asp-Gln-Thr-Tyr-Cys-Thr-Leu-Met-Xaa3-Xaa3-Asp-Xaa1 (SEQ ID NO:7);
• (c) Tx6.9:
• Xaa1-Xaa1-Arg-Xaa1-Gly-Gly-Cys-Met-Ala-Xaa1-Phe-Gly-Leu-Cys-Ser-Arg-Asp-Ser-Xaa2-Cys-Cys-Ser-Asn-Ser-Cys-Asp-Val-Thr-Arg-Cys-Xaa2-Leu-Met-Xaa3-Phe-Xaa3-Xaa3-Asp-Xaa1 (SEQ ID NO:8);
• (d) J010:
• Cys-Lys-Thr-Try-Ser-Lys-Try-Cys-Xaa2-Ala-Asp-Ser-Xaa2-Cys-Cys-Thr-Xaa2-Gln-Cys-Val-Arg-Ser-Tyr-Cys-Thr-Leu-Phe (SEQ ID NO:9);
• (e) Tx6.6:
• Asp-Xaa1-Xaa1-Asp-Asp-Gly-Cys-Ser-Val-Xaa1-Gly-Xaa3-Cys-Thr-Val-Asn-Ala-Xaa2-Cys-Cys-Ser-Gly-Asp-Cys-His-Xaa2-Thr-Cys-Ile-Phe-Gly-Xaa1-Xaa2-Val (SEQ ID NO:10);
• (f) Tx6.5:
• Gly-Met-Xaa1-Gly-Xaa2-Cys-Lys-Asp-Gly-Leu-Thr-Thr-Cys-Leu-Ala-Xaa3-Ser-Xaa2-Cys-Cys-Ser-Xaa2-Asp-Cys-Xaa2-Gly-Ser-Cys-Thr-Met-Xaa1 (SEQ ID NO:11);
• (g) Gm6.7:
• Xaa2-Cys-Arg-Ala-Xaa1-Tyr-Ala-Xaa3-Cys-Ser-Xaa3-Gly-Ala-Gln-Cys-Cys-Ser-Leu-Leu-Met-Cys-Ser-Lys-Ala-Thr-Ser-Arg-Cys-Ile-Leu-Ala-Leu (SEQ ID NO:12);
• (h) Mr6.1:
• Asn-Gly-Gln-Cys-Xaa2-Asp-Val-Xaa1-Met-Xaa3-Cys-Thr-Ser-Asn-Xaa1-Xaa2-Cys-Cys-Ser-Leu-Asp-Cys-Xaa2-Met-Tyr-Cys-Thr-Gln-Ile (SEQ ID NO:13);
• (i) Mr6.2:
• Cys-Gly-Gly-Xaa1-Ser-Thr-Tyr-Cys-Xaa2-Val-Asp-Xaa2-Xaa2-Cys-Cys-Ser-Xaa2-Ser-Cys-Val-Arg-Ser-Tyr-Cys-Thr-Leu-Phe (SEQ ID NO:14);
• and
• (j) Mr6.3:
• Asn-Gly-Gly-Cys-Lys-Ala-Thr-Xaa1-Met-Ser-Cys-Ser-Ser-Gly-Xaa1-Xaa2 Cys-Cys-Ser-Met-Ser-Cys-Asp-Met-Try-Cys (SEQ ID NO:15),
• wherein Xaa1 is Trp or 6-bromo-Trp;
• Xaa2 is Glu or γ-carboxyglutamic acid (γ-Glu);
• and Xaa3 is Pro or hydroxy-Pro (Hyp).