US2006223984A1PendingUtilityA1

Gamma-conopeptides

Assignee: UNIV UTAH RES FOUNDPriority: Dec 16, 1997Filed: Aug 26, 2003Published: Oct 5, 2006

Est. expiryDec 16, 2017(expired)· nominal 20-yr term from priority

Inventors:Michael Fainzilber Karel S. Kits Alma L. Burlingame Baldomero M. Olivera Craig Walker Maren Watkins Reshma Shetty Lourdes J. Cruz Julita Imperial Clark Colledge

A61P 9/00A61P 43/00C07K 14/43504A61K 38/00A61P 25/00

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References

Claims

Abstract

This invention relates to relatively short peptides about 25-40 residues in length, which are naturally available in minute amounts in the venom of the cone snails or analogs to the naturally available peptides, and which include three cyclizing disulfide linkages and one or more gammacarboxyglutamate residues. More specifically, the present invention is directed to gamma-conopeptides having the general formula I: Xaa1-Cys-Xaa2-Cys-Xaa3-Xaa4-Cys-Cys-Xaa5-Cys-Xaa6-Cys-Xaa7 (SEQ ID NO:1), as described herein; or having the general formula II: Xaa1-Cys-Xaa2-Cys-Xaa3-Xaa4-Cys-Cys-Xaa5-Xaa6-Cys-Xaa7-Cys-Xaa8 (SEQ ID NO:2), as defined herein; or having the general formula III: Xaa1-Cys-Xaa2-Cys-Xaa3-Xaa4-Xaa5-Cys-Cys-Ser-Asn-Ser-Cys-Asp-Xaa6-Cys-Xaa7 (SEQ ID NO:3), as described herein; or 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), as described herein; or 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), as described herein. The invention further relates to specific gamma-conopeptides, specific pro-gamma-conopeptides and nucleic acids encoding the pro-gamma-conopeptides. The invention also includes pharmaceutically acceptable salts of the conopeptides. These conopeptides are useful as agonists of neuronal pacemaker calcium channels.

Claims

exact text as granted — not AI-modified

1 . A substantially pure conopeptide or pharmaceutically acceptable salt thereof, said conopeptide having the general formula I: Xaa 1 -Cys-Xaa 2 -Cys-Xaa 3 -Xaa 4 -Cys-Cys-Xaa 5 -Cys-Xaa 6 -Cys-Xaa 7  (SEQ ID NO:1), wherein Xaa 1  is des-Xaa 1  or a peptide having 1-6 amino acids; Xaa 2  is a peptide having 5-6 amino acids; Xaa 3  is a peptide having 4 amino acids; Xaa 4  is Glu, γ-carboxyglutamic acid (γ-Glu) or Gln; Xaa 5  is a peptide having 3-4 amino acids; Xaa 6  is a peptide having 3-6 amino acids; and Xaa 7  is des-Xaa 7  or a peptide having 2-9 amino acids, with the proviso that when Xaa 1  is des-Xaa 1 , then Xaa 5  is not the tripeptide Ser-Asp-Asn.  
     
     
         2 . The conopeptide of  claim 1 , wherein Xaa 4  is γ-Glu.  
     
     
         3 . The conopeptide of  claim 1 , wherein Xaa 1  is des-Xaa 1 .  
     
     
         4 . The conopeptide of  claim 1 , wherein Xaa 1  is a peptide having 1-6 amino acids.  
     
     
         5 . The conopeptide of  claim 1 , wherein Xaa 7  is des-Xaa 7 .  
     
     
         6 . The conopeptide of  claim 1 , wherein Xaa 7  is a peptide having 2-9 amino acids.  
     
     
         7 . A substantially pure conopeptide or pharmaceutically acceptable salt thereof, said conopeptide having the general formula II: Xaa 1 -Cys-Xaa 2 -Cys-Xaa 3 -Xaa 4 -Cys-Cys-Xaa 5 -Xaa 6 -Cys-Xaa 7 -Cys-Xaa 8  (SEQ ID NO:2), wherein Xaa 1  is des-Xaa 1  or a peptide having 1-6 amino acids; Xaa 2  is a peptide having 5-6 amino acids; Xaa 3  is a peptide having 4 amino acids; Xaa 4  is Glu, γ-carboxyglutamic acid (γ-Glu) or Gln; Xaa 5  is Ser or Thr; Xaa 6  is a peptide having 2-3 amino acids; Xaa 7  is a peptide having 3-6 amino acids; and Xaa 8  is des-Xaa 8  or a peptide having 2-9 amino acids, with the proviso that when Xaa 1  is des-Xaa 1  and Xaa 5  is Ser, then Xaa 6  is not the dipeptide Asp-Asn.  
     
     
         8 . The conopeptide of  claim 7 , wherein Xaa 4  is γ-Glu.  
     
     
         9 . The conopeptide of  claim 7 , wherein Xaa 1  is des-Xaa 1 .  
     
     
         10 . The conopeptide of  claim 7 , wherein Xaa 1  is a peptide having 1-6 amino acids.  
     
     
         11 . The conopeptide of  claim 7 , wherein Xaa 5  is Ser or Thr.  
     
     
         12 . The conopeptide of  claim 7 , wherein Xaa 8  is des-Xaa 8 .  
     
     
         13 . The conopeptide of  claim 1 , wherein Xaa 8  is a peptide having 2-9 amino acids.  
     
     
         14 . A substantially pure conopeptide or pharmaceutically acceptable salt thereof, said conopeptide having the general formula III: Xaa 1 -Cys-Xaa 2 -Cys-Xaa 3 -Xaa 4 -Cys-Cys-Ser-Asn-Ser-Cys-Asp-Xaa 5 -Cys-Xaa 6  (SEQ ID NO:3), wherein Xaa 1  is a peptide having 1-6 amino acids; Xaa 2  is a hexapeptide; Xaa 3  is a peptide having 4 amino acids; Xaa 4  is Glu or γ-carboxyglutamic acid (γ-Glu); Xaa 5  is a tripeptide; and Xaa 6  is a peptide having 7-9 amino acids.  
     
     
         15 . The conopeptide of  claim 14 , wherein Xaa 4  is γ-Glu.  
     
     
         16 . A substantially pure conopeptide or pharmaceutically acceptable salt thereof, said conopeptide having the general formula IV: Xaa 1 -Cys-Xaa 2 -Cys-Xaa 3 -Xaa 4 -Xaa 5 -Cys-Cys-Ser-Asn-Ser-Cys-Asp-Xaa 6 -Cys-Xaa 7  (SEQ ID NO:4), wherein Xaa 1  is a peptide having 1-6 amino acids; Xaa 2  is a hexapeptide; Xaa 3  is Ser or Thr; Xaa 4  is a tripeptide; Xaa 5  is Glu or γ-carboxyglutamic acid (γ-Glu); Xaa 6  is a tripeptide; and Xaa 7  is a peptide having 7-9 amino acids.  
     
     
         17 . The conopeptide of  claim 16 , wherein Xaa 5  is γ-Glu.  
     
     
         18 . A substantially pure conopeptide or pharmaceutically acceptable salt thereof, said conopeptide having the general formula V: Xaa 1 -Xaa 2 -Cys-Xaa 3 -Xaa 4 -Phe-Xaa 5 -Cys-Thr-Xaa 6 -Ser-Xaa 7 -Cys-Cys-Ser-Asn-Ser-Cys-Asp-Gln-Thr-Tyr-Cys-Xaa 8 -Leu-Xaa 9  (SEQ ID NO:5), wherein Xaa 1  is des-Xaa 1  or a dipeptide; Xaa 2  is Asp, Glu or γ-carboxyglutamic acid (γ-Glu); Xaa 3  is a dipeptide; Xaa 4  is Trp or 6-bromo-Trp; Xaa 5  is a dipeptide; Xaa 6  is a dipeptide; Xaa 7  is Glu or γ-Glu; Xaa 8  is any amino acid; and, Xaa 9  is a pentapeptide.  
     
     
         19 . The conopeptide of  claim 18 , wherein Xaa 7  is γ-Glu.  
     
     
         20 . A substantially pure conopeptide selected from the group consisting of: 
 (a) PnVIIA: Asp-Cys-Thr-Ser-Xaa 1 -Phe-Gly-Arg-Cys-Thr-Val-Asn-Ser-Xaa 2 -Cys-Cys-Ser-Asn-Ser-Cys-Asp-Gln-Thr-Tyr-Cys-Xaa 2 -Leu-Tyr-Ala-Phe-Xaa 3 -Ser (SEQ ID NO:6);    (b) Tx6.4: Xaa 1 -Leu-Xaa 2 -Cys-Ser-Val-Xaa 1 -Phe-Ser-His-Cys-Thr-Lys-Asp-Ser-Xaa 2 -Cys-Cys-Ser-Asn-Ser-Cys-Asp-Gln-Thr-Tyr-Cys-Thr-Leu-Met-Xaa 3 -Xaa 3 -Asp-Xaa 1  (SEQ ID NO:7);    (c) Tx6.9: Xaa 1 -Xaa 1 -Arg-Xaa 1 -Gly-Gly-Cys-Met-Ala-Xaa 1 -Phe-Gly-Leu-Cys-Ser-Arg-Asp-Ser-Xaa 2 -Cys-Cys-Ser-Asn-Ser-Cys-Asp-Val-Thr-Arg-Cys-Xaa 2 -Leu-Met-Xaa 3 -Phe-Xaa 3 -Xaa 3 -Asp-Xaa 1  (SEQ ID NO:8);    (d) J010: Cys-Lys-Thr-Try-Ser-Lys-Try-Cys-Xaa 2 -Ala-Asp-Ser-Xaa 2 -Cys-Cys-Thr-Xaa 2 -Gln-Cys-Val-Arg-Ser-Tyr-Cys-Thr-Leu-Phe (SEQ ID NO:9);    (e) Tx6.6: Asp-Xaa 1 -Xaa 1 -Asp-Asp-Gly-Cys-Ser-Val-Xaa 1 -Gly-Xaa 3 -Cys-Thr-Val-Asn-Ala-Xaa 2 -Cys-Cys-Ser-Gly-Asp-Cys-His-Xaa 2 -Thr-Cys-Ile-Phe-Gly-Xaa 1 -Xaa 2 -Val (SEQ ID NO:10);    (f) Tx6.5: Gly-Met-Xaa 1 -Gly-Xaa 2 -Cys-Lys-Asp-Gly-Leu-Thr-Thr-Cys-Leu-Ala-Xaa 3 -Ser-Xaa 2 -Cys-Cys-Ser-Xaa 2 -Asp-Cys-Xaa 2 -Gly-Ser-Cys-Thr-Met-Xaa 1  (SEQ ID NO:11);    (g) Gm6.7: Xaa 2 -Cys-Arg-Ala-Xaa 1 -Tyr-Ala-Xaa 3 -Cys-Ser-Xaa 3 -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-Xaa 2 -Asp-Val-Xaa 1 -Met-Xaa 3 -Cys-Thr-Ser-Asn-Xaa 1 -Xaa 2 -Cys-Cys-Ser-Leu-Asp-Cys-Xaa 2 -Met-Tyr-Cys-Thr-Gln-Ile (SEQ ID NO:13);    (i) Mr6.2: Cys-Gly-Gly-Xaa 1 -Ser-Thr-Tyr-Cys-Xaa 2 -Val-Asp-Xaa 2 -Xaa 2 -Cys-Cys-Ser-Xaa 2 -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-Xaa 1 -Met-Ser-Cys-Ser-Ser-Gly-Xaa 1 -Xaa 2  Cys-Cys-Ser-Met-Ser-Cys-Asp-Met-Try-Cys (SEQ ID NO:15),    wherein Xaa 1  is Trp or 6-bromo-Trp; Xaa 2  is Glu or γ-carboxyglutamic acid (γ-Glu); and Xaa 3  is Pro or hydroxy-Pro (Hyp).

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