IP Library › Granted Patent US 7,390,785
Granted Patent B2
US 7,390,785 · App. 11/267,257 · Granted Jun 24, 2008

τ-conotoxin peptides

Assignees: The University of Utah Research Foundation; Cognetix, Inc.
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 7,390,785
App. No.
11/267,257
Granted
Jun 24, 2008
Kind
B2
Abstract

The invention relates to relatively short peptides (termed τ-conotoxins herein), about 10-25 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 (108)

1. A method for inducing analgesia in an individual which comprises administering an effective amount of a substantially pure τ-conotoxin peptide having the generic formula I: Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Cys-Cys-Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Cys-Cys-Xaa 10 -Xaa 11 -Xaa 12 -Xaa 13 -Xaa 14 -Xaa 15 -Xaa 16 -Xaa 17 -Xaa 18 -Xaa 19 (SEQ ID NO:1), wherein Xaa 1 is des-Xaa 1 , Asp, Glu or γ-carboxy-Glu (Gla); Xaa 2 is des-Xaa 2 , Gln, Asn, Glu, Trp (D or L), neo-Trp, halo-Trp or any unnatural aromatic amino acid; Xaa 3 is des-Xaa 3 , Gly, Ala, Asn or Gln; Xaa 4 is des-Xaa 4 , Val, Leu (D or L), Ile, Ala, Gly, Glu, Gla, Asp, Ser, Thr, Phe, Trp (D or L), neo-Trp, halo-Trp (D or L) or any unnatural aromatic amino acid; Xaa 5 is Pro, hydroxy-Pro, Gln, Asn, Glu, Gla, Ala, Gly, Lys, Arg, Ile, Val, homoarginine, ornithine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 6 is Val, Phe, Thr, Ser, Glu, Gla, Asp, Asn, Gln, Ala, Gly, Ile, Leu (D or L), Met, Pro, hydroxy-Pro, Arg, homoarginine, ornithine, 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 7 is any Val, Ile, Asn, Leu (D or L), Gln, Gly, Ala, Phe, Glu, Gla, Arg, ornithine, homoarginine, Lys, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid or any unnatural aromatic amino acid; Xaa 8 is Ile, Leu (D or L), Met, Thr, Ser, Pro, hydroxy-Pro, Gln, Asp, Glu, Gla, Asn, Arg, homoarginine, ornithine, Lys, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, any unnatural basic amino acid, any unnatural aromatic amino acid or any unnatural hydroxy containing amino acid; Xaa 9 is des-Xaa 9 , Ala, Gly, Asp, Glu, Gla, Trp (D or L) neo-Trp, halo-Trp (D or L), Lys, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, Arg, homoarginine, ornithine, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural basic amino acid; Xaa 10 is des-Xaa 10 , Ile, Leu (D or L), Val, Glu, Gla, Asp, Thr, Ser, Pro, hydroxy-Pro, Trp (D or L), neo-Trp, halo-Trp (D or L), Phe, any unnatural aromatic amino acid or any unnatural hydroxy containing amino acid; Xaa 11 is des-Xaa 11 , Gln, Asn, Leu (D or L), Ile, Val, Ala, Gly, Trp (D or L), neo-Trp, halo-Trp (D or L), Arg, homoarginine, ornithine, Lys, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid or any unnatural aromatic amino acid; Xaa 12 is des-Xaa 12 , Ala, Gly, Phe, Trp (D or L), neo-Trp, halo-Trp (D or L) or any unnatural aromatic amino acid; Xaa 13 is des-Xaa 13 , Glu, Gla, Asp, Phe or any unnatural aromatic amino acid; Xaa 14 is des-Xaa 14 , Ile, Val or Leu (D or L); Xaa 15 is des-Xaa 15 , Thr, Ser, Arg, homoarginine, ornithine, Lys, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 16 is des-Xaa 16 , Glu, Gla or Asp; Xaa 17 is des-Xaa 17 , Asn or Gln; Xaa 18 is des-Xaa 18 , Asp, Glu or Gla; Xaa 19 is des-Xaa 19 , Phe or any unnatural aromatic amino acid; and the C-terminus contains a free carboxyl group or an amide group.

2. The method of claim 1 , wherein the peptide is selected for the group consisting of:

(SEQ ID NO:2);

Phe-Cys-Cys-Xaa 1 -Val-Ile-Arg-Xaa 2 -Cys-Cys-Xaa 3

(SEQ ID NO:3);

Phe-Cys-Cys-Xaa 1 -Phe-Ile-Arg-Xaa 2 -Cys-Cys-Xaa 3

(SEQ ID NO:4);

Cys-Cys-Gln-Thr-Phe-Xaa 2 -Xaa 3 -Cys-Cys-Gln

(SEQ ID NO:5);

Xaa 4 -Gly-Xaa 3 -Cys-Cys-Xaa 5 -Xaa 6 -Asn-Ile-Ala-Cys-

Cys-Ile

(SEQ ID NO:6);

Gly-Cys-Cys-Ala-Arg-Leu-Thr-Cys-Cys-Val

(SEQ ID NO:7);

Asn-Gly-Cys-Cys-Xaa 1 -Xaa 5 -Gln-Met-Arg-Cys-Cys-Thr

(SEQ ID NO:8);

Asp-Xaa 3 -Asn-Ser-Cys-Cys-Gly-Xaa 5 -Asn-Xaa 1 -Gly-

Cys-Cys-Xaa 1 -Xaa 3

(SEQ ID NO:9);

Xaa 4 -Gly-Xaa 3 -Cys-Cys-Xaa 5 -Xaa 6 -Asn-Ile-Arg-

Cys-Cys-Val

(SEQ ID NO:10);

Xaa 6 -Cys-Cys-Xaa 6 -Asp-Gly-Xaa 3 -Cys-Cys-Thr-Ala-

Ala-Xaa 1 -Leu-Thr

(SEQ ID NO:11);

Gly-Cys-Cys-Xaa 6 -Asp-Gly-Xaa 3 -Cys-Cys-Thr-Ala-Ala-Xaa 1 -Leu-Thr

(SEQ ID NO:12);

Asn-Gly-Cys-Cys-Arg-Ala-Gly-Asp-Cys-Cys-Ser-Arg-

Phe-Xaa 6 -Ile-Xaa 5 -Xaa 6 -Asn-Asp-Phe

(SEQ ID NO:13);

Asn-Ala-Cys-Cys-Ile-Val-Arg-Gln-Cys-Cys

(SEQ ID NO:14);

Asn-Gly-Cys-Cys-Arg-Ala-Gly-Asp-Cys-Cys-Ser

(SEQ ID NO:15);

Cys-Cys-Xaa 1 -Arg-Arg-Leu-Ala-Cys-Cys-Ile-Ile

(SEQ ID NO:16);

Cys-Cys-Xaa 1 -Asn-Xaa 5 -Xaa 1 -Cys-Cys-Phe-Ile

(SEQ ID NO:17);

Gly-Cys-Cys-Ala-Met-Leu-Thr-Cys-Cys-Val

(SEQ ID NO:18); and

Leu-Cys-Cys-Val-Thr-Xaa 6 -Asp-Xaa 3 -Cys-Cys-Xaa 6 -

Xaa 3 -Xaa 3

(SEQ ID NO:19);

Val-Cys-Cys-Arg-Xaa 1 -Val-Gln-Asp-Cys-Cys-Ser.

wherein Xaa 1 is Pro or hydroxy-Pro; Xaa 2 is Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; Xaa 3 is Trp or halo-Trp; Xaa 4 is Gln or pyro-Glu; Xaa 5 is Lys, N-methyl-Lys, N,N-dimethyl-Lys or N,n,N-trimethyl-Lys, Xaa 6 is Glu or gamma-carboxy-Glu (Gla); and the C-terminus contains a carboxyl or amide group.

3. The method of claim 1 , wherein the substantially pure τ-conotoxin peptide is modified to contain an O-glycan, an S-glycan or an N-glycan.

4. The method of claim 2 , wherein the substantially pure τ-conotoxin peptide is modified to contain an O-glycan, an S-glycan or an N-glycan.

5. A method for inducing analgesia in an individual which comprises administering an effective amount of a pharmaceutical composition comprising a τ-conotoxin peptide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, said τ-conotoxin peptide having the generic formula I: Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Cys-Cys-Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Cys-Cys-Xaa 10 -Xaa 11 -Xaa 12 -Xaa 13 -Xaa 14 -Xaa 15 -Xaa 16 -Xaa 17 -Xaa 18 -Xaa 19 (SEQ ID NO:1), wherein Xaa 1 is des-Xaa 1 , Asp, Glu or γ-carboxy-Glu (Gla); Xaa 2 is des-Xaa 2 , Gln, Asn, Glu, Trp (D or L), neo-Trp, halo-Trp or any unnatural aromatic amino acid; Xaa 3 is des-Xaa 3 , Gly, Ala, Asn or Gln; Xaa 4 is des-Xaa 4 , Val, Leu (D or L), Ile, Ala, Gly, Glu, Gla, Asp, Ser, Thr, Phe, Trp (D or L), neo-Trp, halo-Trp (D or L) or any unnatural aromatic amino acid; Xaa 5 is Pro, hydroxy-Pro, Gln, Asn, Glu, Gla, Ala, Gly, Lys, Arg, Ile, Val, homoarginine, ornithine, N-methyl-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 6 is Val, Phe, Thr, Ser, Glu, Gla, Asp, Asn, Gln, Ala, Gly, Ile, Leu (D or L), Met, Pro, hydroxy-Pro, Arg, homoarginine, ornithine, 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 7 is any Val, Ile, Asn, Leu (D or L), Gln, Gly, Ala, Phe, Glu, Gla, Arg, ornithine, homoarginine, Lys, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid or any unnatural aromatic amino acid; Xaa 1 is Ile, Leu (D or L), Met, Thr, Ser, Pro, hydroxy-Pro, Gln, Asp, Glu, Gla, Asn, Arg, homoarginine, ornithine, Lys, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr, any unnatural basic amino acid, any unnatural aromatic amino acid or any unnatural hydroxy containing amino acid; Xaa 9 is des-Xaa 9 , Ala, Gly, Asp, Glu, Gla, Trp (D or L) neo-Trp, halo-Trp (D or L), Lys, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, Arg, homoarginine, ornithine, Tyr, nor-Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr, nitro-Tyr or any unnatural basic amino acid; Xaa 10 is des-Xaa 10 , Ile, Leu (D or L), Val, Glu, Gla, Asp, Thr, Ser, Pro, hydroxy-Pro, Trp (D or L), neo-Trp, halo-Trp (D or L), Phe, any unnatural aromatic amino acid or any unnatural hydroxy containing amino acid; Xaa 11 is des-Xaa 11 Gln, Asn, Leu (D or L), Ile, Val, Ala, Gly, Trp (D or L), neo-Trp, halo-Trp (D or L), Arg, homoarginine, ornithine, Lys, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys, any unnatural basic amino acid or any unnatural aromatic amino acid; Xaa 12 is des-Xaa 12 , Ala, Gly, Phe, Trp (D or L), neo-Trp, halo-Trp (D or L) or any unnatural aromatic amino acid; Xaa 13 is des-Xaa 13 , Glu, Gla, Asp, Phe or any unnatural aromatic amino acid; Xaa 14 is des-Xaa 14 , Ile, Val or Leu (D or L); Xaa 15 is des-Xaa 15 , Thr, Ser, Arg, homoarginine, ornithine, Lys, N-methy-Lys, N,N-dimethyl-Lys, N,N,N-trimethyl-Lys or any unnatural basic amino acid; Xaa 16 is des-Xaa 16 , Glu, Gla or Asp; Xaa 17 is des-Xaa 17 , Asn or Gln; Xaa 18 is des-Xaa 18 , Asp, Glu or Gla; Xaa 19 is des-Xaa 19 , Phe or any unnatural aromatic amino acid; and the C-terminus contains a free carboxyl group or an amide group.

6. The method of claim 5 , wherein the τ-conotoxin peptide is modified to contain an O-glycan, an S-glycan or an N-glycan.

7. A method for inducing analgesia in an individual which comprises administering an effective amount of a pharmaceutical composition comprising a τ-conotoxin peptide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, said τ-conotoxin peptide selected from the group consisting of:

Phe-Cys-Cys-Xaa 1 -Val-Ile-Arg-Xaa 2 -

(SEQ ID NO:2)

Cys-Cys-Xaa 3 ;

Phe-Cys-Cys-Xaa 1 -Phe-Ile-Arg-Xaa 2 -

(SEQ ID NO:3)

Cys-Cys-Xaa 3 ;

Cys-Cys-Gln-Thr-Phe-Xaa 2 -Xaa 3 -Cys-

(SEQ ID NO:4)

Cys-Gln;

Xaa 4 -Gly-Xaa 3 -Cys-Cys-Xaa 5 -Xaa 6 -Asn-

(SEQ ID NO:5)

Ile-Ala-Cys-Cys-Ile;

Gly-Cys-Cys-Ala-Arg-Leu-Thr-Cys-Cys-

(SEQ ID NO:6)

Val;

Asn-Gly-Cys-Cys-Xaa 1 -Xaa 5 -Gln-Met-

(SEQ ID NO:7)

Arg-Cys-Cys-Thr;

Asp-Xaa 3 -Asn-Ser-Cys-Cys-Gly-Xaa 5 -

(SEQ ID NO:8)

Asn-Xaa 1 -Gly-Cys-Cys-Xaa 1 -Xaa 3 ;

Xaa 4 -Gly-Xaa 3 -Cys-Cys-Xaa 5 -Xaa 6 -Asn-

(SEQ ID NO:9)

Ile-Arg-Cys-Cys-Val;

Xaa 6 -Cys-Cys-Xaa 6 -Asp-Gly-Xaa 3 -Cys-

(SEQ ID NO:10)

Cys-Thr-Ala-Ala-Xaa 1 -Leu-Thr;

Gly-Cys-Cys-Xaa 6 -Asp-Gly-Xaa 3 -Cys-

(SEQ ID NO:11)

Cys-Thr-Ala-Ala-Xaa 1 -Leu-Thr;

Asn-Gly-Cys-Cys-Arg-Ala-Gly-Asp-Cys-

(SEQ ID NO:12)

Cys-Ser-Arg-Phe-Xaa 6 -Ile-Xaa 5 -Xaa 6 -

Asn-Asp-Phe;

Asn-Ala-Cys-Cys-Ile-Val-Arg-Gln-Cys-

(SEQ ID NO:13)

Cys;

Asn-Gly-Cys-Cys-Arg-Ala-Gly-Asp-Cys-

(SEQ ID NO:14)

Cys-Ser;

Cys-Cys-Xaa 1 -Arg-Arg-Leu-Ala-Cys-

(SEQ ID NO:15)

Cys-Ile-Ile;

Cys-Cys-Xaa 1 -Asn-Xaa 5 -Xaa 1 -Cys-Cys-

(SEQ ID NO:16)

Phe-Ile;

Gly-Cys-Cys-Ala-Met-Leu-Thr-Cys-Cys-

(SEQ ID NO:17)

Val;

Leu-Cys-Cys-Val-Thr-Xaa 6 -Asp-Xaa 3 -

(SEQ ID NO:18)

Cys-Cys-Xaa 6 -Xaa 3 -Xaa 3 ;

and

Val-Cys-Cys-Arg-Xaa 1 -Val-Gln-Asp-

(SEQ ID NO:19)

Cys-Cys-Ser;

wherein Xaa 1 is Pro or hydroxy-Pro; Xaa 2 is Tyr, mono-halo-Tyr, di-halo-Tyr, O-sulpho-Tyr, O-phospho-Tyr or nitro-Tyr; Xaa 3 is Trp or halo-Typ; Xaa 4 is Gln or pyro-Glu; Xaa 5 is Lys, N-methyl-Lys, N,N-dimethyl-Lys or N,n,N-trimethyl-Lys, Xaa 6 is Glu or gamma-carboxy-Glu (Gla); and the C-terminus contains a carboxyl or amide group.

8. The method of claim 7 , wherein the τ-conotoxin peptide is modified to contain an O-glycan, an S-glycan or an N-glycan.

Assignments (1)
CONFIRMATORY LICENSE Recorded May 18, 2015
From: UNIVERSITY OF UTAH
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 035706/0355 →
Continuity (4)
Continuation 1061947300 · Jul 16, 2003
Division 0949749100 · Feb 4, 2000
Provisional Application 6011864200 · Feb 4, 1999
Related Publication 20070173457A1 · Jul 26, 2007