Conotoxin peptides
The present invention relates conotoxin peptides that are analogs of the α-conotoxin peptide RgIA. These conotoxin peptides block the α9α10 subtype of the nicotinic acetylcholine receptor (nAChR) and can be used for treating pain, such as neuropathic pain and inflammatory pain, inflammatory disorders, such as rheumatic diseases, and in the treatment of breast cancer.
1. An isolated conotoxin peptide having the formula X1GX2CX3DPRX4X5X6X7CX8X9 (SEQ ID NO:2), wherein:
X1 is des-X1, pyroglutamic acid, Tyr, mono-halo-Tyr, or a fluorescent tag;
X2 is Cys, selenocysteine (sel), or homocysteine;
X3 is Ser, Thr, Ala, Tyr, halo-Tyr, Asn, Ile, or Arg;
X4 is Cys or sel;
X5 is Arg, citrulline, ω-nitro-Arg, homo-Arg, ornithine, or δ-N-acetyl-ornithine;
X6 is Tyr, mono-halo-Tyr, Trp, or Phe;
X7 is Arg, Gln, or His;
X8 is Leu, Glu, Gln, or Lys; and
X9 is des-X9, Tyr, mono-halo-Tyr, or a fluorescent tag; with the proviso that the conotoxin peptide of SEQ ID NO:2 is not a conotoxin peptide having the formula:
GCCSDPRCRYRCK (SEQ ID NO:8).
2. A method of treating pain in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of an active agent or a pharmaceutically acceptable salt thereof, the active agent comprising an isolated conotoxin peptide having the formula X1GX2CX3DPRX4X5X6X7CX8X9 (SEQ ID NO:2), wherein:
X1 is des-X1, pyroglutamic acid, Tyr, mono-halo-Tyr, or a fluorescent tag;
X2 is Cys, selenocysteine (sel), or homocysteine;
X3 is Ser, Thr, Ala, Tyr, halo-Tyr, Asn, Ile, or Arg;
X4 is Cys or sel;
X5 is Arg, citrulline, ω-nitro-Arg, homo-Arg, ornithine, or δ-N-acetyl-ornithine;
X6 is Tyr, mono-halo-Tyr, Trp, or Phe;
X7 is Arg, Gln, or His;
X8 is Leu, Glu, Gln, or Lys; and
X9 is des-X9, Tyr, mono-halo-Tyr, or a fluorescent tag; with the proviso that the conotoxin peptide of SEQ ID NO:2 is not a conotoxin peptide having the formula: GCCSDPRCRYRCK (SEQ ID NO:8), thereby treating pain in the individual.
3. A method of treating inflammation mediated by immune cells in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of an active agent or a pharmaceutically acceptable salt thereof, the active agent comprising an isolated conotoxin peptide having the formula X1 GX2CX3DPRX4X5X6X7CX8X9 (SEQ ID NO:2), wherein:
X1 is des-X1, pyroglutamic acid, Tyr, mono-halo-Tyr, or a fluorescent tag;
X2 is Cys, selenocysteine (sel), or homocysteine;
X3 is Ser, Thr, Ala, Tyr, halo-Tyr, Asn, Ile, or Arg;
X4 is Cys or sel;
X5 is Arg, citrulline, ω-nitro-Arg, homo-Arg, ornithine, or δ-N-acetyl-ornithine;
X6 is Tyr, mono-halo-Tyr, Trp, or Phe;
X7 is Arg, Gln, or His;
X8 is Leu, Glu, Gln, or Lys; and
X9 is des-X9, Tyr, mono-halo-Tyr, or a fluorescent tag; with the proviso that the conotoxin peptide of SEQ ID NO:2 is not a conotoxin peptide having the formula: GCCSDPRCRYRCK (SEQ ID NO:8), thereby treating inflammation mediated by immune cells in the individual.