PEPTIDE ANTAGONISTS OF THE CALCITONIN CGRP FAMILY OF PEPTIDE HORMONES AND THEIR USE

摘要

The embodiments provide a modified calcitonin gene-related peptide antagonist including an N-terminal fragment of modified calcitonin gene-related peptide or related protein family member where at least two residues of the N-terminal fragment are cysteine (Cys) and at least one amino acid comprises a non-threonine substitution of a threonine (Thr) residue; a central core where the central core comprises an a-helix; and a C-terminal fragment of modified calcitonin gene-related peptide or related protein family member comprising a C-terminal amide and where at least one amino acid of the C-terminal fragment is phenylalanine (Phe), proline (Pro), tyrosine (Tyr) or hydroxyproline (Hyp) or pharmaceutically acceptable salt thereof, as well as compositions, including pharmaceutical compositions, comprising a subject peptide. The embodiments further provide treatment methods, including methods of treating a migraine, the methods generally involving administering to an individual in need thereof an effective amount of a subject peptide or composition.

主权项

1. A modified calcitonin gene-related peptide antagonist, or a pharmaceutically acceptable salt thereof, said antagonist having the structure of Formula I:
X1—Y1—Z1   (I) wherein: X1 is a modified N-terminal fragment of calcitonin gene-related peptide other comprising from five to seven amino acid residues, wherein two amino acid residues of the N-terminal fragment are cysteine (Cys), wherein the C-terminal amino residue of the fragment is cysteine (Cys), and wherein the residue immediately preceding the C-terminal Cys residue of the N-terminal fragment is a non-threonine substitution of threonine, wherein the two cysteine residues are separated by four, five or six amino acids and wherein the two cysteine residues can form a disulfide bond; Y1 is a central core comprising 15 to 22 amino acids wherein at least one amino acid of the central core is arginine (Arg) or lysine (Lys) and the central core comprises an a-helix; and Z1 is Val-Gly-Ser-Lys-Ala-Phe-NH2.