Amylin Peptides and Derivatives and Uses Thereof

摘要

There are provided polypeptide conjugates having enhanced duration of biological activity, and methods of use thereof. The polypeptide conjugates include duration enhancing moieties, including water soluble polymers, bound to the polypeptide components of defined sequence. Methods of use are provided for treatment of metabolic disorders. Methods of use are provided for treatment of an eating disorder, insulin resistance, obesity, overweight, abnormal postprandial hyperglycemia, Type I diabetes, Type II diabetes, gestational diabetes, metabolic syndrome, dumping syndrome, hypertension, dyslipidemia, cardiovascular disease, hyper lipidemia, sleep apnea, cancer, pulmonary hypertension, cholescystitis, osteoarthritis, or short bowel syndrome.

主权项

1. A polypeptide conjugate comprising a polypeptide component covalently linked to a duration enhancing moiety, wherein the polypeptide component comprises an amino acid sequence of residues 1-37 of Formula (I):(I)(SEQ ID NO: 4)X′-Xaa1-Cys2-Asn3-Thr4-Ala5-Thr6-Cys7-Ala8-Thr9-Gln10-Arg11-Leu12-Ala13-Asn14-Phe15-Leu16-Val17-Xaa18-Ser19-Ser20-Xaa21-Asn22-Phe23-Xaa24-Xaa25-Xaa26-Xaa27-Xaa28-Xaa29-Thr30-Xaa31-Val32-Gly33-Xaa34-Xaa35-Thr36-Tyr37-Xwherein up to 25% of the amino acids set forth in Formula (I) may be deleted or substituted with a different amino acid; wherein
X′ is hydrogen, an N-terminal capping group, a bond to a duration enhancing moiety, or a linker to a duration enhancing moiety; Xaa1 is Lys or a bond; Xaa18 is Lys, Cys, or His, Xaa21 is Lys, Cys, or Asn; Xaa24 is Lys, Cys, or Gly; Xaa25 is Lys, Cys, or Pro; Xaa26 is Lys, Cys, or Ile; Xaa27 is Lys, Cys, or Leu; Xaa28 is Lys, Cys, or Pro; Xaa29 is Lys, Cys, or Pro; Xaa31 is Lys, Cys, or Asn; Xaa34 is Lys, Cys, or Ser; and Xaa35 is Lys, Cys, or Asn, X is substituted or unsubstituted amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted cycloalkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted aralkylamino, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted aralkyloxy, hydroxyl, a bond to a duration enhancing moiety, or a linker to a duration enhancing moiety; wherein the duration enhancing moiety is covalently linked, optionally through a linker, to a side chain of a linking amino acid residue, X′ or X.