主权项 |
1. A glucagon analogue derivative comprising a polypeptide and a substituent;
wherein the polypeptide comprises the amino acid sequenceImp-X2-His-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-X12-Tyr-Leu-X15-X16-Arg-Arg-Ala-X20-X21-Phe-Val-X24-Trp-Leu-X27-X28-X29-X30 [I]; whereinX2 is Ser or Aib;X10 is Tyr, Leu, Ile or Val;X12 is Lys or Arg;X15 is Asp or Glu;X16 is Ser, Ala, Leu, Thr, Aib, Ile, Val or Lys;X20 is Gln, Glu, Aib or Lys;X21 is Asp, Glu or Lys;X24 is Gln, Ala, Glu, Aib or Lys;X27 is Met, Leu or Val;X28 is Asn, Ser, Thr, Gln, Ala, Gly, Glu or Lys;X29 is Thr, Gly, Ser, Gln, Ala, Glu or Lys; andX30 is absent or is Lys;
wherein the substituent is covalently attached to the nitrogen atom of the side chain of a lysine in the polypeptide at a position selected from the group consisting of X12, X16, X20, X21, X24, X28, X29 and X30; wherein the substituent comprises the formula Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12-; wherein Y1 is selected from the group consisting of hydrogen, a C2-6 acyl group, and a succinoyl moiety; wherein Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11 and Y12 individually are absent or represents an amino acid residue selected from the group consisting of Ser, Ala, Gly, whereinindividually has stereochemistry L or D; and
wherein the substituent comprises three to ten negatively charged moieties selected from the group consisting of or a pharmaceutically acceptable salt, amide, or ester thereof. |