| 主权项 |
1. A glucagon derivative comprising
a peptide comprising the amino acid sequence His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-X12-Tyr-Leu-X15-X16-X17-X18-Ala-X20-X21-Phe-Val-X24-Trp-Leu-X27-X28-X29-X30; a substituent comprising a lipophilic moiety and at least three negatively charged moieties; and a C-terminal amide; wherein, X2 represents Aib, Acb or Acpr; X3 represents Gin or His; X10 represents Leu, Ile or Val; X12 represents Lys or Arg; X15 represents Asp or Glu; X16 represents Ser, Ala, Leu, Thr, Glu, Aib, Ile, Val or Lys; X17 represents Arg or Lys; X18 represents Arg, Ala or Lys; X20 represents Gln, Arg, Glu, Aib or Lys; X21 represents Asp, Glu, Ser, or Lys; X24 represents Gln, Ala, Arg, Glu, Aib or Lys; X27 represents Met, Leu or Val; X28 represents Asn, Ser, Thr, Gln, Ala, Gly, Glu or Lys; X29 represents Thr, Gly, Ser, Gln, Ala, Glu or Lys; and X30 represents Lys or is absent; wherein Lys is present at one or more positions selected from the group consisting of X12, X16, X17, X18, X20, X21, X24, X28, X29, and X30; wherein said substituent comprises Z1-Z2-Z3-Z4-Z5-Z6-Z7-Z8-Z9-Z10-; wherein Z1 isn is 6-20, and the symbol * represents the attachment point to the nitrogen of a neighbouring group;
wherein Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, and Z10 individually are absent or an amino acid selected from the group consisting of Glu, γGlu, Gly, Ser, Ala, Thr, and Ado; wherein at least two of residues Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, and Z10 are present; wherein Z1-Z2-Z3-Z4-Z5-Z6-Z7-Z8-Z9-Z10 together contains at least three negative charges; wherein one of said negatively charged moieties is distal of said lipophilic moiety; and wherein said substituent is attached to said peptide at the epsilon position of a Lys residue at one amino acid position selected from the group consisting of X16, X17, X18, X20, X21, X24, X28, X20, and X30; or a pharmaceutically acceptable salt or prodrug thereof. |
