CHEMO-ENZYMATIC SYNTHESIS OF SEMAGLUTIDE, LIRAGLUTIDE AND GLP-1

摘要

A method for synthesizing a peptide having the sequence His-X-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Y-Glu-Phe-Ile-Ala-Trp-Leu-Val-Z-Gly-Arg-Gly is disclosed. The method includes enzymatically coupling:(a) a peptide C-terminal ester or thioester having a first peptide fragment with the sequence His-X-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-(thio)ester; and(b) a peptide nucleophile having an N-terminally unprotected amine having a second peptide fragment with the sequence H-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Y-Glu-Phe-Ile-Ala-Trp-Leu-Val-Z-Gly-Arg-Gly; wherein: X is Ala or an α-amino-isobutyric acid (Aib) residue;Y is Lys, which Lys has a free side-chain ε-amino group or of which Lys the side-chain ε-amino group is protected with a protective group or of which Lys the side-chain ε-amino group is functionalized with an amino acid or another functional group; andZ is Arg or Lys.