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

摘要

The invention relates to a method for preparing a coupling product having the sequence P_q-W_v-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. The method includes enzymatically coupling(a) a peptide C-terminal ester or thioester having a first peptide fragment represented by the formula P_q-W_v-His-X-Glu-(thio)ester; and(b) a peptide nucleophile having an N-terminally unprotected amine having a second peptide fragment with the sequence H-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 wherein P represents a protective group at the N-terminal α-amino function of the peptide C-terminal ester or thioester and q is an integer having a value of 1 or 0;W represents one or more amino acid residues, which may be the same or different and v is an integer having a value of 1 or more representing the number of amino acid residues W;X is Ala or an α-amino-isobutyric acid unit (Aib);Y is Lys, which Lys has a free side-chain ε-amino group or a side-chain ε-amino group that is protected with a protective group or a side-chain ε-amino group that is functionalized with an amino acid or another functional group; andZ is Arg or Lys.