A bifunctional vinyl-sulfonium tethered peptide induced by thio-Michael-type addition reaction

The modification and functionalization of peptides is of great significance in modern biotechnology and drug development. Here we report a highly reactive Michael-type warhead for the covalently modification of cysteine on peptide and protein. By installing a vinyl group onto a methionine residue of peptide, the produced vinyl sulfonium can be efficiently nucleophilic added by appropriate cysteine residue of this peptide, and thus yield a cyclized peptide. This peptide cyclization strategy was proven to exhibit improved cell penetration and good stability. Moreover, a peptide ligand bearing vinyl sulfonium could covalently bind to the cysteine in the target protein, indicating the potential of vinyl sulfonium as a novel warhead for developing covalent peptide inhibitor. (C) 2021 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Automated summary

The modification and functionalization of peptides play a crucial role in biotechnology and drug development. A highly reactive Michael-type warhead is reported here for the covalent modification of cysteine on peptides and proteins. By incorporating a vinyl group onto a methionine residue, the resulting vinyl sulfonium can be efficiently nucleophilically added by a suitable cysteine residue, leading to the formation of cyclized peptides. This peptide cyclization strategy demonstrates improved cell penetration and stability. Furthermore, a peptide ligand containing vinyl sulfonium can covalently bind to cysteine in the target protein, indicating the potential of vinyl sulfonium as a novel warhead for developing covalent peptide inhibitors.