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.