A unique peptide stabilization method provides a tethered sulfonium that can rapidly and selectively modify protein cysteine in close vicinity.

We report a facile thiol-yne type reaction triggered by the sulfonium center. After facile propargylation of thiolethers, the resulting sulfonium could undergo facile addition with thiols in aqueous media at ambient temperature. Further applying this reaction in unprotected peptides bearing neighboring methionine and cysteine could enable a facile intramolecular addition to construct cyclic peptides with better stability, good glutathione resistance, and increased cellular uptakes. Also, the propargylated sulfonium may be used as robust and versatile probes to target cysteines containing biomolecules.

A novel amidation strategy using electrophilic sulfonium, which is soluble and stable in aqueous conditions, was developed. The sulfoniums could activate thioacid and carboxyl acid to efficiently react with amines to afford amides. This method enables applications in amidation in both aqueous media and solid-phase peptide synthesis, peptide/protein modifications, and reactive lysines of a proteome at pH 10 with activity-based protein profiling. A peptide ligand-directed labeling of the USP7–UBL2 domain was also performed using this method.