Sulfonium is an electrophilic and biocompatible group that is widely applied in synthetic chemistry on small molecules. However, there have been few developments of peptide or protein-based sulfonium tools. We recently reported sulfonium-mediated tryptophan crosslinking and developed NleS+me2 (norleucine-dimethylsulfonium) peptides as dimethyllysine mimics that crosslink site-specific methyllysine readers. Therefore, sulfonium probes show great potential for investigating methyllysine readers and other aromatic cage-containing proteins. However, the current synthesis is not very efficient and is limited to peptide probes that, in many cases, cannot mimic protein–protein interactions. In addition to peptidyl conjugates that are valuable for reader identification, there are unavoidable methyl conjugates as side products. As a result, a robust method to prepare peptide and protein sulfonium tools with great crosslinking reactivity and selectivity is highly desirable. Here, we report a cysteine alkylation method to introduce site-specific sulfonium at protein level with excellent yield. In addition to dimethylsulfonium, we also developed cyclic sulfonium warheads that enhanced peptidyl conjugate selectivity. The method thus made it possible to prepare nucleosome probes in which LEDGF and NSD2, as H3K36 methylation readers were readily crosslinked. We thus believe this method will accelerate the development of sulfonium peptide and protein tool sets for broad applications in chemical biology studies.
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