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

This article is Open Access

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