Versatile Sulfonium Tools for Chemoselective Modification of Proteins

Protein modifications are important for regulating or expanding protein functions. In eukaryotic cells, protein post-translational modifications are important mechanisms for the precise regulation of cellular activities. In addition, incorporation of chemical groups in laboratories enables protein tools and protein drugs for broad applications. Therefore, it is very important to develop chemical methods to prepare proteins with specific modifications. Chemoselective modification of proteins is a straightforward method using chemical reagents on proteins of interest, and the key challenge is the development of reagents with both reactivity and selectivity. Sulfonium is a unique electron-deficient group that has potential in substitution, elimination, and addition reactions. In biochemistry, S-adenosyl methionine, as a natural sulfonium, demonstrates reactivity and biocompatibility. Therefore, sulfonium has potential for diverse protein modifications, and many reagents have indeed been reported. In this perspective, we summarize the research on the development of sulfonium tools for protein modifications. In early times, sulfonium was developed for cysteine- and lysine-selective modification. As the demand for site-selective modification has increased in the field, more types of sulfonium tools have been developed to target cysteine, lysine, arginine, tryptophan, and tyrosine with site precision. The sulfonium tools enable covalent drugs for cancer therapy, covalent probes for protein identification, etc. Finally, we discuss our perspective on sulfonium tool development in the future.