Nonenzymatic Stereoselective S-Glycosylation of Polypeptides and Proteins

Here we report a nonenzymatic glycosylation reaction that builds axial S-glycosidic bonds under biorelevant conditions. This strategy is enabled by the design and use of allyl glycosyl sulfones as precursors to glycosyl radicals and exploits the exceptional functional group tolerance of radical processes. Our method introduces a variety of unprotected glycosyl units to the cysteine residues of peptides in a highly selective fashion. Through developing the second-generation protocol, we applied our method in the direct glycosylation of complex polypeptides and proteins. Computational studies were performed to elucidate the reaction mechanism.

Automated summary

This study presents a nonenzymatic glycosylation reaction that forms axial S-glycosidic bonds under biorelevant conditions. By using allyl glycosyl sulfones as precursors to glycosyl radicals and taking advantage of the exceptional functional group tolerance of radical processes, various unprotected glycosyl units can be selectively introduced to cysteine residues of peptides. The method was successfully applied for direct glycosylation of complex polypeptides and proteins after developing a second-generation protocol, with computational studies performed to elucidate the reaction mechanism.