Controlled reversible methionine-selective sulfimidation of peptides.

Abstract

Site-selective chemical peptide manipulation is an effective strategy to understand and regulate structure and function. However, methionine-selective modification remains one of the most difficult challenges in peptide chemistry, with notable limited strategies. In this study, we report a general reversible modification strategy at methionine sites that uses the ruthenium-catalyzed sulfimidation of peptides. This method provides a convenient and effective strategy for late-stage peptide functionalization. The N═S bonds of the conjugates are reduced in the presence of glutathione, resulting the traceless releasing of corresponding peptides and amides. Practical applications are then demonstrated using precise reversible modifications of bioactive peptides, the stapling and linearization of peptides, peptide-drug conjugates, and split-and-pool synthesis. This on/off strategy through methionine-selective and reversible sulfimidation provides a unique tool for peptide chemistry and peptide-based drug discovery.