Cleavable and Cysteine-Selective Peptide Stapling Via Bifunctional Aryl Thioethers

Stapled peptides exhibit superior drug-likeness over linear analogues, and peptide stapling has become a significant strategy for drug discovery. Herein, we report a cleavable, cysteine-selective peptide stapling approach based on aryl thioether derivatives. This efficient method tolerates diverse reagents and peptide sequences. The stapled peptides retain stable α-helical conformations and exhibit improved chemical and enzymatic stability and enhanced cellular membrane permeability. Notably, the stapling moiety is cleavable by exogenous thiols to release native linear peptides, providing a promising tool for peptide drug development.