Redox-activated chemistry for probing and perturbing the proteome: Lessons from protein redox switches.
Covalent drug discovery and chemical proteomics have historically relied on a nucleophilic logic, where electrophilic "warheads" react with nucleophilic amino acid side chains. While powerful, this paradigm probes only a single dimension of the protein's chemical surface. In contrast, biology leverages a second axis: redox potential. This is exemplified by the regulated redox proteome, where specific residues undergo reversible oxidation and reduction as functional post-translational modifications. Inspired by this natural machinery, researchers are developing redox-activated probes to label proteins at oxidizable residues and deploying similar chemistry to selectively perturb protein function. This review highlights recent advances in redox-activated covalent chemistry and explores its burgeoning potential for the development of next-generation targeted therapeutics.