Redox-based reagents for chemoselective methionine bioconjugation

Targeting proteins at the other sulfur As the only amino acid with a thiol (SH) group, cysteine is easily targeted for site-selective protein modifications. Hydrophobic methionine also has sulfur in its side chain, but its capping methyl group has hindered analogous targeting efforts. Lin et al. introduce a complementary protocol to tether new substituents exclusively to methionine, even in the presence of cysteine. They used an oxaziridine group as an oxidant to form sulfimide (S=N) linkages. The approach allowed antibody-drug conjugation and chemoproteomic screening for reactive methionine surface residues. Science, this issue p. 597 An oxaziridine reagent selectively modifies proteins at methionine amino acid side chains via S=N bond formation. Cysteine can be specifically functionalized by a myriad of acid-base conjugation strategies for applications ranging from probing protein function to antibody-drug conjugates and proteomics. In contrast, selective ligation to the other sulfur-containing amino acid, methionine, has been precluded by its intrinsically weaker nucleophilicity. Here, we report a strategy for chemoselective methionine bioconjugation through redox reactivity, using oxaziridine-based reagents to achieve highly selective, rapid, and robust methionine labeling under a range of biocompatible reaction conditions. We highlight the broad utility of this conjugation method to enable precise addition of payloads to proteins, synthesis of antibody-drug conjugates, and identification of hyperreactive methionine residues in whole proteomes.