A Practical Palladium-Catalyzed Cysteine Arylation Platform for Late-Stage Functionalization of Peptides and Proteins

Abstract Site-selective modification of cysteine residues is central to the construction of peptide- and protein-based probes and therapeutics, yet existing methods are often constrained by linkage instability, narrow substrate scope, or harsh, nonbiocompatible reaction conditions. Here we report a palladium-catalyzed, site-selective cysteine arylation of peptides and proteins using readily accessible aryl thianthrenium salts. Enabled by the RuPhos-Pd-G3 catalyst, the reaction proceeds in aqueous buffer at 37 °C without added base, photoinitiator, or organic cosolvent, and tolerates a broad range of electron-rich, -neutral, and -deficient arylating reagents bearing diverse functional groups. Modification occurs with exclusive cysteine selectivity even amid numerous competing nucleophilic residues, enabling the installation of drug fragments, biotin, carbohydrates, fluorophores, and clickable handles onto unprotected peptides and the native protein BSA. As a methodological proof of concept, we further employ this strategy to assemble a receptor-targeting peptide-drug conjugate, establishing aryl thianthrenium salts as a versatile, biocompatible platform for stable aryl-thioether bioconjugation.