Cyclometalated Gold(III)‐Mediated Cysteine Arylation: A Bioorthogonal Platform for Covalent Targeting of Intrinsically Disordered Proteins

Intrinsically disordered proteins (IDPs) remain largely inaccessible to covalent chemical tools due to their structural plasticity and lack of defined pockets. We introduce a bioorthogonal cyclometalated gold(III) platform of monodentate phosphine-supported AuP1-8 complexes that selectively and irreversibly arylate cysteine residues via enhanced Lewis acidity. This platform enables targeting of low-reactivity, buried, or dynamically disordered cysteines across the human proteome. Chemoproteomic, structural, and computational analyses establish an expanded ligandable cysteinome, including transiently helical LLCLL motifs in intrinsically disordered regions (IDRs). Our findings establish a new class of metal-mediated bioorthogonal reagents for proteome-wide cysteine labeling, functional interrogation of disordered proteins, and future therapeutic and diagnostic applications.