Oxidant‐Triggered Bioconjugation Chemistry: Expanding the Landscape of Ligandable Lysine Residues in the Proteome

Abstract The development of covalent drugs targeting lysine residues represents a transformative frontier in chemical biology and drug discovery. Despite the abundance of lysine (5.6% of proteomic residues) and its functional versatility, exploration has been hindered by the lack of robust methods to profile its reactivity and ligandability. This work introduces a new oxidant‐triggered bioconjugation platform that enables global mapping of lysine residues, and reveals over 7,000 covalently modifiable sites. By leveraging hydroxamic acid probes activated by soluble and low‐toxicity sodium periodate (NaIO 4 ), this strategy overcomes the limitations of traditional electrophiles and provides insights into the role of lysines in protein function and disease. The platform can be applied to kinase profiling, cancer target discovery, and covalent inhibitor development, offering a potential strategy for addressing “undruggable” proteins.