Cyclopropanol - A Caged Dual-Functional Warhead for Selective Electrochemical Bioconjugation

Bioorthogonal reactions are powerful tools for studying and manipulating biological systems, yet achieving precise spatial and temporal control remains a major challenge. Here, we introduce cyclopropanol (CPol) as a compact, energy-loaded warhead that remains inert under physiological conditions and is selectively activated by mild electrochemical stimuli. This strategy generates reactive β-haloketone moieties in situ, enabling dual-function bioconjugation for cellular labeling and proteomic analysis. Upon oxidative ring opening, CPol preferentially modifies carboxylic acid-containing residues, such as glutamate and aspartate, rather than the expected tyrosine or tryptophan. The electrochemical activation of CPol is biocompatible in living systems, enabling direct protein labeling, real-time visualization with a fluorogenic CPol probe, and selective targeting of membrane-associated and cytoplasmic proteins with a choline-derived probe through integration into cellular phosphatidylcholine metabolism. Coupling bioorthogonality with electrochemical control, this approach enables precise protein profiling, live-cell imaging, and broader applications in chemical biology.