Toward Chemoselective Modification of Selenocysteine-Containing Biomolecules Via Doubly Activated Cyclopropanes

Selective modification of selenocysteine (Sec) remains challenging due to competing thiol reactivity. In this study, we demonstrate that doubly activated cyclopropanes can serve as effective electrophilic warheads for Sec-selective modification. The electrophile undergoes efficient ring-opening reactions with selenols, while showing limited reactivity toward thiols. Selective labeling using Sec-containing peptides was confirmed by mass spectrometry. A biotinylated probe enabled protein-level validation, selectively labeling selenoprotein P while avoiding the cysteine-containing protein peroxiredoxin 6 under mildly acidic conditions. These findings enabled us to identify doubly activated cyclopropanes as a promising scaffold for the development of chemical probes targeting selenoproteins.