Photocontrolled hERG channel blockade by diazirine integrated into BeKm-1 pharmacophore

Summary Here we report that incorporation of diazirine-containing amino acids, including photoleucine and photomethionine, into the pharmacophore of the hERG blocker BeKm-1 enables optical control of peptide activity and, in specific cases, induces irreversible channel inhibition upon UV illumination. These analogs retain blocking activity in the dark while displaying light-dependent modulation of potency, reflecting dynamic reorganization of the pharmacophore. Notably, photoactivation can trigger covalent crosslinking to the channel under physiological conditions, resulting in prolonged inhibitory effects. This dual capability overcomes key limitations of peptide therapeutics, including rapid clearance and off-target effects, by enabling spatial and temporal control of activity at low concentrations. Our findings establish a generalizable photopharmacological strategy to tune peptide-target interactions and achieve tissue-restricted, on-demand therapeutic effects, opening new avenues for precision therapeutics.