Photocontrolled hERG channel blockade by diazirine integrated into BeKm-1 pharmacophore
Abstract
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.
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BibTeX
@article{poulet2026photocontrolled,
title = {{Photocontrolled hERG channel blockade by diazirine integrated into BeKm-1 pharmacophore}},
author = {Mathilde Poulet and Barbara Ribeiro de Oliveira and Aline Rio and Oliver Brun and Alina Akisheva and Hugo Millet and Claude Zoukimian and Yanis Achouba and Malak Alameh and Rémy Béroud and Frédéric Lesage and Mikael Croyal and Arnaud Tessier and Jérôme Montnach and Michel de Waard},
journal = {Cell Reports Physical Science},
year = {2026},
month = sep,
doi = {10.1016/j.xcrp.2026.103336},
url = {https://hal.science/hal-05761054v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Photocontrolled hERG channel blockade by diazirine integrated into BeKm-1 pharmacophore
AU - Mathilde Poulet
AU - Barbara Ribeiro de Oliveira
AU - Aline Rio
AU - Oliver Brun
AU - Alina Akisheva
AU - Hugo Millet
AU - Claude Zoukimian
AU - Yanis Achouba
AU - Malak Alameh
AU - Rémy Béroud
AU - Frédéric Lesage
AU - Mikael Croyal
AU - Arnaud Tessier
AU - Jérôme Montnach
AU - Michel de Waard
PY - 2026
DA - 2026/09/23
JO - Cell Reports Physical Science
DO - 10.1016/j.xcrp.2026.103336
UR - https://hal.science/hal-05761054v1
AB - 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.
SN - 2666-3864
ER -