Optical control of cardiac rhythm by in vivo photoactivation of an ERG channel peptide inhibitor

Montnach, J.; Millet, H.; Persello, A.; Meudal, H.; De Waard, S.; Mesirca, P.; Ribeiro, B.; Richard, J.; Hivonnait, A.; Tessier, A.; Lauzier, B.; Charpentier, F.; Mangoni, M. E.; Landon, C.; jopling, C.; De Waard, M.

doi:10.1101/2023.03.23.534038

bioRxiv · 10.1101/2023.03.23.534038

Optical control of cardiac rhythm by in vivo photoactivation of an ERG channel peptide inhibitor

Montnach, J.·Millet, H.·Persello, A.·Meudal, H.·De Waard, S.·Mesirca, P.·Ribeiro, B.·Richard, J.·Hivonnait, A.·Tessier, A.·Lauzier, B.·Charpentier, F.·Mangoni, M. E.·Landon, C.·jopling, C.·De Waard, M.

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Abstract

RATIONALECardiac rhythm, conduction and synchronization of electrical activity require the coordinated action of different types of ion channels that differ according to transmural and regional specificities. Classical pharmacology affects these ion channels in a non-regionalized way which explains why treating arrhythmias, that often occur in specific foci, has often limited efficacy in addition to negative side-effects on non-targeted organs. Photopharmacology is an emergent technology that has the potential to counteract all the negative aspects of classical pharmacology by restricting drug activity in a spatio-temporal manner. OBJECTIVEWe tested the potential of photopharmacology in specifically regulating heart activity by using a caged derivative of a natural peptide inhibitor of the ERG channel, BeKm1. The peptide was uncaged and activity monitored in vitro on a cell line expressing the hERG channel, on human cardiomyocytes derived from iPS cells, and ex vivo and in vivo on zebrafish larvae and rat hearts. METHODS AND RESULTSCaged BeKm-1 is inactive and fully active upon uncaging. Uncaging of the peptide on human iPS-derived cardiomyocytes enlarges the action potential duration and triggers arrhythmias. Uncaging also triggers bradycardia and disturbs cardiac conduction within the atria in perfused rat hearts upon illumination. The potency of photopharmacology for cardiac electrical modulation was further validated in zebrafish larvae where illumination of the caged compound induces bradycardia and atrio-ventricular desynchrony. Finally, in anesthetized rats, illumination of the caged peptide in the right atria, containing the sino-atrial node, leads to bradycardia without arrhythmia. CONCLUSIONSThis report demonstrates that photopharmacology, using the caged peptide strategy, can be used for dynamically regulating cardiac electrical activity in vivo and that spatial illumination restriction can dissociate the bradycardic effect from the arrhythmic one. The technology is applicable to all kinds of cardiac ion channels and regions of interest to create arrhythmogenic models or investigate new clinical applications.

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Montnach, J., Millet, H., Persello, A., Meudal, H., De Waard, S., Mesirca, P., Ribeiro, B., Richard, J., Hivonnait, A., Tessier, A., Lauzier, B., Charpentier, F., Mangoni, M. E., Landon, C., jopling, C., De Waard, M.. 2023-03-30. Optical control of cardiac rhythm by in vivo photoactivation of an ERG channel peptide inhibitor. https://doi.org/10.1101/2023.03.23.534038

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