Structural basis for the severe adverse interaction of sofosbuvir and amiodarone on L-type Ca_v channels.

ABSTRACT: Drug-drug interaction of the antiviral sofosbuvir and the antiarrhythmics amiodarone has been reported to cause fatal heartbeat slowing. Sofosbuvir and its analog, MNI-1, were reported to potentiate the inhibition of cardiomyocyte calcium handling by amiodarone, which functions as a multi-channel antagonist, and implicate its inhibitory effect on L-type Ca_v channels, but the molecular mechanism has remained unclear. Here we present systematic cryo-EM structural analysis of Ca_v1.1 and Ca_v1.3 treated with amiodarone or sofosbuvir alone, or sofosbuvir/MNI-1 combined with amiodarone. Whereas amiodarone alone occupies the dihydropyridine binding site, sofosbuvir is not found in the channel when applied on its own. In the presence of amiodarone, sofosbuvir/MNI-1

SUBMITTER: Yao X 

PROVIDER: S-EPMC9891081 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature