@article{7a1484f221f842dbbd4e4e2a4073b033,
title = "Structural basis for the severe adverse interaction of sofosbuvir and amiodarone on L-type Cav 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 Cav channels, but the molecular mechanism has remained unclear. Here we present systematic cryo-EM structural analysis of Cav1.1 and Cav1.3 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 is anchored in the central cavity of the pore domain through specific interaction with amiodarone and directly obstructs the ion permeation path. Our study reveals the molecular basis for the physical, pharmacodynamic interaction of two drugs on the scaffold of Cav channels.",
keywords = "amiodarone, Ca1.1, Ca1.3, cryo-EM, drug safety, drug-drug interactions, L-type Ca channels, severe bradycardia, sofosbuvir, voltage-gated calcium channels",
author = "Xia Yao and Shuai Gao and Jixin Wang and Zhangqiang Li and Jian Huang and Yan Wang and Zhifei Wang and Jiaofeng Chen and Xiao Fan and Weipeng Wang and Xueqin Jin and Xiaojing Pan and Yong Yu and Armando Lagrutta and Nieng Yan",
note = "Funding Information: We thank the cryo-EM facility at Princeton Imaging and Analysis Center operated by the Princeton Institute of Materials at Princeton University, which is supported in part by the Princeton Center for Complex Materials, a National Science Foundation Materials Research Science and Engineering Center (Grant No. DMR-2011750). The work was supported by grant from NIH (5R01GM130762 to N.Y. and R01DK125404 to Y.Y.). N.Y. conceived the project. X.Y. and S.G. conducted cryo-EM studies. J.W. and A.L. conducted Cav1.2 calcium influx experiments. Z.L. X.F. and W.W. helped with cryo-EM analyses. J.H. performed molecular docking simulation. Y.Y. Y.W. Z.W. J.C. X.J. and X.P. helped with functional characterizations. All authors contributed to data analysis and manuscript preparation. N.Y. X.Y. and S.G. wrote the manuscript. Jixin Wang and Armando Lagrutta are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc. Rahway, NJ, USA and potentially own stock and/or hold stock options in Merck & Co. Inc. Rahway, NJ, USA. Funding Information: We thank the cryo- EM facility at Princeton Imaging and Analysis Center operated by the Princeton Institute of Materials at Princeton University , which is supported in part by the Princeton Center for Complex Materials , a National Science Foundation Materials Research Science and Engineering Center (Grant No. DMR-2011750). The work was supported by grant from NIH (5R01GM130762 to N.Y. and R01DK125404 to Y.Y.). Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = dec,
day = "8",
doi = "10.1016/j.cell.2022.10.024",
language = "English (US)",
volume = "185",
pages = "4801--4810.e13",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "25",
}