2. Academic Validation
  3. Structural basis for the severe adverse interaction of sofosbuvir and amiodarone on L-type Cav channels

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

  • Cell. 2022 Nov 17;S0092-8674(22)01370-8. doi: 10.1016/j.cell.2022.10.024.
Xia Yao 1,  Shuai Gao 2,  Jixin Wang 3,  Zhangqiang Li 4,  Jian Huang 1,  Yan Wang 5,  Zhifei Wang 5,  Jiaofeng Chen 4,  Xiao Fan 1,  Weipeng Wang 4,  Xueqin Jin 4,  Xiaojing Pan 4,  Yong Yu 5,  Armando Lagrutta 3,  Nieng Yan 6
Affiliations

Affiliations

  • 1 Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
  • 2 Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. Electronic address: gaoshuai812@whu.edu.cn.
  • 3 Department of Genetic and Cellular Toxicology, ADME & Discovery Toxicology, Preclinical Development, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • 4 State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 5 Department of Biological Sciences, St. John's University, Queens, NY 11439, USA.
  • 6 Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. Electronic address: nyan@princeton.edu.
PMID: 36417914 DOI: 10.1016/j.cell.2022.10.024
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

Ca(v)1.1; Ca(v)1.3; L-type Ca(v) channels; amiodarone; cryo-EM; drug safety; drug-drug interactions; severe bradycardia; sofosbuvir; voltage-gated calcium channels.

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