Bepridil is potent against SARS-CoV-2 in vitro

Erol C Vatansever; Kai S Yang; Aleksandra K Drelich; Kaci C Kratch; Chia-Chuan Cho; Kempaiah Rayavara Kempaiah; Jason C Hsu; Drake M Mellott; Shiqing Xu; Chien-Te K Tseng; Wenshe Ray Liu

doi:10.1073/pnas.2012201118

Bepridil is potent against SARS-CoV-2 in vitro

Proc Natl Acad Sci U S A. 2021 Mar 9;118(10):e2012201118. doi: 10.1073/pnas.2012201118.

Authors

Affiliations

¹ The Texas A&M Drug Discovery Laboratory, Department of Chemistry, Texas A&M University, College Station, TX 77843.
² Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555.
³ Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843.
⁴ Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555; sktseng@utmb.edu wliu@chem.tamu.edu.
⁵ Center of Biodefense and Emerging Disease, University of Texas Medical Branch, Galveston, TX 77555.
⁶ The Texas A&M Drug Discovery Laboratory, Department of Chemistry, Texas A&M University, College Station, TX 77843; sktseng@utmb.edu wliu@chem.tamu.edu.
⁷ Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, TX 77030.
⁸ Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX 77030.
⁹ Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University, College Station, TX 77843.

Abstract

Guided by a computational docking analysis, about 30 Food and Drug Administration/European Medicines Agency (FDA/EMA)-approved small-molecule medicines were characterized on their inhibition of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M^p^ro). Of these small molecules tested, six displayed a concentration that inhibits response by 50% (IC₅₀) value below 100 μM in inhibiting M^p^ro, and, importantly, three, that is, pimozide, ebastine, and bepridil, are basic molecules that potentiate dual functions by both raising endosomal pH to interfere with SARS-CoV-2 entry into the human cell host and inhibiting M^p^ro in infected cells. A live virus-based modified microneutralization assay revealed that bepridil possesses significant anti-SARS-CoV-2 activity in both Vero E6 and A459/ACE2 cells in a dose-dependent manner with low micromolar effective concentration, 50% (EC₅₀) values. Therefore, the current study urges serious considerations of using bepridil in COVID-19 clinical tests.

Keywords: COVID-19; SARS-CoV-2; bepridil; drug repurposing; main protease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Animals
Antiviral Agents / pharmacology*
Bepridil / pharmacology*
Chlorocebus aethiops
Drug Discovery*
Humans
Molecular Docking Simulation
Molecular Structure
SARS-CoV-2 / drug effects*
Small Molecule Libraries
Vero Cells

Substances

Antiviral Agents
Small Molecule Libraries
Bepridil