Diltiazem inhibits SARS-CoV-2 cell attachment and internalization and decreases the viral infection in mouse lung.

Jinying Ge,Renqiang Liu,Xijun He,Gongxun Zhong,Ronghong Hua,Zhigao Bu,Huizhen Cao,Jie Luo,Chong Wang,Lei Shuai,Xijun Wang,Xinxin Wang,Stanley Perlman,Zhiyuan Wen,Ziruo Sun,Jinliang Wang

doi:10.1371/journal.ppat.1010343

Abstract

The continuous emergence of severe acute respiratory coronavirus 2 (SARS-CoV-2) variants and the increasing number of breakthrough infection cases among vaccinated people support the urgent need for research and development of antiviral drugs. Viral entry is an intriguing target for antiviral drug development. We found that diltiazem, a blocker of the L-type calcium channel Cav1.2 pore-forming subunit (Cav1.2 α1c) and an FDA-approved drug, inhibits the binding and internalization of SARS-CoV-2, and decreases SARS-CoV-2 infection in cells and mouse lung. Cav1.2 α1c interacts with SARS-CoV-2 spike protein and ACE2, and affects the attachment and internalization of SARS-CoV-2. Our finding suggests that diltiazem has potential as a drug against SARS-CoV-2 infection and that Cav1.2 α1c is a promising target for antiviral drug development for COVID-19.

Highlights

As of December 29, 2021, the COVID-19 pandemic has resulted in more than 280 million confirmed cases and approximately 5.4 million deaths worldwide according to the World Health Organization
Remdesivir remains the only authorized drug approved by the US FDA for emergency use, and it appears to have little effect on hospitalized COVID-19 patients
We found that the calcium channel blocker diltiazem, which has been approved in the US since 1982 and is cheap and widely used in clinical practice for many indications, inhibits the binding and internalization of SARS-CoV-2, and decreases SARS-CoV-2 infection in cells and mouse lung

Summary

Introduction

As of December 29, 2021, the COVID-19 pandemic has resulted in more than 280 million confirmed cases and approximately 5.4 million deaths worldwide according to the World Health Organization. A novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the causative pathogen of the disease. SARS-CoV-2 is an enveloped non-segmented positive RNA virus that belongs to the betacoronavirus genus [1]. The spike (S) protein of SARS-CoV-2 is responsible for binding to cellular receptors and subsequent viral entry into host cells. SARS-CoV-2 S protein is composed of the S1 and S2 subdomains. S1 contains the receptor-binding domain (RBD) and is responsible for binding to specific receptors. S2 contains a fusion peptide and is responsible for the fusion of the viral membrane with the cellular membrane [2,3]. Angiotensin-converting enzyme 2 (ACE2) is a recognized cellular receptor for SARS-CoV-2 [1,4,5]. After binding to the cell surface, SARS-CoV-2 enters cells via receptor-mediated endocytosis [18,19] and transmembrane serine protease 2 (TMPRSS2)-mediated direct fusion with the plasma membrane [4]

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Conclusion