Identification of SARS-CoV-2 entry inhibitors among already approved drugs

Li Yang; Rong-Juan Pei; Heng Li; Xin-Na Ma; Yu Zhou; Feng-Hua Zhu; Pei-Lan He; Wei Tang; Ye-Cheng Zhang; Jin Xiong; Shu-Qi Xiao; Xian-Kun Tong; Bo Zhang; Jian-Ping Zuo

doi:10.1038/s41401-020-00556-6

Identification of SARS-CoV-2 entry inhibitors among already approved drugs

Acta Pharmacol Sin. 2021 Aug;42(8):1347-1353. doi: 10.1038/s41401-020-00556-6. Epub 2020 Oct 28.

Authors

Li Yang^#¹, Rong-Juan Pei^#², Heng Li^#^{1

3}, Xin-Na Ma⁴, Yu Zhou¹, Feng-Hua Zhu¹, Pei-Lan He¹, Wei Tang¹, Ye-Cheng Zhang², Jin Xiong², Shu-Qi Xiao², Xian-Kun Tong⁵, Bo Zhang⁶, Jian-Ping Zuo^{7

8

9}

Affiliations

¹ Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
² Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.
³ University of Chinese Academy of Sciences, Beijing, 100049, China.
⁴ Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
⁵ Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
⁶ Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China. [email protected].
⁷ Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
⁸ University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
⁹ Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. [email protected].

^# Contributed equally.

Abstract

To discover effective drugs for COVID-19 treatment amongst already clinically approved drugs, we developed a high throughput screening assay for SARS-CoV-2 virus entry inhibitors using SARS2-S pseudotyped virus. An approved drug library of 1800 small molecular drugs was screened for SARS2 entry inhibitors and 15 active drugs were identified as specific SARS2-S pseudovirus entry inhibitors. Antiviral tests using native SARS-CoV-2 virus in Vero E6 cells confirmed that 7 of these drugs (clemastine, amiodarone, trimeprazine, bosutinib, toremifene, flupenthixol, and azelastine) significantly inhibited SARS2 replication, reducing supernatant viral RNA load with a promising level of activity. Three of the drugs were classified as histamine receptor antagonists with clemastine showing the strongest anti-SARS2 activity (EC₅₀ = 0.95 ± 0.83 µM). Our work suggests that these 7 drugs could enter into further in vivo studies and clinical investigations for COVID-19 treatment.

Keywords: COVID-19; SARS-CoV-2; approved drug library; clemastine; high throughput screening assay; histamine receptor antagonists; virus entry inhibitors.

MeSH terms

Antiviral Agents / therapeutic use*
COVID-19 Drug Treatment*
Cell Line
Drug Approval
Drug Repositioning*
High-Throughput Screening Assays
Humans
Microbial Sensitivity Tests
SARS-CoV-2 / drug effects*
SARS-CoV-2 / physiology
Spike Glycoprotein, Coronavirus / drug effects
Virus Internalization / drug effects*

Substances

Antiviral Agents
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2