Repurposing existing drugs: identification of SARS-CoV-2 3C-like protease inhibitors

Wei-Chung Chiou; Meng-Shiuan Hsu; Yun-Ti Chen; Jinn-Moon Yang; Yeou-Guang Tsay; Hsiu-Chen Huang; Cheng Huang

doi:10.1080/14756366.2020.1850710

Repurposing existing drugs: identification of SARS-CoV-2 3C-like protease inhibitors

J Enzyme Inhib Med Chem. 2021 Dec;36(1):147-153. doi: 10.1080/14756366.2020.1850710.

Authors

Wei-Chung Chiou¹, Meng-Shiuan Hsu², Yun-Ti Chen³, Jinn-Moon Yang^{3

4

5

6

7}, Yeou-Guang Tsay⁸, Hsiu-Chen Huang⁹, Cheng Huang¹

Affiliations

¹ Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
² Departments of Infectious Disease, Far Eastern Memorial Hospital, Taipei, Taiwan.
³ Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.
⁴ Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
⁵ Center for Intelligent Drug Systems and Smart Bio-devices, National Chiao Tung University, Hsinchu, Taiwan.
⁶ Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan.
⁷ Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan.
⁸ Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
⁹ Department of Applied Science, National Tsing Hua University South Campus, Hsinchu, Taiwan.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19). Since its emergence, the COVID-19 pandemic has not only distressed medical services but also caused economic upheavals, marking urgent the need for effective therapeutics. The experience of combating SARS-CoV and MERS-CoV has shown that inhibiting the 3-chymotrypsin-like protease (3CLpro) blocks the replication of the virus. Given the well-studied properties of FDA-approved drugs, identification of SARS-CoV-2 3CLpro inhibitors in an FDA-approved drug library would be of great therapeutic value. Here, we screened a library consisting of 774 FDA-approved drugs for potent SARS-CoV-2 3CLpro inhibitors, using an intramolecularly quenched fluorescence (IQF) peptide substrate. Ethacrynic acid, naproxen, allopurinol, butenafine hydrochloride, raloxifene hydrochloride, tranylcypromine hydrochloride, and saquinavir mesylate have been found to block the proteolytic activity of SARS-CoV-2 3CLpro. The inhibitory activity of these repurposing drugs against SARS-CoV-2 3CLpro highlights their therapeutic potential for treating COVID-19 and other Betacoronavirus infections.

Keywords: 3CLpro inhibitors; FRET; SARS-CoV-2 3CL protease; antiviral; repurposing drugs.

MeSH terms

Antiviral Agents / pharmacology*
COVID-19 / virology*
COVID-19 Drug Treatment*
Catalytic Domain
Coronavirus 3C Proteases / antagonists & inhibitors*
Coronavirus 3C Proteases / chemistry
Cysteine Proteinase Inhibitors / pharmacology*
Drug Evaluation, Preclinical
Drug Repositioning*
Fluorescent Dyes
Humans
Molecular Docking Simulation
SARS-CoV-2 / drug effects*
SARS-CoV-2 / enzymology*
Substrate Specificity

Substances

Antiviral Agents
Cysteine Proteinase Inhibitors
Fluorescent Dyes
3C-like proteinase, SARS-CoV-2
Coronavirus 3C Proteases

Grants and funding

This work was supported by research grant [MOST 109–2327-B-010–006] – from the Ministry of Science and Technology, Taiwan.