Tafenoquine and its derivatives as inhibitors for the severe acute respiratory syndrome coronavirus 2

Yeh Chen; Wen-Hao Yang; Hsiao-Fan Chen; Li-Min Huang; Jing-Yan Gao; Cheng-Wen Lin; Yu-Chuan Wang; Chia-Shin Yang; Yi-Liang Liu; Mei-Hui Hou; Chia-Ling Tsai; Yi-Zhen Chou; Bao-Yue Huang; Chian-Fang Hung; Yu-Lin Hung; Wei-Jan Wang; Wen-Chi Su; Vathan Kumar; Yu-Chieh Wu; Shih-Wei Chao; Chih-Shiang Chang; Jin-Shing Chen; Yu-Ping Chiang; Der-Yang Cho; Long-Bin Jeng; Chang-Hai Tsai; Mien-Chie Hung

doi:10.1016/j.jbc.2022.101658

Tafenoquine and its derivatives as inhibitors for the severe acute respiratory syndrome coronavirus 2

J Biol Chem. 2022 Mar;298(3):101658. doi: 10.1016/j.jbc.2022.101658. Epub 2022 Jan 29.

Authors

Yeh Chen¹, Wen-Hao Yang², Hsiao-Fan Chen³, Li-Min Huang⁴, Jing-Yan Gao⁵, Cheng-Wen Lin⁶, Yu-Chuan Wang⁷, Chia-Shin Yang⁷, Yi-Liang Liu⁸, Mei-Hui Hou⁷, Chia-Ling Tsai⁷, Yi-Zhen Chou⁷, Bao-Yue Huang³, Chian-Fang Hung³, Yu-Lin Hung⁹, Wei-Jan Wang¹⁰, Wen-Chi Su³, Vathan Kumar¹¹, Yu-Chieh Wu¹², Shih-Wei Chao¹¹, Chih-Shiang Chang⁵, Jin-Shing Chen¹³, Yu-Ping Chiang⁴, Der-Yang Cho¹⁴, Long-Bin Jeng¹⁵, Chang-Hai Tsai¹⁶, Mien-Chie Hung¹⁷

Affiliations

¹ Institute of New Drug Development, China Medical University, Taichung, Taiwan; Drug Development Center, China Medical University, Taichung, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, Taiwan. Electronic address: bluecrystalprotein@gmail.com.
² Drug Development Center, China Medical University, Taichung, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
³ Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
⁴ Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁵ Drug Development Center, China Medical University, Taichung, Taiwan; School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.
⁶ Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan; Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan.
⁷ Institute of New Drug Development, China Medical University, Taichung, Taiwan.
⁸ Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
⁹ Program of Digital Health Innovation, China Medical University, Taichung, Taiwan.
¹⁰ Research Center for Cancer Biology, China Medical University, Taichung, Taiwan; Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
¹¹ Drug Development Center, China Medical University, Taichung, Taiwan.
¹² School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.
¹³ Department of Surgery, College of Medicine, National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan.
¹⁴ Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan.
¹⁵ School of Medicine, China Medical University, Taichung, Taiwan; Department of Surgery, China Medical University Hospital, China Medical University, Taichung, Taiwan.
¹⁶ School of Medicine, China Medical University, Taichung, Taiwan; China Medical University Children's Hospital, China Medical University, Taichung, Taiwan.
¹⁷ Drug Development Center, China Medical University, Taichung, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Center for Molecular Medicine, China Medical University, Taichung, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan. Electronic address: mhung@cmu.edu.tw.

Abstract

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has severely affected human lives around the world as well as the global economy. Therefore, effective treatments against COVID-19 are urgently needed. Here, we screened a library containing Food and Drug Administration (FDA)-approved compounds to identify drugs that could target the SARS-CoV-2 main protease (M^pro), which is indispensable for viral protein maturation and regard as an important therapeutic target. We identified antimalarial drug tafenoquine (TFQ), which is approved for radical cure of Plasmodium vivax and malaria prophylaxis, as a top candidate to inhibit M^pro protease activity. The crystal structure of SARS-CoV-2 M^pro in complex with TFQ revealed that TFQ noncovalently bound to and reshaped the substrate-binding pocket of M^pro by altering the loop region (residues 139-144) near the catalytic Cys145, which could block the catalysis of its peptide substrates. We also found that TFQ inhibited human transmembrane protease serine 2 (TMPRSS2). Furthermore, one TFQ derivative, compound 7, showed a better therapeutic index than TFQ on TMPRSS2 and may therefore inhibit the infectibility of SARS-CoV-2, including that of several mutant variants. These results suggest new potential strategies to block infection of SARS-CoV-2 and rising variants.

Keywords: COVID-19; SARS-CoV-2; TMPRSS2; drug action; drug design; drug discovery; main protease; tafenoquine; viral protease; virus entry.

MeSH terms

Aminoquinolines* / chemistry
Aminoquinolines* / pharmacology
Antiviral Agents* / chemistry
Antiviral Agents* / pharmacology
COVID-19 Drug Treatment*
Coronavirus 3C Proteases* / antagonists & inhibitors
Humans
Molecular Docking Simulation
Pandemics
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology
SARS-CoV-2* / drug effects
SARS-CoV-2* / enzymology
Virus Internalization / drug effects

Substances

Aminoquinolines
Antiviral Agents
Protease Inhibitors
tafenoquine
3C-like proteinase, SARS-CoV-2
Coronavirus 3C Proteases