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Inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 main protease by tafenoquine in vitro

Yeh Chen, Wen-Hao Yang, Li-Min Huang, 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, Jin-Shing Chen, Yu-Ping Chiang, Der-Yang Cho, Long-Bin Jeng, Chang-Hai Tsai, Mien-Chie Hung
doi: https://doi.org/10.1101/2020.08.14.250258
Yeh Chen
1Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan
11Drug Development Center, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 40402, Taiwan
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Wen-Hao Yang
2Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
11Drug Development Center, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 40402, Taiwan
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Li-Min Huang
3Department of Pediatrics, College of Medicine, National Taiwan University, Taipei 10617, Taiwan
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Yu-Chuan Wang
1Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan
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Chia-Shin Yang
1Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan
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Yi-Liang Liu
4Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan
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Mei-Hui Hou
1Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan
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Chia-Ling Tsai
1Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan
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Yi-Zhen Chou
1Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan
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Bao-Yue Huang
2Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
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Chian-Fang Hung
2Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
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Yu-Lin Hung
5Program of Digital Health Innovation, China Medical University, Taichung 40402, Taiwan.
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Jin-Shing Chen
6Department of Surgery, College of Medicine, National Taiwan University Hospital and National Taiwan University, Taipei 10617, Taiwan
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Yu-Ping Chiang
3Department of Pediatrics, College of Medicine, National Taiwan University, Taipei 10617, Taiwan
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Der-Yang Cho
2Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
7Department of Neurosurgery, China Medical University Hospital, Taichung 40402, Taiwan
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Long-Bin Jeng
8School of Medicine, China Medical University, Taichung 40402, Taiwan
9Department of Surgery, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
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Chang-Hai Tsai
8School of Medicine, China Medical University, Taichung 40402, Taiwan
10China Medical University Children’s Hospital, China Medical University, Taichung 40402, Taiwan
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Mien-Chie Hung
2Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
11Drug Development Center, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 40402, Taiwan
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  • For correspondence: mhung@cmu.edu.tw
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Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the current pandemic, coronavirus disease 2019 (COVID-19), has taken a huge toll on human lives and the global economy. Therefore, effective treatments against this disease are urgently needed. Here, we established a fluorescence resonance energy transfer (FRET)-based high-throughput screening platform to screen compound libraries to identify drugs targeting the SARS-CoV-2 main protease (Mpro), in particular those which are FDA-approved, to be used immediately to treat patients with COVID-19. Mpro has been shown to be one of the most important drug targets among SARS-related coronaviruses as impairment of Mpro blocks processing of viral polyproteins which halts viral replication in host cells. Our findings indicate that the anti-malarial drug tafenoquine (TFQ) induces significant conformational change in SARS-CoV-2 Mpro and diminishes its protease activity. Specifically, TFQ reduces the α-helical content of Mpro, which converts it into an inactive form. Moreover, TFQ greatly inhibits SARS-CoV-2 infection in cell culture system. Hence, the current study provides a mechanistic insight into the mode of action of TFQ against SARS-CoV-2 Mpro. Moreover, the low clinical toxicity of TFQ and its strong antiviral activity against SARS-CoV-2 should warrant further testing in clinical trials.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • One Sentence Summary: Tafenoquine diminishes SARS-CoV-2 Mpro activity to inhibit virus infection.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted August 15, 2020.
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Inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 main protease by tafenoquine in vitro
Yeh Chen, Wen-Hao Yang, Li-Min Huang, 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, Jin-Shing Chen, Yu-Ping Chiang, Der-Yang Cho, Long-Bin Jeng, Chang-Hai Tsai, Mien-Chie Hung
bioRxiv 2020.08.14.250258; doi: https://doi.org/10.1101/2020.08.14.250258
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Inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 main protease by tafenoquine in vitro
Yeh Chen, Wen-Hao Yang, Li-Min Huang, 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, Jin-Shing Chen, Yu-Ping Chiang, Der-Yang Cho, Long-Bin Jeng, Chang-Hai Tsai, Mien-Chie Hung
bioRxiv 2020.08.14.250258; doi: https://doi.org/10.1101/2020.08.14.250258

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