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The anticoagulant nafamostat potently inhibits SARS-CoV-2 infection in vitro: an existing drug with multiple possible therapeutic effects

Mizuki Yamamoto, Maki Kiso, Yuko Sakai-Tagawa, Kiyoko Iwatsuki-Horimoto, Masaki Imai, Makoto Takeda, Noriko Kinoshita, Norio Ohmagari, Jin Gohda, Kentaro Semba, Zene Matsuda, Yasushi Kawaguchi, Yoshihiro Kawaoka, View ORCID ProfileJun-ichiro Inoue
doi: https://doi.org/10.1101/2020.04.22.054981
Mizuki Yamamoto
1Research Center for Asian Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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Maki Kiso
2Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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Yuko Sakai-Tagawa
2Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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Kiyoko Iwatsuki-Horimoto
2Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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Masaki Imai
2Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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Makoto Takeda
3Department of Virology 3, National Institute of Infectious Diseases, Musashimurayama, Tokyo 208-0011, Japan
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Noriko Kinoshita
4Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
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Norio Ohmagari
4Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
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Jin Gohda
1Research Center for Asian Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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Kentaro Semba
5Department of Life Science and Medical Bio-Science, Waseda University, Shinjuku-ku, Tokyo, 162-8480, Japan
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Zene Matsuda
1Research Center for Asian Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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Yasushi Kawaguchi
1Research Center for Asian Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
6Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
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Yoshihiro Kawaoka
2Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
7Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, WI 53711, USA
8Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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Jun-ichiro Inoue
1Research Center for Asian Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
9Senior Professor Office, University of Tokyo, Tokyo 113-0033, Japan
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  • ORCID record for Jun-ichiro Inoue
  • For correspondence: jun-i@ims.u-tokyo.ac.jp
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Abstract

Although infection by SARS-CoV-2, the causative agent of COVID-19, is spreading rapidly worldwide, no drug has been shown to be sufficiently effective for treating COVID-19. We previously found that nafamostat mesylate, an existing drug used for disseminated intravascular coagulation (DIC), effectively blocked MERS-CoV S protein-initiated cell fusion by targeting TMPRSS2, and inhibited MERS-CoV infection of human lung epithelium-derived Calu-3 cells. Here we established a quantitative fusion assay dependent on SARS-CoV-2 S protein, ACE2 and TMPRSS2, and found that nafamostat mesylate potently inhibited the fusion while camostat mesylate was about 10-fold less active. Furthermore, nafamostat mesylate blocked SARS-CoV-2 infection of Calu-3 cells with an EC50 around 10 nM, which is below its average blood concentration after intravenous administration through continuous infusion. These findings, together with accumulated clinical data regarding its safety, make nafamostat a likely candidate drug to treat COVID-19.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 23, 2020.
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The anticoagulant nafamostat potently inhibits SARS-CoV-2 infection in vitro: an existing drug with multiple possible therapeutic effects
Mizuki Yamamoto, Maki Kiso, Yuko Sakai-Tagawa, Kiyoko Iwatsuki-Horimoto, Masaki Imai, Makoto Takeda, Noriko Kinoshita, Norio Ohmagari, Jin Gohda, Kentaro Semba, Zene Matsuda, Yasushi Kawaguchi, Yoshihiro Kawaoka, Jun-ichiro Inoue
bioRxiv 2020.04.22.054981; doi: https://doi.org/10.1101/2020.04.22.054981
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The anticoagulant nafamostat potently inhibits SARS-CoV-2 infection in vitro: an existing drug with multiple possible therapeutic effects
Mizuki Yamamoto, Maki Kiso, Yuko Sakai-Tagawa, Kiyoko Iwatsuki-Horimoto, Masaki Imai, Makoto Takeda, Noriko Kinoshita, Norio Ohmagari, Jin Gohda, Kentaro Semba, Zene Matsuda, Yasushi Kawaguchi, Yoshihiro Kawaoka, Jun-ichiro Inoue
bioRxiv 2020.04.22.054981; doi: https://doi.org/10.1101/2020.04.22.054981

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