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Communication

The Anticoagulant Nafamostat Potently Inhibits SARS-CoV-2 S Protein-Mediated Fusion in a Cell Fusion Assay System and Viral Infection In Vitro in a Cell-Type-Dependent Manner

1
Research Center for Asian Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
2
Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
3
Department of Virology 3, National Institute of Infectious Diseases, Musashimurayama, Tokyo 208-0011, Japan
4
Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
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Department of Life Science and Medical Bio-Science, Waseda University, Shinjuku-ku, Tokyo 162-8480, Japan
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Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
7
Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53711, USA
8
Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
9
Senior Professor Office, University of Tokyo, Tokyo 113-0033, Japan
*
Author to whom correspondence should be addressed.
Viruses 2020, 12(6), 629; https://doi.org/10.3390/v12060629
Received: 29 April 2020 / Revised: 8 June 2020 / Accepted: 9 June 2020 / Published: 10 June 2020
(This article belongs to the Special Issue Pathogenesis of Human and Animal Coronaviruses)
Although infection by SARS-CoV-2, the causative agent of coronavirus pneumonia disease (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 Middle East respiratory syndrome coronavirus (MERS-CoV) S protein-mediated cell fusion by targeting transmembrane serine protease 2 (TMPRSS2), and inhibited MERS-CoV infection of human lung epithelium-derived Calu-3 cells. Here we established a quantitative fusion assay dependent on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein, angiotensin I converting enzyme 2 (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 effective concentration (EC)50 around 10 nM, which is below its average blood concentration after intravenous administration through continuous infusion. On the other hand, a significantly higher dose (EC50 around 30 μM) was required for VeroE6/TMPRSS2 cells, where the TMPRSS2-independent but cathepsin-dependent endosomal infection pathway likely predominates. Together, our study shows that nafamostat mesylate potently inhibits SARS-CoV-2 S protein-mediated fusion in a cell fusion assay system and also inhibits SARS-CoV-2 infection in vitro in a cell-type-dependent manner. These findings, together with accumulated clinical data regarding nafamostat’s safety, make it a likely candidate drug to treat COVID-19. View Full-Text
Keywords: SARS-CoV-2; TMPRSS2; fusion inhibitor SARS-CoV-2; TMPRSS2; fusion inhibitor
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MDPI and ACS Style

Yamamoto, M.; Kiso, M.; Sakai-Tagawa, Y.; Iwatsuki-Horimoto, K.; Imai, M.; Takeda, M.; Kinoshita, N.; Ohmagari, N.; Gohda, J.; Semba, K.; Matsuda, Z.; Kawaguchi, Y.; Kawaoka, Y.; Inoue, J.-i. The Anticoagulant Nafamostat Potently Inhibits SARS-CoV-2 S Protein-Mediated Fusion in a Cell Fusion Assay System and Viral Infection In Vitro in a Cell-Type-Dependent Manner. Viruses 2020, 12, 629. https://doi.org/10.3390/v12060629

AMA Style

Yamamoto M, Kiso M, Sakai-Tagawa Y, Iwatsuki-Horimoto K, Imai M, Takeda M, Kinoshita N, Ohmagari N, Gohda J, Semba K, Matsuda Z, Kawaguchi Y, Kawaoka Y, Inoue J-i. The Anticoagulant Nafamostat Potently Inhibits SARS-CoV-2 S Protein-Mediated Fusion in a Cell Fusion Assay System and Viral Infection In Vitro in a Cell-Type-Dependent Manner. Viruses. 2020; 12(6):629. https://doi.org/10.3390/v12060629

Chicago/Turabian Style

Yamamoto, Mizuki, 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, and Jun-ichiro Inoue. 2020. "The Anticoagulant Nafamostat Potently Inhibits SARS-CoV-2 S Protein-Mediated Fusion in a Cell Fusion Assay System and Viral Infection In Vitro in a Cell-Type-Dependent Manner" Viruses 12, no. 6: 629. https://doi.org/10.3390/v12060629

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