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

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

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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.

元の言語English
記事番号v12060629
ジャーナルViruses
12
発行部数6
DOI
出版物ステータスPublished - 2020 6

ASJC Scopus subject areas

  • Infectious Diseases
  • Virology

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    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. (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(6), [v12060629]. https://doi.org/10.3390/v12060629