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
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 intravasc...
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| Published in | Viruses Vol. 12; no. 6; p. 629 |
|---|---|
| Main Authors | , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Switzerland
MDPI
10.06.2020
MDPI AG |
| Subjects | |
| Online Access | Get full text |
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| Abstract | 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. |
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| AbstractList | 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. 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 mM) 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.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 mM) 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. 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. 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 (EC 50 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. 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) around 10 nM, which is below its average blood concentration after intravenous administration through continuous infusion. On the other hand, a significantly higher dose (EC around 30 mM) 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. |
| Author | Takeda, Makoto Ohmagari, Norio Semba, Kentaro Matsuda, Zene Iwatsuki-Horimoto, Kiyoko Kinoshita, Noriko Kawaguchi, Yasushi Inoue, Jun-ichiro Gohda, Jin Yamamoto, Mizuki Kiso, Maki Kawaoka, Yoshihiro Sakai-Tagawa, Yuko Imai, Masaki |
| AuthorAffiliation | 6 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 5 Department of Life Science and Medical Bio-Science, Waseda University, Shinjuku-ku, Tokyo 162-8480, Japan; ksemba@waseda.jp 1 Research Center for Asian Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; mizuyama@ims.u-tokyo.ac.jp (M.Y.); jgohda@ims.u-tokyo.ac.jp (J.G.); zmatsuda@ims.u-tokyo.ac.jp (Z.M.); ykawagu@ims.u-tokyo.ac.jp (Y.K.) 8 Department of Special Pathogens, International Research Center for 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; |
| AuthorAffiliation_xml | – name: 9 Senior Professor Office, University of Tokyo, Tokyo 113-0033, Japan – name: 8 Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan – name: 4 Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; nkinoshita@hosp.ncgm.go.jp (N.K.); nohmagari@hosp.ncgm.go.jp (N.O.) – name: 2 Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; kisomaki@ims.u-tokyo.ac.jp (M.K.); ytsakai@ims.u-tokyo.ac.jp (Y.S.-T.); kenken@ims.u-tokyo.ac.jp (K.I.-H.); mimai@ims.u-tokyo.ac.jp (M.I.); yoshihiro.kawaoka@wisc.edu (Y.K.) – name: 5 Department of Life Science and Medical Bio-Science, Waseda University, Shinjuku-ku, Tokyo 162-8480, Japan; ksemba@waseda.jp – name: 6 Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan – name: 7 Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53711, USA – name: 1 Research Center for Asian Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; mizuyama@ims.u-tokyo.ac.jp (M.Y.); jgohda@ims.u-tokyo.ac.jp (J.G.); zmatsuda@ims.u-tokyo.ac.jp (Z.M.); ykawagu@ims.u-tokyo.ac.jp (Y.K.) – name: 3 Department of Virology 3, National Institute of Infectious Diseases, Musashimurayama, Tokyo 208-0011, Japan; mtakeda@nih.go.jp |
| Author_xml | – sequence: 1 givenname: Mizuki orcidid: 0000-0003-3731-1702 surname: Yamamoto fullname: Yamamoto, Mizuki – sequence: 2 givenname: Maki surname: Kiso fullname: Kiso, Maki – sequence: 3 givenname: Yuko surname: Sakai-Tagawa fullname: Sakai-Tagawa, Yuko – sequence: 4 givenname: Kiyoko surname: Iwatsuki-Horimoto fullname: Iwatsuki-Horimoto, Kiyoko – sequence: 5 givenname: Masaki surname: Imai fullname: Imai, Masaki – sequence: 6 givenname: Makoto orcidid: 0000-0002-8194-7727 surname: Takeda fullname: Takeda, Makoto – sequence: 7 givenname: Noriko orcidid: 0000-0001-5471-7363 surname: Kinoshita fullname: Kinoshita, Noriko – sequence: 8 givenname: Norio surname: Ohmagari fullname: Ohmagari, Norio – sequence: 9 givenname: Jin surname: Gohda fullname: Gohda, Jin – sequence: 10 givenname: Kentaro surname: Semba fullname: Semba, Kentaro – sequence: 11 givenname: Zene surname: Matsuda fullname: Matsuda, Zene – sequence: 12 givenname: Yasushi surname: Kawaguchi fullname: Kawaguchi, Yasushi – sequence: 13 givenname: Yoshihiro surname: Kawaoka fullname: Kawaoka, Yoshihiro – sequence: 14 givenname: Jun-ichiro orcidid: 0000-0001-6389-7036 surname: Inoue fullname: Inoue, Jun-ichiro |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32532094$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Angiotensin-Converting Enzyme 2 Angiotensin-Converting Enzyme Inhibitors - pharmacology Animals anticoagulants Anticoagulants - pharmacology Betacoronavirus - drug effects Betacoronavirus - metabolism blood cell fusion Cell Line Chlorocebus aethiops Communication Coronavirus Infections - drug therapy Coronavirus Infections - virology COVID-19 COVID-19 infection disseminated intravascular coagulation etiological agents fusion inhibitor Gabexate - analogs & derivatives Gabexate - pharmacology Guanidines - pharmacology HEK293 Cells Humans intravenous injection lungs median effective concentration Middle East respiratory syndrome coronavirus Pandemics peptidyl-dipeptidase A Peptidyl-Dipeptidase A - metabolism pneumonia Pneumonia, Viral - drug therapy Pneumonia, Viral - virology SARS-CoV-2 Serine Endopeptidases - metabolism serine proteinases Severe acute respiratory syndrome coronavirus 2 Spike Glycoprotein, Coronavirus - antagonists & inhibitors Spike Glycoprotein, Coronavirus - metabolism TMPRSS2 Vero Cells Virus Internalization - drug effects |
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| Title | 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 |
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