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The TMPRSS2 Inhibitor Nafamostat Reduces SARS-CoV-2 Pulmonary Infection in Mouse Models of COVID-19
Journal article   Open access   Peer reviewed

The TMPRSS2 Inhibitor Nafamostat Reduces SARS-CoV-2 Pulmonary Infection in Mouse Models of COVID-19

Kun Li, David K Meyerholz, Jennifer A Bartlett and Paul B McCray
mBio, Vol.12(4), pp.e0097021-e0097021
08/31/2021
DOI: 10.1128/mBio.00970-21
PMCID: PMC8406266
PMID: 34340553
url
https://doi.org/10.1128/mBio.00970-21View
Published (Version of record) Open Access

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has caused significant morbidity and mortality on a global scale. The etiologic agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), initiates host cell entry when its spike protein (S) binds to its receptor, angiotensin-converting enzyme 2 (ACE2). In airway epithelia, the spike protein is cleaved by the cell surface protease TMPRSS2, facilitating membrane fusion and entry at the cell surface. This dependence on TMPRSS2 and related proteases suggests that protease inhibitors might limit SARS-CoV-2 infection in the respiratory tract. Here, we tested two serine protease inhibitors, camostat mesylate and nafamostat mesylate, for their ability to inhibit entry of SARS-CoV-2 and that of a second pathogenic coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV). Both camostat and nafamostat reduced infection in primary human airway epithelia and in the Calu-3 2B4 cell line, with nafamostat exhibiting greater potency. We then assessed whether nafamostat was protective against SARS-CoV-2 using two mouse models. In mice sensitized to SARS-CoV-2 infection by transduction with human , intranasal nafamostat treatment prior to or shortly after SARS-CoV-2 infection significantly reduced weight loss and lung tissue titers. Similarly, prophylactic intranasal treatment with nafamostat reduced weight loss, viral burden, and mortality in K18- transgenic mice. These findings establish nafamostat as a candidate for the prevention or treatment of SARS-CoV-2 infection and disease pathogenesis. The causative agent of COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), requires host cell surface proteases for membrane fusion and entry into airway epithelia. We tested the hypothesis that inhibitors of these proteases, the serine protease inhibitors camostat and nafamostat, block infection by SARS-CoV-2. We found that both camostat and nafamostat reduce infection in human airway epithelia, with nafamostat showing greater potency. We then asked whether nafamostat protects mice against SARS-CoV-2 infection and subsequent COVID-19 lung disease. We performed infections in mice made susceptible to SARS-CoV-2 infection by introducing the human version of ACE2, the SARS-CoV-2 receptor, into their airway epithelia. We observed that pretreating these mice with nafamostat prior to SARS-CoV-2 infection resulted in better outcomes, in the form of less virus-induced weight loss, viral replication, and mortality than that observed in the untreated control mice. These results provide preclinical evidence for the efficacy of nafamostat in treating and/or preventing COVID-19.
 Angiotensin-Converting Enzyme 2 - genetics Animals Benzamidines - pharmacology Cells, Cultured COVID-19 - drug therapy Disease Models, Animal Drug Evaluation, Preclinical Esters - pharmacology Guanidines - pharmacology Humans Lung - pathology Mice Mice, Inbred C57BL Mice, Transgenic Middle East Respiratory Syndrome Coronavirus - drug effects Respiratory Mucosa - pathology Respiratory Mucosa - virology SARS-CoV-2 - drug effects Serine Endopeptidases - metabolism Serine Proteinase Inhibitors - pharmacology Spike Glycoprotein, Coronavirus - metabolism Virus Internalization - drug effects

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