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A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.

ABSTRACT: The COVID-19 pandemic caused by the SARS-CoV-2 virus remains a global public health crisis. Although widespread vaccination campaigns are underway, their efficacy is reduced owing to emerging variants of concern^1,2. Development of host-directed therapeutics and prophylactics could limit such resistance and offer urgently needed protection against variants of concern^3,4. Attractive pharmacological targets to impede viral entry include type-II transmembrane serine proteases (TTSPs) such as TMPRSS2; these proteases cleave the viral spike protein to expose the fusion peptide for cell entry, and thus have an essential role in the virus lifecycle^5,6. Here we identify and characterize a small-molecule compound, N-0385, which exhibits low nanomolar potency and a selectivity index of higher than 10⁶ in inhibiting SARS-CoV-2 infection in human lung cells and in donor-derived colonoids⁷. In Calu-3 cells it inhibits the entry of the SARS-CoV-2 variants of concern B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta). Notably, in the K18-human ACE2 transgenic mouse model of severe COVID-19, we found that N-0385 affords a high level of prophylactic and therapeutic benefit after multiple administrations or even after a single administration. Together, our findings show that TTSP-mediated proteolytic maturation of the spike protein is critical for SARS-CoV-2 infection in vivo, and suggest that N-0385 provides an effective early treatment option against COVID-19 and emerging SARS-CoV-2 variants of concern.

SUBMITTER: Shapira T

PROVIDER: S-EPMC9095466 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.

Shapira Tirosh T Monreal I Abrrey IA Dion Sébastien P SP Buchholz David W DW Imbiakha Brian B Olmstead Andrea D AD Jager Mason M Désilets Antoine A Gao Guang G Martins Mathias M Vandal Thierry T Thompson Connor A H CAH Chin Aaleigha A Rees William D WD Steiner Theodore T Nabi Ivan Robert IR Marsault Eric E Sahler Julie J Diel Diego G DG Van de Walle Gerlinde R GR August Avery A Whittaker Gary R GR Boudreault Pierre-Luc PL Leduc Richard R Aguilar Hector C HC Jean François F

Nature 20220328 7909

The COVID-19 pandemic caused by the SARS-CoV-2 virus remains a global public health crisis. Although widespread vaccination campaigns are underway, their efficacy is reduced owing to emerging variants of concern<sup>1,2</sup>. Development of host-directed therapeutics and prophylactics could limit such resistance and offer urgently needed protection against variants of concern<sup>3,4</sup>. Attractive pharmacological targets to impede viral entry include type-II transmembrane serine proteases ( ...[more]

PMID: 35344983

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Project description: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 in vivo using two mouse models. In mice sensitized to SARS-CoV-2 infection by transduction with human ACE2, 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-hACE2 transgenic mice. These findings establish nafamostat as a candidate for the prevention or treatment of SARS-CoV-2 infection and disease pathogenesis. IMPORTANCE 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.

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A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.

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A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.

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A﻿ TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.

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A﻿ TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.

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OmicsDI is part of the ELIXIR infrastructure

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A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.

A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.