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Synergistic Block of SARS-CoV-2 Infection by Combined Drug Inhibition of the Host Entry Factors PIKfyve Kinase and TMPRSS2 Protease.
Kreutzberger, Alex J B; Sanyal, Anwesha; Ojha, Ravi; Pyle, Jesse D; Vapalahti, Olli; Balistreri, Giuseppe; Kirchhausen, Tom.
  • Kreutzberger AJB; Department of Cell Biology, Harvard Medical Schoolgrid.471403.5, Boston, Massachusetts, USA.
  • Sanyal A; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
  • Ojha R; Department of Cell Biology, Harvard Medical Schoolgrid.471403.5, Boston, Massachusetts, USA.
  • Pyle JD; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
  • Vapalahti O; Department of Virology, Faculty of Medicine, University of Helsinkigrid.7737.4, Helsinki, Finland.
  • Balistreri G; Program in Virology, Harvard Medical Schoolgrid.471403.5, Boston, Massachusetts, USA.
  • Kirchhausen T; Department of Virology, Faculty of Medicine, University of Helsinkigrid.7737.4, Helsinki, Finland.
J Virol ; 95(21): e0097521, 2021 10 13.
Article in English | MEDLINE | ID: covidwho-1361966
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ABSTRACT
Repurposing FDA-approved inhibitors able to prevent infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could provide a rapid path to establish new therapeutic options to mitigate the effects of coronavirus disease 2019 (COVID-19). Proteolytic cleavages of the spike (S) protein of SARS-CoV-2, mediated by the host cell proteases cathepsin and TMPRSS2, alone or in combination, are key early activation steps required for efficient infection. The PIKfyve kinase inhibitor apilimod interferes with late endosomal viral traffic and through an ill-defined mechanism prevents in vitro infection through late endosomes mediated by cathepsin. Similarly, inhibition of TMPRSS2 protease activity by camostat mesylate or nafamostat mesylate prevents infection mediated by the TMPRSS2-dependent and cathepsin-independent pathway. Here, we combined the use of apilimod with camostat mesylate or nafamostat mesylate and found an unexpected ∼5- to 10-fold increase in their effectiveness to prevent SARS-CoV-2 infection in different cell types. Comparable synergism was observed using both a chimeric vesicular stomatitis virus (VSV) containing S of SARS-CoV-2 (VSV-SARS-CoV-2) and SARS-CoV-2. The substantial ∼5-fold or higher decrease of the half-maximal effective concentrations (EC50s) suggests a plausible treatment strategy based on the combined use of these inhibitors. IMPORTANCE Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the coronavirus disease 2019 (COVID-2019) global pandemic. There are ongoing efforts to uncover effective antiviral agents that could mitigate the severity of the disease by controlling the ensuing viral replication. Promising candidates include small molecules that inhibit the enzymatic activities of host proteins, thus preventing SARS-CoV-2 entry and infection. They include apilimod, an inhibitor of PIKfyve kinase, and camostat mesylate and nafamostat mesylate, inhibitors of TMPRSS2 protease. Our research is significant for having uncovered an unexpected synergism in the effective inhibitory activity of apilimod used together with camostat mesylate or nafamostat mesylate.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pyrimidines / Benzamidines / Serine Endopeptidases / Morpholines / Phosphatidylinositol 3-Kinases / Esters / SARS-CoV-2 / Guanidines / Hydrazones Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: J Virol Year: 2021 Document Type: Article Affiliation country: Jvi.00975-21

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pyrimidines / Benzamidines / Serine Endopeptidases / Morpholines / Phosphatidylinositol 3-Kinases / Esters / SARS-CoV-2 / Guanidines / Hydrazones Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: J Virol Year: 2021 Document Type: Article Affiliation country: Jvi.00975-21