Cell Reports
Volume 33, Issue 2, 13 October 2020, 108254
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Article
Furin Inhibitors Block SARS-CoV-2 Spike Protein Cleavage to Suppress Virus Production and Cytopathic Effects

https://doi.org/10.1016/j.celrep.2020.108254Get rights and content
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Highlights

  • The furin cleavage site in the SARS-CoV-2 spike protein mediates syncytium formation

  • The SARS-CoV-2 spike-mediated syncytium is suppressed by specific furin inhibitors

  • Furin inhibitors block SARS-CoV-2 virus entry and virus replication

  • Furin inhibitors are potential antiviral agents for SARS-CoV-2 infection and pathogenesis

Summary

Development of specific antiviral agents is an urgent unmet need for SARS-coronavirus 2 (SARS-CoV-2) infection. This study focuses on host proteases that proteolytically activate the SARS-CoV-2 spike protein, critical for its fusion after binding to angiotensin-converting enzyme 2 (ACE2), as antiviral targets. We first validate cleavage at a putative furin substrate motif at SARS-CoV-2 spikes by expressing it in VeroE6 cells and find prominent syncytium formation. Cleavage and the syncytium are abolished by treatment with the furin inhibitors decanoyl-RVKR-chloromethylketone (CMK) and naphthofluorescein, but not by the transmembrane protease serine 2 (TMPRSS2) inhibitor camostat. CMK and naphthofluorescein show antiviral effects on SARS-CoV-2-infected cells by decreasing virus production and cytopathic effects. Further analysis reveals that, similar to camostat, CMK blocks virus entry, but it further suppresses cleavage of spikes and the syncytium. Naphthofluorescein acts primarily by suppressing viral RNA transcription. Therefore, furin inhibitors may be promising antiviral agents for prevention and treatment of SARS-CoV-2 infection.

Keywords

SARS-CoV-2
spike
furin
syncytium
cytopathic effect

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