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Furin cleaves SARS-CoV-2 spike-glycoprotein at S1/S2 and S2’ for viral fusion/entry: indirect role of TMPRSS2

Rachid Essalmani, Jaspreet Jain, View ORCID ProfileDelia Susan-Resiga, View ORCID ProfileUrsula Andréo, Alexandra Evagelidis, Rabeb Mouna Derbali, David N. Huynh, Frédéric Dallaire, Mélanie Laporte, Adrien Delpal, Priscila Sutto-Ortiz, View ORCID ProfileBruno Coutard, View ORCID ProfileClaudine Mapa, Keith Wilcoxen, View ORCID ProfileÉtienne Decroly, Tram NQ Pham, View ORCID ProfileÉric A. Cohen, View ORCID ProfileNabil G. Seidah
doi: https://doi.org/10.1101/2020.12.18.423106
Rachid Essalmani
1Laboratory of Biochemical Neuroendocrinology Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal) 110 Pine Ave west, Montreal, QC, H2W1R7, Canada
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Jaspreet Jain
2Laboratory of Human Retrovirology Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal) 110 Pine Ave west, Montreal, QC, H2W1R7, Canada
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Delia Susan-Resiga
1Laboratory of Biochemical Neuroendocrinology Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal) 110 Pine Ave west, Montreal, QC, H2W1R7, Canada
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Ursula Andréo
1Laboratory of Biochemical Neuroendocrinology Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal) 110 Pine Ave west, Montreal, QC, H2W1R7, Canada
2Laboratory of Human Retrovirology Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal) 110 Pine Ave west, Montreal, QC, H2W1R7, Canada
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Alexandra Evagelidis
1Laboratory of Biochemical Neuroendocrinology Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal) 110 Pine Ave west, Montreal, QC, H2W1R7, Canada
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Rabeb Mouna Derbali
1Laboratory of Biochemical Neuroendocrinology Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal) 110 Pine Ave west, Montreal, QC, H2W1R7, Canada
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David N. Huynh
1Laboratory of Biochemical Neuroendocrinology Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal) 110 Pine Ave west, Montreal, QC, H2W1R7, Canada
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Frédéric Dallaire
2Laboratory of Human Retrovirology Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal) 110 Pine Ave west, Montreal, QC, H2W1R7, Canada
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Mélanie Laporte
2Laboratory of Human Retrovirology Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal) 110 Pine Ave west, Montreal, QC, H2W1R7, Canada
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Adrien Delpal
3AFMB, CNRS, Université Aix-Marseille, UMR 7257, Case 925, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France, Marseille, France
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Priscila Sutto-Ortiz
3AFMB, CNRS, Université Aix-Marseille, UMR 7257, Case 925, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France, Marseille, France
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Bruno Coutard
4Unité des Virus Émergents (UVE: Aix-Marseille Univ - IRD 190 - Inserm 1207 - IHU Méditerranée Infection), Marseille, France
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Claudine Mapa
5Boston Pharmaceuticals, Translational Research, 55 Cambridge Parkway, Suite 400, Cambridge, MA 02142, USA
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Keith Wilcoxen
5Boston Pharmaceuticals, Translational Research, 55 Cambridge Parkway, Suite 400, Cambridge, MA 02142, USA
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Étienne Decroly
3AFMB, CNRS, Université Aix-Marseille, UMR 7257, Case 925, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France, Marseille, France
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Tram NQ Pham
2Laboratory of Human Retrovirology Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal) 110 Pine Ave west, Montreal, QC, H2W1R7, Canada
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Éric A. Cohen
2Laboratory of Human Retrovirology Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal) 110 Pine Ave west, Montreal, QC, H2W1R7, Canada
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  • For correspondence: seidahn@ircm.qc.ca eric.cohen@ircm.qc.ca
Nabil G. Seidah
1Laboratory of Biochemical Neuroendocrinology Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal) 110 Pine Ave west, Montreal, QC, H2W1R7, Canada
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  • ORCID record for Nabil G. Seidah
  • For correspondence: seidahn@ircm.qc.ca eric.cohen@ircm.qc.ca
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Abstract

The Spike (S)-protein of SARS-CoV-2 binds host-cell receptor ACE2 and requires proteolytic “priming” (S1/S2) and “fusion-activation” (S2’) for viral entry. The S-protein furin-like motifs PRRAR685↓ and KPSKR815↓ indicated that proprotein convertases promote virus entry. We demonstrate that furin and PC5A induce cleavage at both sites, ACE2 enhances S2’ processing, and their pharmacological inhibition (BOS-inhibitors) block endogenous cleavages. S1/S2-mutations (μS1/S2) limit S-protein-mediated cell-to-cell fusion, similarly to BOS-inhibitors. Unexpectedly, TMPRSS2 does not cleave at S1/S2 or S2’, but it can: (i) cleave/inactivate S-protein into S2a/S2b; (ii) shed ACE2; (iii) cleave S1-subunit into secreted S1’, activities inhibited by Camostat. In lung-derived Calu-3 cells, BOS-inhibitors and µS1/S2 severely curtail “pH-independent” viral entry, and BOS-inhibitors alone/with Camostat potently reduce infectious viral titer and cytopathic effects. Overall, our results show that: furin plays a critical role in generating fusion-competent S-protein, and indirectly, TMPRSS2 promotes viral entry, supporting furin and TMPRSS2 inhibitors as potential antivirals against SARS-CoV-2.

Competing Interest Statement

The authors have declared no competing interest.

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Furin cleaves SARS-CoV-2 spike-glycoprotein at S1/S2 and S2’ for viral fusion/entry: indirect role of TMPRSS2
Rachid Essalmani, Jaspreet Jain, Delia Susan-Resiga, Ursula Andréo, Alexandra Evagelidis, Rabeb Mouna Derbali, David N. Huynh, Frédéric Dallaire, Mélanie Laporte, Adrien Delpal, Priscila Sutto-Ortiz, Bruno Coutard, Claudine Mapa, Keith Wilcoxen, Étienne Decroly, Tram NQ Pham, Éric A. Cohen, Nabil G. Seidah
bioRxiv 2020.12.18.423106; doi: https://doi.org/10.1101/2020.12.18.423106
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Furin cleaves SARS-CoV-2 spike-glycoprotein at S1/S2 and S2’ for viral fusion/entry: indirect role of TMPRSS2
Rachid Essalmani, Jaspreet Jain, Delia Susan-Resiga, Ursula Andréo, Alexandra Evagelidis, Rabeb Mouna Derbali, David N. Huynh, Frédéric Dallaire, Mélanie Laporte, Adrien Delpal, Priscila Sutto-Ortiz, Bruno Coutard, Claudine Mapa, Keith Wilcoxen, Étienne Decroly, Tram NQ Pham, Éric A. Cohen, Nabil G. Seidah
bioRxiv 2020.12.18.423106; doi: https://doi.org/10.1101/2020.12.18.423106

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