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A novel highly potent inhibitor of TMPRSS2-like proteases blocks SARS-CoV-2 variants of concern and is broadly protective against infection and mortality in mice

Tirosh Shapira, I. Abrrey Monreal, Sébastien P. Dion, Mason Jager, Antoine Désilets, View ORCID ProfileAndrea D. Olmstead, Thierry Vandal, David W. Buchholz, Brian Imbiakha, Guang Gao, Aaleigha Chin, William D. Rees, Theodore Steiner, View ORCID ProfileIvan Robert Nabi, Eric Marsault, Julie Sahler, Avery August, Gerlinde Van de Walle, View ORCID ProfileGary R. Whittaker, View ORCID ProfilePierre-Luc Boudreault, View ORCID ProfileHector C. Aguilar, View ORCID ProfileRichard Leduc, View ORCID ProfileFrançois Jean
doi: https://doi.org/10.1101/2021.05.03.442520
Tirosh Shapira
1Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
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I. Abrrey Monreal
2Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, 14853, USA
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Sébastien P. Dion
3Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada
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Mason Jager
2Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, 14853, USA
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Antoine Désilets
3Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada
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Andrea D. Olmstead
1Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
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  • ORCID record for Andrea D. Olmstead
Thierry Vandal
3Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada
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David W. Buchholz
2Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, 14853, USA
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Brian Imbiakha
2Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, 14853, USA
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Guang Gao
1Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
5Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
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Aaleigha Chin
1Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
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William D. Rees
4Department of Medicine, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
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Theodore Steiner
4Department of Medicine, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
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Ivan Robert Nabi
5Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
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Eric Marsault
3Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada
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Julie Sahler
2Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, 14853, USA
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Avery August
2Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, 14853, USA
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Gerlinde Van de Walle
2Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, 14853, USA
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Gary R. Whittaker
2Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, 14853, USA
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Pierre-Luc Boudreault
3Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada
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Hector C. Aguilar
2Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, 14853, USA
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  • For correspondence: ha363@cornell.edu richard.leduc@usherbrooke.ca fjean@mail.ubc.ca
Richard Leduc
3Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada
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  • For correspondence: ha363@cornell.edu richard.leduc@usherbrooke.ca fjean@mail.ubc.ca
François Jean
1Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
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  • ORCID record for François Jean
  • For correspondence: ha363@cornell.edu richard.leduc@usherbrooke.ca fjean@mail.ubc.ca
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Summary

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 against emerging variants of concern (VOCs) 1,2. Development of host-directed therapeutics and prophylactics could limit such resistance and offer urgently needed protection against VOCs 3,4. Attractive pharmacological targets to impede viral entry include type-II transmembrane serine proteases (TTSPs), such as TMPRSS2, whose essential role in the virus lifecycle is responsible for the cleavage and priming of the viral spike protein 5–7. Here, we identify and characterize a small-molecule compound, N-0385, as the most potent inhibitor of TMPRSS2 reported to date. N-0385 exhibited low nanomolar potency and a selectivity index of >106 at inhibiting SARS-CoV-2 infection in human lung cells and in donor-derived colonoids 8. Importantly, N-0385 acted as a broad-spectrum coronavirus inhibitor of two SARS-CoV-2 VOCs, B.1.1.7 and B.1.351. Strikingly, single daily intranasal administration of N-0385 early in infection significantly improved weight loss and clinical outcomes, and yielded 100% survival in the severe K18-human ACE2 transgenic mouse model of SARS-CoV-2 disease. This demonstrates that TTSP-mediated proteolytic maturation of spike is critical for SARS-CoV-2 infection in vivo and suggests that N-0385 provides a novel effective early treatment option against COVID-19 and emerging SARS-CoV-2 VOCs.

Competing Interest Statement

RL and PLB hold patent WO2012162828A1 related to peptidomimetic serine protease inhibitors. The remaining authors declare that they have no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 04, 2021.
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A novel highly potent inhibitor of TMPRSS2-like proteases blocks SARS-CoV-2 variants of concern and is broadly protective against infection and mortality in mice
Tirosh Shapira, I. Abrrey Monreal, Sébastien P. Dion, Mason Jager, Antoine Désilets, Andrea D. Olmstead, Thierry Vandal, David W. Buchholz, Brian Imbiakha, Guang Gao, Aaleigha Chin, William D. Rees, Theodore Steiner, Ivan Robert Nabi, Eric Marsault, Julie Sahler, Avery August, Gerlinde Van de Walle, Gary R. Whittaker, Pierre-Luc Boudreault, Hector C. Aguilar, Richard Leduc, François Jean
bioRxiv 2021.05.03.442520; doi: https://doi.org/10.1101/2021.05.03.442520
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A novel highly potent inhibitor of TMPRSS2-like proteases blocks SARS-CoV-2 variants of concern and is broadly protective against infection and mortality in mice
Tirosh Shapira, I. Abrrey Monreal, Sébastien P. Dion, Mason Jager, Antoine Désilets, Andrea D. Olmstead, Thierry Vandal, David W. Buchholz, Brian Imbiakha, Guang Gao, Aaleigha Chin, William D. Rees, Theodore Steiner, Ivan Robert Nabi, Eric Marsault, Julie Sahler, Avery August, Gerlinde Van de Walle, Gary R. Whittaker, Pierre-Luc Boudreault, Hector C. Aguilar, Richard Leduc, François Jean
bioRxiv 2021.05.03.442520; doi: https://doi.org/10.1101/2021.05.03.442520

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