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

Author

Listed:
  • Tirosh Shapira

    (University of British Columbia)

  • I. Abrrey Monreal

    (Cornell University College of Veterinary Medicine)

  • Sébastien P. Dion

    (Université de Sherbrooke)

  • David W. Buchholz

    (Cornell University College of Veterinary Medicine)

  • Brian Imbiakha

    (Cornell University College of Veterinary Medicine)

  • Andrea D. Olmstead

    (University of British Columbia)

  • Mason Jager

    (Cornell University College of Veterinary Medicine)

  • Antoine Désilets

    (Université de Sherbrooke)

  • Guang Gao

    (University of British Columbia
    University of British Columbia)

  • Mathias Martins

    (Cornell University College of Veterinary Medicine)

  • Thierry Vandal

    (Université de Sherbrooke)

  • Connor A. H. Thompson

    (University of British Columbia)

  • Aaleigha Chin

    (University of British Columbia)

  • William D. Rees

    (University of British Columbia)

  • Theodore Steiner

    (University of British Columbia)

  • Ivan Robert Nabi

    (University of British Columbia)

  • Eric Marsault

    (Université de Sherbrooke)

  • Julie Sahler

    (Cornell University College of Veterinary Medicine)

  • Diego G. Diel

    (Cornell University College of Veterinary Medicine)

  • Gerlinde R. Walle

    (Cornell University College of Veterinary Medicine)

  • Avery August

    (Cornell University College of Veterinary Medicine)

  • Gary R. Whittaker

    (Cornell University College of Veterinary Medicine)

  • Pierre-Luc Boudreault

    (Université de Sherbrooke)

  • Richard Leduc

    (Université de Sherbrooke)

  • Hector C. Aguilar

    (Cornell University College of Veterinary Medicine)

  • François Jean

    (University of British Columbia)

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 concern1,2. Development of host-directed therapeutics and prophylactics could limit such resistance and offer urgently needed protection against variants of concern3,4. 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 lifecycle5,6. 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.

Suggested Citation

  • Tirosh Shapira & I. Abrrey Monreal & Sébastien P. Dion & David W. Buchholz & Brian Imbiakha & Andrea D. Olmstead & Mason Jager & Antoine Désilets & Guang Gao & Mathias Martins & Thierry Vandal & Conno, 2022. "A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic," Nature, Nature, vol. 605(7909), pages 340-348, May.
  • Handle: RePEc:nat:nature:v:605:y:2022:i:7909:d:10.1038_s41586-022-04661-w
    DOI: 10.1038/s41586-022-04661-w
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    Cited by:

    1. Zhenzhen Wang & Shiqi Hu & Kristen D. Popowski & Shuo Liu & Dashuai Zhu & Xuan Mei & Junlang Li & Yilan Hu & Phuong-Uyen C. Dinh & Xiaojie Wang & Ke Cheng, 2024. "Inhalation of ACE2-expressing lung exosomes provides prophylactic protection against SARS-CoV-2," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Zhongmou Chao & Ekaterina Selivanovitch & Konstantinos Kallitsis & Zixuan Lu & Ambika Pachaury & Róisín Owens & Susan Daniel, 2024. "Recreating the biological steps of viral infection on a cell-free bioelectronic platform to profile viral variants of concern," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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