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

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 due to 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 to cleave the viral spike protein to expose the fusion peptide for cell entry^5,6. Here, we identify and characterize a small-molecule compound, N-0385, which exhibits low nanomolar potency and a selectivity index of >10⁶ at inhibiting SARS-CoV-2 infection in human lung cells and in donor-derived colonoids⁷. In Calu-3 cells it inhibits entry of SARS-CoV-2 VOCs, B.1.1.7, B.1.351, P.1 and B.1.617.2. Importantly, in the K18-human ACE2 transgenic mouse model of severe SARS-CoV-2 disease, we found that N-0385 affords a high level of prophylactic and therapeutic benefit following either multiple or even a single administration. 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.

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Author notes

1. These authors contributed equally: Tirosh Shapira, I. Abrrey Monrea

Affiliations

1. Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada

   Tirosh Shapira, Andrea D. Olmstead, Guang Gao, Connor A. H. Thompson, Aaleigha Chin & François Jean

2. Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY, USA

   I. Abrrey Monreal, David W. Buchholz, Brian Imbiakha, Mason Jager, Julie Sahler, Gerlinde R. Van de Walle, Avery August, Gary R. Whittaker & Hector C. Aguilar

3. Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada

   Sébastien P. Dion, Antoine Désilets, Thierry Vandal, Eric Marsault, Pierre-Luc Boudreault & Richard Leduc

4. Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada

   Guang Gao & Ivan Robert Nabi

5. Department of Population Medicine and Diagnostic Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, USA

   Mathias Martins & Diego G. Diel

6. Department of Medicine, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada

   William D. Rees & Theodore Steiner

Authors

1. Tirosh Shapira
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2. I. Abrrey Monreal
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3. Sébastien P. Dion
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4. David W. Buchholz
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5. Brian Imbiakha
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6. Andrea D. Olmstead
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7. Mason Jager
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8. Antoine Désilets
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9. Guang Gao
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10. Mathias Martins
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11. Thierry Vandal
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12. Connor A. H. Thompson
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13. Aaleigha Chin
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14. William D. Rees
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15. Theodore Steiner
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16. Ivan Robert Nabi
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17. Eric Marsault
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18. Julie Sahler
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19. Diego G. Diel
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20. Gerlinde R. Van de Walle
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21. Avery August
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22. Gary R. Whittaker
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23. Pierre-Luc Boudreault
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24. Richard Leduc
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25. Hector C. Aguilar
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26. François Jean
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Corresponding authors

Correspondence to Richard Leduc, Hector C. Aguilar or François Jean.

Supplementary information

Supplementary Information

This file includes compound synthesis schemes and characterization of final compounds (Supplementary Schemes 1 to 10); Supplementary Tables that summarize high-resolution mass measurements (Supplementary Tables 1–8); and Supplementary Figures summarizing isotopic profiles, UPLC-MS, and NMR analysis of peptidomimetic compounds (Supplementary Figures 1–27).

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Video 1

| Representative video from a 3D volume rendering of SARS-CoV-2 B.1.617.2 Delta-infected cells. Hoechst is shown in blue, dsRNA in green, nucleocapsid in red, and actin in cyan. Images captured with a Leica TCS SP8 STED 3× laser scanning confocal microscope.

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Shapira, T., Monreal, I.A., Dion, S.P. et al. A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic. Nature (2022). https://ift.tt/uotmjbE

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• Received: 14 May 2021

• Accepted: 18 March 2022

• Published: 28 March 2022

• DOI: https://ift.tt/uotmjbE

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