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

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, Connor A. H. Thompson, Aaleigha Chin, William D. Rees, Theodore Steiner, Ivan Robert Nabi, Eric Marsault, Julie Sahler, Diego G. Diel, Gerlinde R. Walle, Avery August, Gary R. Whittaker, Pierre-Luc Boudreault, Richard Leduc (), Hector C. Aguilar () and François Jean ()
Additional contact information
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
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

Nature, 2022, vol. 605, issue 7909, 340-348

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04661-w

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