A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic. Academic Article uri icon


  • 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.

published proceedings

  • Nature

altmetric score

  • 1263.64

author list (cited authors)

  • Shapira, T., Monreal, I. A., Dion, S. P., Buchholz, D. W., Imbiakha, B., Olmstead, A. D., ... Jean, F.

citation count

  • 70

complete list of authors

  • Shapira, Tirosh||Monreal, I Abrrey||Dion, Sébastien P||Buchholz, David W||Imbiakha, Brian||Olmstead, Andrea D||Jager, Mason||Désilets, Antoine||Gao, Guang||Martins, Mathias||Vandal, Thierry||Thompson, Connor AH||Chin, Aaleigha||Rees, William D||Steiner, Theodore||Nabi, Ivan Robert||Marsault, Eric||Sahler, Julie||Diel, Diego G||Van de Walle, Gerlinde R||August, Avery||Whittaker, Gary R||Boudreault, Pierre-Luc||Leduc, Richard||Aguilar, Hector C||Jean, François

publication date

  • May 2022

published in