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

• Published in: Nature (London) Vol. 605; no. 7909; pp. 340 - 348
• Main 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 A. H., 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.05.2022; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/51; 14/19; 14/63; 38/1; 38/77; 631/154/1435/2417; 631/154/556; 631/326/596/2555; 631/326/596/4130; 631/337/474; 64/60; ACE2; Angiotensin-converting enzyme 2; Animals; Cell fusion; Coronaviruses; COVID-19; COVID-19 - prevention & control; COVID-19 - virology; Disease Models, Animal; Disease transmission; Drug development; Humanities and Social Sciences; Humans; Infections; Influenza; Investigations; Mice; Mice, Transgenic; multidisciplinary; Pandemics; Peptides; Proteins; Proteolysis; Public health; RNA polymerase; SARS-CoV-2 - drug effects; Science; Science (multidisciplinary); Selectivity; Serine Endopeptidases; Serine proteinase; Serine Proteinase Inhibitors - pharmacology; Serine Proteinase Inhibitors - therapeutic use; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - metabolism; Spike protein; Transgenic mice; Vaccination; Viral diseases; Virus Internalization - drug effects; Viruses
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-022-04661-w

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 concern 1 , 2 . Development of host-directed therapeutics and prophylactics could limit such resistance and offer urgently needed protection against variants of concern 3 , 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 lifecycle 5 , 6 . Here we identify and characterize a small-molecule compound, N-0385, which exhibits low nanomolar potency and a selectivity index of higher than 10 6 in inhibiting SARS-CoV-2 infection in human lung cells and in donor-derived colonoids 7 . 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. A small-molecule inhibitor of TMPRSS2 is effective against SARS-CoV-2 variants of concern in human lung cells and in donor-derived colonoids, and also shows prophylactic and therapeutic benefits in a mouse model of COVID-19.