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

Nature. 2022 May;605(7909):340-348. doi: 10.1038/s41586-022-04661-w. Epub 2022 Mar 28.


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.

MeSH terms

  • Animals
  • COVID-19* / prevention & control
  • COVID-19* / virology
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Transgenic
  • SARS-CoV-2* / drug effects
  • Serine Endopeptidases
  • Serine Proteinase Inhibitors* / pharmacology
  • Serine Proteinase Inhibitors* / therapeutic use
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / metabolism
  • Virus Internalization / drug effects


  • Serine Proteinase Inhibitors
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Serine Endopeptidases
  • TMPRSS2 protein, human

Supplementary concepts

  • SARS-CoV-2 variants