| First Author | Shapira T | Year | 2022 |
| Journal | Nature | Volume | 605 |
| Issue | 7909 | Pages | 340-348 |
| PubMed ID | 35344983 | Mgi Jnum | J:336214 |
| Mgi Id | MGI:7367057 | Doi | 10.1038/s41586-022-04661-w |
| Citation | Shapira T, et al. (2022) A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic. Nature 605(7909):340-348 |
| abstractText | 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. |
