A novel highly potent inhibitor of TMPRSS2-like proteases blocks SARS-CoV-2 variants of concern and is broadly protective against infection and mortality in mice

bioRxiv, 2021

Abstract

The host cell serine protease TMPRSS2is an attractive therapeutic target for COVID-19 drug discovery. This protease activates theSpike protein of Severe Acute Respiratory SyndromeCoronavirus 2 (SARS-CoV-2)and of other coronaviruses and is essential for viral spread in the lung.Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we have discovereda novel class of small molecule ketobenzothiazole TMPRSS2 inhibitors withsignificantly improved activity over existing irreversible inhibitors Camostat and Nafamostat. Lead compound MM3122(4)has an IC50of 340 pMagainst recombinant full-length TMPRSS2 protein, an EC50of 430 pMin blocking host cell entry into Calu-3 human lung epithelial cells of a newly developed VSV SARS-CoV-2 chimeric virus, and an EC50of 74nM in inhibiting cytopathic effects induced by SARS-CoV-2 virus inCalu-3 cells.Further,MM3122 blocks Middle East Respiratory Syndrome Coronavirus (MERS-CoV)cell entry with an EC50of 870 pM.MM3122 has excellent metabolic stability, safety,and pharmacokinetics in mice with a half-life of 8.6 hours in plasma and 7.5h in lung tissue, making it suitable for in vivo efficacy evaluation and a promising drug candidate for COVID-19 treatment.

Scicons´s Mouse anti double-stranded RNA (J2), IgG2a kappa, Monoclonal Antibody NMB-10010500  is featured in this Publication.