A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells
Matthew Mahoney, Vishnu C Damalanka, Michael A Tartell, Dong Hee Chung, André Luiz Lourenco, Dustin Pwee, Anne E Mayer Bridwell, Markus Hoffmann, Jorine Voss, Partha Karmakar, Nurit Azouz, Andrea M Klingler, Paul W Rothlauf, Cassandra E Thompson, Melody Lee, Lidija Klampfer, Christina Stallings, Marc E Rothenberg, Stefan Pöhlmann, Sean P Whelan, Anthony J O’Donoghue, Charles S Craik, James W Janetka
The host cell serine protease TMPRSS2 is definitely an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of Severe Acute Respiratory system Syndrome Coronavirus 2 (SARS-CoV-2) as well as other coronaviruses and it is required for viral spread within the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we’ve discovered a singular type of small molecule ketobenzothiazole TMPRSS2 inhibitors with considerably improved activity over existing irreversible inhibitors Camostat and Nafamostat. Lead compound MM3122 ( 4 ) comes with an IC 50 of 340 pM against recombinant full-length TMPRSS2 protein, an EC 50 of 430 pM in blocking host cell entry into Calu-3 human lung epithelial cells of the recently developed VSV SARS-CoV-2 chimeric virus, as well as an EC 50 of 74 nM in inhibiting cytopathic effects caused by SARS-CoV-2 virus in Calu-3 cells. Further, MM3122 blocks Middle East Respiratory system Syndrome Coronavirus (MERS-CoV) cell entry by having an EC 50 of 870 pM. MM3122 has excellent metabolic stability, safety, and pharmacokinetics in rodents having a half-existence of 8.6 hrs in plasma and seven.5 h in lung tissue, which makes it appropriate for in vivo effectiveness evaluation along with a promising drug candidate for COVID-19 treatment.