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A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells

The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of severe acute respiratory syndrome coronavirus 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 discovered covalent small-molecule ketobenzothiazole (kbt) TMPRSS2 inhibitors which are structurally distinct from and have significantly improved activity over the existing known inhibitors Camostat and Nafamostat. Lead compound MM3122 (4) has an IC50 (half-maximal inhibitory concentration) of 340 pM against recombinant full-length TMPRSS2 protein, an EC50 (half-maximal effective concentration) of 430 pM in blocking host cell entry into Calu-3 human lung epithelial cells of a newly developed VSV-SARS-CoV-2 chimeric virus, and an EC50 of 74 nM in inhibiting cytopathic effects induced by SARS-CoV-2 virus in Calu-3 cells. Further, MM3122 blocks Middle East respiratory syndrome coronavirus (MERS-CoV) cell entry with an EC50 of 870 pM. MM3122 has excellent metabolic stability, safety, and pharmacokinetics in mice, with a half-life of 8.6 h in plasma and 7.5 h in lung tissue, making it suitable for in vivo efficacy evaluation and a promising drug candidate for COVID-19 treatment.

 

Comments:

That's an impressive discovery! MM3122 seems quite promising as a potential therapeutic for COVID-19 treatment, especially considering its potency against TMPRSS2 and its efficacy in blocking viral entry into lung cells. The fact that it also demonstrates activity against other coronaviruses like MERS-CoV is a significant advantage.

The compound's favorable pharmacokinetic properties in mice, including metabolic stability and suitable half-life in both plasma and lung tissue, are encouraging for its potential as a viable drug candidate. The in vivo efficacy evaluation will provide crucial insights into its performance within a living organism, further determining its suitability for clinical trials.

It's fascinating to see the utilization of rational structure-based drug design coupled with substrate specificity screening to develop novel inhibitors that outperform existing ones like Camostat and Nafamostat. This type of targeted approach is essential in the quest for more effective treatments against viral infections like COVID-19.

As this field continues to evolve, ongoing research and clinical trials will likely shed more light on the therapeutic potential of MM3122 and similar compounds in the fight against coronaviruses.

Related Products

Cat.No. Product Name Information
E1074 MM3122 MM3122 is a selective inhibitor of host cell serine protease TMPRSS2 (transmembrane protease serine 2) with IC50 of 0.34 nM against recombinant full-length TMPRSS2 protein.

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