A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells.
Matthew MahoneyVishnu C DamalankaMichael A TartellDong Hee ChungAndré Luiz LourençoDustin PweeAnne E Mayer BridwellMarkus HoffmannJorine VossPartha KarmakarNurit P AzouzAndrea M KlinglerPaul W RothlaufCassandra E ThompsonMelody LeeLidija KlampferChristina L StallingsMarc E RothenbergStefan H PöhlmannSean P J WhelanAnthony J O'DonoghueCharles S CraikJames W JanetkaPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
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.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- cell therapy
- small molecule
- induced apoptosis
- single cell
- coronavirus disease
- drug discovery
- air pollution
- particulate matter
- heavy metals
- protein protein
- type diabetes
- signaling pathway
- photodynamic therapy
- heart rate
- polycyclic aromatic hydrocarbons
- risk assessment
- adipose tissue
- oxidative stress
- stem cells
- emergency department
- blood pressure
- skeletal muscle
- binding protein
- cell death
- water soluble
- induced pluripotent stem cells
- drug induced
- resistance training
- insulin resistance
- smoking cessation
- cell free