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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
Proceedings of the National Academy of Sciences - PNAS, 2021-10, Vol.118 (43)
2021

Details

Autor(en) / Beteiligte
Titel
A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells
Ist Teil von
  • Proceedings of the National Academy of Sciences - PNAS, 2021-10, Vol.118 (43)
Ort / Verlag
United States: National Academy of Sciences
Erscheinungsjahr
2021
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
  • 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 IC (half-maximal inhibitory concentration) of 340 pM against recombinant full-length TMPRSS2 protein, an EC (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 EC 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 EC 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.
Sprache
Englisch
Identifikatoren
ISSN: 0027-8424
eISSN: 1091-6490
DOI: 10.1073/pnas.2108728118
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8694051
Format
–
Schlagworte
Animals, Benzamidines - chemistry, Benzothiazoles - pharmacokinetics, Benzothiazoles - pharmacology, Biological Sciences, Blocking, Cell Line, Coronaviruses, COVID-19, COVID-19 - drug therapy, COVID-19 - genetics, COVID-19 - virology, Drug Design, Drug development, Epithelial cells, Epithelial Cells - drug effects, Epithelial Cells - virology, Epithelium, Esters - chemistry, Guanidines - chemistry, Humans, Inhibitors, Lead compounds, Lung - drug effects, Lung - virology, Lungs, Mice, Middle East respiratory syndrome, Middle East Respiratory Syndrome Coronavirus - drug effects, Middle East Respiratory Syndrome Coronavirus - pathogenicity, Oligopeptides - pharmacokinetics, Oligopeptides - pharmacology, Pharmacokinetics, Physical Sciences, Protease, Proteins, Respiratory diseases, SARS-CoV-2 - drug effects, SARS-CoV-2 - pathogenicity, Serine Endopeptidases - drug effects, Serine Endopeptidases - genetics, Serine Endopeptidases - ultrastructure, Serine proteinase, Severe acute respiratory syndrome, Severe acute respiratory syndrome coronavirus 2, Small Molecule Libraries - pharmacology, Spike protein, Substrate specificity, Substrate Specificity - drug effects, Substrates, Therapeutic targets, Viral diseases, Virus Internalization - drug effects, Viruses

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