Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 43, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2108728118
Keywords
antiviral; protease inhibitor; COVID-19; structure-based drug discovery; PS-SCL
Categories
Funding
- Siteman Cancer Center of Washington University [16-FY18-02, SCC P30CA091842]
- Barnes Jewish Hospital Foundation in Saint Louis [BJHF 4984]
- NIH [R43 CA243941, R43 CA224832, U19 AI142784, P50AI150476, U19 AI070235]
- Campaign Urging Research for Eosinophilic Diseases Foundation
- Fast Grant from Emergent Ventures at the Mercatus 9 Center, GeorgeMason University
- Bundesministerium fur Bildung und Forschung (German: Federal Ministry of Education and Research
- Bonn, Germany)
- RAPID Consortium [01KI1723D, 01KI2006D]
- RENACO [01KI20328A]
- SARS_S1S2 award [01KI20396]
- Charite -Universitatsmedizin Berlin (Forschungsnetzwerk der Universitatsmedizin zu Covid, COVIM consortium [01KX2021]
- country of Lower Saxony [14-76103-184]
- German Research Foundation [PO 716/11-1, PO 716/14-1]
- Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease Award [17008]
Ask authors/readers for more resources
A novel TMPRSS2 inhibitor, MM3122, has shown exceptional potency in inhibiting viral entry and reducing cytopathic effects, with promising potential as a treatment for COVID-19. This compound, discovered using SBDD, exhibits unique structural features and excellent pharmacokinetic properties, making it a strong candidate for in vivo efficacy evaluation.
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 VSVSARS-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.
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