2. Academic Validation
  3. From N-0385 to N-0920: Unveiling a Host-Directed Protease Inhibitor with Picomolar Antiviral Efficacy against Prevalent SARS-CoV-2 Variants

From N-0385 to N-0920: Unveiling a Host-Directed Protease Inhibitor with Picomolar Antiviral Efficacy against Prevalent SARS-CoV-2 Variants

  • J Med Chem. 2025 Apr 10;68(7):7119-7136. doi: 10.1021/acs.jmedchem.4c02468.
Gabriel Lemieux 1,  Jimena Pérez-Vargas 2,  Antoine Désilets 1,  Malihe Hassanzadeh 1,  Connor A H Thompson 2,  Alice Gravel-Trudeau 1,  Alexandre Joushomme 1,  Siobhan Ennis 3,  Ivan Villanueva 2,  Étienne Marouseau 1,  Bryan J Fraser 4 5,  William Champagne 1,  Matthieu Lepage 1,  Masahiro Niikura 3,  Cheryl H Arrowsmith 4 5 6,  François Jean 2,  Richard Leduc 1,  Pierre-Luc Boudreault 1
Affiliations

Affiliations

  • 1 Department of Pharmacology-Physiology, Institut de Pharmacologie de Sherbrooke, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke J1H5N4, Quebec, Canada.
  • 2 Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver V6T 1Z3, British Columbia, Canada.
  • 3 Faculty of Health Sciences, Simon Fraser University, Burnaby J1H5N4, British Columbia, Canada.
  • 4 Department of Medical Biophysics, University of Toronto, Toronto M5S 1A1, Ontario, Canada.
  • 5 Structural Genomics Consortium, University of Toronto, Toronto M5S 1A1, Ontario, Canada.
  • 6 Princess Margaret Cancer Centre, Toronto M5S 1A1, Ontario, Canada.
PMID: 40163818 DOI: 10.1021/acs.jmedchem.4c02468
Abstract

The worldwide spread of new SARS-CoV-2 variants emphasizes the need to diversify existing therapeutic strategies. TMPRSS2, a host protease crucial for SARS-CoV-2 entry, has garnered significant research attention as a potential target for therapeutic intervention. Here, we optimized N-0385, a previously reported TMPRSS2 ketobenzothiazole-based peptidomimetic inhibitor, by screening 135 derivatives for target affinity and Antiviral potency. Among the top candidates, N-0695 exhibited low nanomolar Ki values against three TTSPs associated with respiratory virus entry: TMPRSS2, matriptase, and TMPRSS13. Notably, N-0920 demonstrated exceptional potency in reducing SARS-CoV-2 variants EG.5.1 and JN.1 entry in Calu-3 cells, representing the first in cellulo picomolar inhibitor with EC50 values of 300 and 90 pM, respectively. Additionally, molecular modeling provided insights into the binding interactions between the compounds and their targets. This study underscores the effectiveness of our screening approach in refining an existing peptidomimetic scaffold to enhance selectivity and Antiviral activity.

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