Journal of medicinal chemistry · 2025
From N-0385 to N-0920: Unveiling a Host-Directed Protease Inhibitor with Picomolar Antiviral Efficacy against Prevalent SARS-CoV-2 Variants.
СтатьяНазвание и аннотация: Перевод в очереди
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Lemieux Gabriel, Pérez-Vargas Jimena, Désilets Antoine, Hassanzadeh Malihe, Thompson Connor A H, Gravel-Trudeau Alice, Joushomme Alexandre, Ennis Siobhan, Villanueva Ivan, Marouseau Étienne, Fraser Bryan J, Champagne William, Lepage Matthieu, Niikura Masahiro, Arrowsmith Cheryl H, Jean François, Leduc Richard, Boudreault Pierre-Luc
Аннотация
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.