From N-0385 to N-0920: Unveiling a Host-Directed Protease Inhibitor with Picomolar Antiviral Efficacy against Prevalent SARS-CoV-2 Variants DOI
Gabriel Lemieux, Jimena Pérez‐Vargas, Antoine Désilets

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 31, 2025

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

Language: Английский

From N-0385 to N-0920: Unveiling a Host-Directed Protease Inhibitor with Picomolar Antiviral Efficacy against Prevalent SARS-CoV-2 Variants DOI
Gabriel Lemieux, Jimena Pérez‐Vargas, Antoine Désilets

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 31, 2025

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

Language: Английский

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