Optimization of Ketobenzothiazole‐Based Type II Transmembrane Serine Protease Inhibitors to Block H1N1 Influenza Virus Replication

• Published in: ChemMedChem 2024-01, Vol.19 (2), p.e202300458-n/a
• Main Authors: Colombo, Éloïc, Désilets, Antoine, Hassanzadeh, Malihe, Lemieux, Gabriel, Marois, Isabelle, Cliche, Dominic, Delbrouck, Julien A., Murza, Alexandre, Jean, François, Marsault, Eric, Richter, Martin V., Leduc, Richard, Boudreault, Pierre‐Luc
• Format: Article
• Language: English
• Subjects: Amino acids; Antiviral agents; Crystal structure; Drug resistance; Humans; Influenza; Influenza A virus - physiology; Influenza A Virus, H1N1 Subtype; Influenza, Human - drug therapy; inhibitors; matriptase; Medical innovations; Molecular modelling; Molecular structure; Orthomyxoviridae; Peptidomimetics; Pharmacology; Protease; Protease inhibitors; Protease Inhibitors - pharmacology; Proteinase inhibitors; Replication; Serine Proteases - metabolism; Serine proteinase; Serine Proteinase Inhibitors - pharmacology; Swine flu; type II transmembrane serine protease (TTSP); Virus Replication; Viruses
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202300458

Human influenza viruses cause acute respiratory symptoms that can lead to death. Due to the emergence of antiviral drug‐resistant strains, there is an urgent requirement for novel antiviral agents and innovative therapeutic strategies. Using the peptidomimetic ketobenzothiazole protease inhibitor RQAR‐Kbt (IN‐1, aka N‐0100) as a starting point, we report how substituting P2 and P4 positions with natural and unnatural amino acids can modulate the inhibition potency toward matriptase, a prototypical type II transmembrane serine protease (TTSP) that acts as a priming protease for influenza viruses. We also introduced modifications of the peptidomimetics N‐terminal groups, leading to significant improvements (from μM to nM, 60 times more potent than IN‐1) in their ability to inhibit the replication of influenza H1N1 virus in the Calu‐3 cell line derived from human lungs. The selectivity towards other proteases has been evaluated and explained using molecular modeling with a crystal structure recently obtained by our group. By targeting host cell TTSPs as a therapeutic approach, it may be possible to overcome the high mutational rate of influenza viruses and consequently prevent potential drug resistance. Modifications (highlighted in red) to the type II transmembrane serine protease (TTSP) peptidomimetic inhibitor RQAR‐Kbt (IN‐1, N‐0100) significantly improve the efficacy in blocking multicycle replication of Influenza H1N1 virus in human lung cells. This innovative strategy targets host cell enzymes, addressing the challenge of rapid influenza mutations and potential drug resistance.