Optimization of Ketobenzothiazole‐Based Type II Transmembrane Serine Protease Inhibitors to Block H1N1 Influenza Virus Replication
Abstract: 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.
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Bibliographic citation
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Optimization of Ketobenzothiazole‐Based Type II Transmembrane Serine Protease Inhibitors to Block H1N1 Influenza Virus Replication ; day:31 ; month:10 ; year:2023 ; extent:14
ChemMedChem ; (31.10.2023) (gesamt 14)
- Creator
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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
- DOI
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10.1002/cmdc.202300458
- URN
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urn:nbn:de:101:1-2023110114114901475167
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
- 14.08.2025, 11:01 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- 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
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Expression of trans-membrane serine protease 3 (TMPRSS3) in the human organ of Corti
Peptides to target serpin-serine protease interactions
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Development of peptidomimetic substrates and inhibitors for transmembrane serine proteases
Pharmacoinformatics-based identification of transmembrane protease serine-2 inhibitors from Morus Alba as SARS-CoV-2 cell entry inhibitors
Epigenetic silencing of serine protease HTRA1 drives polyploidy
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Development of new inhibitors for the type II transmembrane serine protease matriptase
Development of new inhibitors for the type II transmembrane serine protease matriptase
Transmembrane serine protease 6, a novel target for inhibition of neuronal tumor growth
Expression of trans-membrane serine protease 3 (TMPRSS3) in the human organ of Corti
Peptides to target serpin-serine protease interactions
Dimerization-dependent serine protease activity of FAM111A prevents replication fork stalling at topoisomerase 1 cleavage complexes
Characterisation of the type II transmembrane serine protease matriptase-2 : analysis of expression, activity modulation and enzyme-ligand interaction
Development of peptidomimetic substrates and inhibitors for transmembrane serine proteases
Pharmacoinformatics-based identification of transmembrane protease serine-2 inhibitors from Morus Alba as SARS-CoV-2 cell entry inhibitors
Epigenetic silencing of serine protease HTRA1 drives polyploidy
Granzyme H : a novel cell death inducing serine protease