Optimization of Ketobenzothiazole-Based Type II Transmembrane Serine Protease Inhibitors to Block H1N1 Influenza Virus Replication
© 2023 The Authors. ChemMedChem published by Wiley-VCH GmbH..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
|---|---|
| Enthalten in: |
ChemMedChem - 19(2024), 2 vom: 15. Jan., Seite e202300458 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Colombo, Éloïc [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 18.01.2024 Date Revised 26.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1002/cmdc.202300458 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM363568972 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM363568972 | ||
| 003 | DE-627 | ||
| 005 | 20240327235353.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1002/cmdc.202300458 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1350.xml |
| 035 | |a (DE-627)NLM363568972 | ||
| 035 | |a (NLM)37864572 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Colombo, Éloïc |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Optimization of Ketobenzothiazole-Based Type II Transmembrane Serine Protease Inhibitors to Block H1N1 Influenza Virus Replication |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 18.01.2024 | ||
| 500 | |a Date Revised 26.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors. ChemMedChem published by Wiley-VCH GmbH. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Antiviral agents | |
| 650 | 4 | |a influenza | |
| 650 | 4 | |a inhibitors | |
| 650 | 4 | |a matriptase | |
| 650 | 4 | |a type II transmembrane serine protease (TTSP) | |
| 650 | 7 | |a Serine Proteinase Inhibitors |2 NLM | |
| 650 | 7 | |a Serine Proteases |2 NLM | |
| 650 | 7 | |a EC 3.4.- |2 NLM | |
| 650 | 7 | |a Protease Inhibitors |2 NLM | |
| 700 | 1 | |a Désilets, Antoine |e verfasserin |4 aut | |
| 700 | 1 | |a Hassanzadeh, Malihe |e verfasserin |4 aut | |
| 700 | 1 | |a Lemieux, Gabriel |e verfasserin |4 aut | |
| 700 | 1 | |a Marois, Isabelle |e verfasserin |4 aut | |
| 700 | 1 | |a Cliche, Dominic |e verfasserin |4 aut | |
| 700 | 1 | |a Delbrouck, Julien A |e verfasserin |4 aut | |
| 700 | 1 | |a Murza, Alexandre |e verfasserin |4 aut | |
| 700 | 1 | |a Jean, François |e verfasserin |4 aut | |
| 700 | 1 | |a Marsault, Eric |e verfasserin |4 aut | |
| 700 | 1 | |a Richter, Martin V |e verfasserin |4 aut | |
| 700 | 1 | |a Leduc, Richard |e verfasserin |4 aut | |
| 700 | 1 | |a Boudreault, Pierre-Luc |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t ChemMedChem |d 2006 |g 19(2024), 2 vom: 15. Jan., Seite e202300458 |w (DE-627)NLM164619577 |x 1860-7187 |7 nnns |
| 773 | 1 | 8 | |g volume:19 |g year:2024 |g number:2 |g day:15 |g month:01 |g pages:e202300458 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1002/cmdc.202300458 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 19 |j 2024 |e 2 |b 15 |c 01 |h e202300458 | ||