Neuraminidase from Influenza A and B Viruses is Susceptible to the Compound 4-(4-Phenyl-1H-1,2,3-Triazol-1-yl)-2,2,6,6-Tetramethylpiperidine-1- Oxyl.
Antiviral Agents
/ chemical synthesis
Cell Survival
/ drug effects
Dose-Response Relationship, Drug
Enzyme Inhibitors
/ chemical synthesis
Influenza A virus
/ drug effects
Influenza B virus
/ drug effects
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Structure
Neuraminidase
/ antagonists & inhibitors
Piperidines
/ chemical synthesis
Structure-Activity Relationship
Thiazoles
/ chemical synthesis
Triazoles
/ chemical synthesis
Hemagglutinin
(HA)
Influenza virus
Neuraminidase
Nitroxide radical
Oseltamivir-resistant
Triazolic compounds.
Journal
Current topics in medicinal chemistry
ISSN: 1873-4294
Titre abrégé: Curr Top Med Chem
Pays: United Arab Emirates
ID NLM: 101119673
Informations de publication
Date de publication:
2020
2020
Historique:
received:
21
08
2019
revised:
13
11
2019
accepted:
29
11
2019
pubmed:
28
12
2019
medline:
21
4
2020
entrez:
28
12
2019
Statut:
ppublish
Résumé
Since the influenza virus is the main cause of acute seasonal respiratory infections and pandemic outbreaks, antiviral drugs are critical to mitigate infections and impair chain of transmission. Neuraminidase inhibitors (NAIs) are the main class of anti-influenza drugs in clinical use. Nevertheless, resistance to oseltamivir (OST), the most used NAI, has been detected in circulating strains of the influenza virus. Therefore, novel compounds with anti-influenza activity are necessary. To verify whether the NA from influenza A and B virus is susceptible to the compound 4-(4- phenyl-1H-1,2,3-triazol-1-yl)-2,2,6,6-tetramethylpiperidine-1-oxyl (Tritempo). Cell-free neuraminidase inhibition assays were performed with Tritempo, using wild-type (WT) and OST-resistant influenza strains. Cell-based assays in MDCKs were performed to confirm Tritempo`s antiviral activity and cytotoxicity. Multiple passages of the influenza virus in increasing concentrations of our compound, followed by the sequencing of NA gene and molecular docking, were used to identify our Tritempo's target. Indeed, Tritempo inhibited the neuraminidase activity of WT and OSTresistant strains of influenza A and B, at the nanomolar range. Tritempo bound to WT and OST-resistant influenza NA isoforms at the sialic acid binding site with low free binding energies. Cell-free assays were confirmed using a prototypic influenza A infection assay in MDCK cells, in which we found an EC50 of 0.38 µM, along with very low cytotoxicity, CC50 > 2,000 µM. When we passaged the influenza A virus in the presence of Tritempo, a mutant virus with the G248P change in the NA was detected. This mutant was resistant to Tritempo but remained sensitive to OST, indicating no cross-resistance between the studied and reference drugs. Our results suggest that Tritempo's chemical structure is a promising one for the development of novel antivirals against influenza.
Sections du résumé
BACKGROUND
BACKGROUND
Since the influenza virus is the main cause of acute seasonal respiratory infections and pandemic outbreaks, antiviral drugs are critical to mitigate infections and impair chain of transmission. Neuraminidase inhibitors (NAIs) are the main class of anti-influenza drugs in clinical use. Nevertheless, resistance to oseltamivir (OST), the most used NAI, has been detected in circulating strains of the influenza virus. Therefore, novel compounds with anti-influenza activity are necessary.
OBJECTIVE
OBJECTIVE
To verify whether the NA from influenza A and B virus is susceptible to the compound 4-(4- phenyl-1H-1,2,3-triazol-1-yl)-2,2,6,6-tetramethylpiperidine-1-oxyl (Tritempo).
METHODS
METHODS
Cell-free neuraminidase inhibition assays were performed with Tritempo, using wild-type (WT) and OST-resistant influenza strains. Cell-based assays in MDCKs were performed to confirm Tritempo`s antiviral activity and cytotoxicity. Multiple passages of the influenza virus in increasing concentrations of our compound, followed by the sequencing of NA gene and molecular docking, were used to identify our Tritempo's target.
RESULTS AND DISCUSSION
CONCLUSIONS
Indeed, Tritempo inhibited the neuraminidase activity of WT and OSTresistant strains of influenza A and B, at the nanomolar range. Tritempo bound to WT and OST-resistant influenza NA isoforms at the sialic acid binding site with low free binding energies. Cell-free assays were confirmed using a prototypic influenza A infection assay in MDCK cells, in which we found an EC50 of 0.38 µM, along with very low cytotoxicity, CC50 > 2,000 µM. When we passaged the influenza A virus in the presence of Tritempo, a mutant virus with the G248P change in the NA was detected. This mutant was resistant to Tritempo but remained sensitive to OST, indicating no cross-resistance between the studied and reference drugs.
CONCLUSION
CONCLUSIONS
Our results suggest that Tritempo's chemical structure is a promising one for the development of novel antivirals against influenza.
Identifiants
pubmed: 31880262
pii: CTMC-EPUB-103287
doi: 10.2174/1568026620666191227142433
doi:
Substances chimiques
4-(4-phenyl-1H-1,2,3-triazol-1-yl)-2,2,6,6-tetramethylpiperidine-1-oxyl
0
Antiviral Agents
0
Enzyme Inhibitors
0
Piperidines
0
Thiazoles
0
Triazoles
0
Neuraminidase
EC 3.2.1.18
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
132-139Informations de copyright
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