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
| Autor: | Caroline S. de Freitas, Andressa Marttorelli, Juliana L. Abrantes, Vitor F. Ferreira, Anna C. Cunha, Gabrielle R. de Melo, Carolina Q. Sacramento, Alessandro K. Jordão, Thiago Moreno L. Souza, Cristiane M. Alves, Natalia Fintelman-Rodrigues |
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| Rok vydání: | 2019 |
| Předmět: |
Oseltamivir
Cell Survival Mutant Neuraminidase Sialic acid binding Microbial Sensitivity Tests medicine.disease_cause 01 natural sciences Antiviral Agents Virus 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Piperidines Drug Discovery Influenza A virus medicine Enzyme Inhibitors Cytotoxicity 030304 developmental biology EC50 0303 health sciences biology Dose-Response Relationship Drug Molecular Structure Chemistry General Medicine Triazoles Virology 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Influenza B virus Thiazoles biology.protein |
| Zdroj: | Current topics in medicinal chemistry. 20(2) |
| ISSN: | 1873-4294 |
| Popis: | 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: 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: 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/Discussion: 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: Our results suggest that Tritempo’s chemical structure is a promising one for the development of novel antivirals against influenza. |
| Databáze: | OpenAIRE |
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