دورية أكاديمية
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.
| العنوان: | 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. |
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| المؤلفون: | Sacramento CQ; Laboratorio de Vírus Respiratorios, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.; National Institute for Science and Technology on Innovation on Diseases of Neglected Populations (INCT/IDNP), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation, Rio de Janeiro, Rio de Janeiro, Brazil., Jordão AK; Laboratório de Síntese Orgânica, Programa de pós-Graduação em Química, Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil.; Unidade Universitária de Farmácia, Fundação Centro Universitário Estadual da Zona Oeste, Rio de Janeiro, Rio de Janeiro, Brazil., Abrantes JL; Instituto de Ciencias Biomedicas, Centro de Ciencias da Saude, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil., Alves CM; Laboratorio de Vírus Respiratorios, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil., Marttorelli A; Laboratorio de Vírus Respiratorios, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.; National Institute for Science and Technology on Innovation on Diseases of Neglected Populations (INCT/IDNP), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation, Rio de Janeiro, Rio de Janeiro, Brazil., Fintelman-Rodrigues N; Laboratorio de Vírus Respiratorios, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.; National Institute for Science and Technology on Innovation on Diseases of Neglected Populations (INCT/IDNP), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation, Rio de Janeiro, Rio de Janeiro, Brazil., de Freitas CS; Laboratorio de Vírus Respiratorios, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.; National Institute for Science and Technology on Innovation on Diseases of Neglected Populations (INCT/IDNP), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation, Rio de Janeiro, Rio de Janeiro, Brazil., de Melo GR; Laboratorio de Vírus Respiratorios, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.; National Institute for Science and Technology on Innovation on Diseases of Neglected Populations (INCT/IDNP), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation, Rio de Janeiro, Rio de Janeiro, Brazil., Cunha AC; Laboratório de Síntese Orgânica, Programa de pós-Graduação em Química, Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil., Ferreira VF; Laboratório de Síntese Orgânica, Programa de pós-Graduação em Química, Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil., Souza TML; Laboratorio de Vírus Respiratorios, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.; National Institute for Science and Technology on Innovation on Diseases of Neglected Populations (INCT/IDNP), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation, Rio de Janeiro, Rio de Janeiro, Brazil. |
| المصدر: | Current topics in medicinal chemistry [Curr Top Med Chem] 2020; Vol. 20 (2), pp. 132-139. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Bentham Science Publishers Country of Publication: United Arab Emirates NLM ID: 101119673 Publication Model: Print Cited Medium: Internet ISSN: 1873-4294 (Electronic) Linking ISSN: 15680266 NLM ISO Abbreviation: Curr Top Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Saif Zone, Sharjah, U.A.E. : Bentham Science Publishers Original Publication: Hilversum, The Netherlands : Bentham Science Publishers, c2001- |
| مواضيع طبية MeSH: | Antiviral Agents/*pharmacology , Enzyme Inhibitors/*pharmacology , Influenza A virus/*drug effects , Influenza B virus/*drug effects , Neuraminidase/*antagonists & inhibitors , Piperidines/*pharmacology , Thiazoles/*pharmacology , Triazoles/*pharmacology, Antiviral Agents/chemical synthesis ; Antiviral Agents/chemistry ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Influenza A virus/enzymology ; Influenza B virus/enzymology ; Microbial Sensitivity Tests ; Molecular Docking Simulation ; Molecular Structure ; Neuraminidase/metabolism ; Piperidines/chemical synthesis ; Piperidines/chemistry ; Structure-Activity Relationship ; Thiazoles/chemical synthesis ; Thiazoles/chemistry ; Triazoles/chemical synthesis ; Triazoles/chemistry |
| مستخلص: | 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 and 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. (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.) |
| فهرسة مساهمة: | Keywords: Hemagglutinin (HA); Influenza virus; Neuraminidase; Nitroxide radical; Oseltamivir-resistant; Triazolic compounds. |
| المشرفين على المادة: | 0 (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) EC 3.2.1.18 (Neuraminidase) |
| تواريخ الأحداث: | Date Created: 20191228 Date Completed: 20200420 Latest Revision: 20210709 |
| رمز التحديث: | 20221213 |
| DOI: | 10.2174/1568026620666191227142433 |
| PMID: | 31880262 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1873-4294 |
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| DOI: | 10.2174/1568026620666191227142433 |