tetano
Editor, Senior Moderator
Curr Top Med Chem. 2019 Dec 27. doi: 10.2174/1568026620666191227142433. [Epub ahead of print] [h=1]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.[/h]
Sacramento CQ[SUP]1[/SUP], Jord?o AK[SUP]2[/SUP], Abrantes JL[SUP]3[/SUP], Alves CM[SUP]4[/SUP], Marttorelli A[SUP]4[/SUP], Fintelman-Rodrigues N[SUP]4[/SUP], de Freitas CS[SUP]4[/SUP], de Melo GR[SUP]4[/SUP], Cunha AC[SUP]2[/SUP], Ferreira VF[SUP]2[/SUP], Souza TML[SUP]4[/SUP].
[h=3]Author information[/h] 1 Laborat?rio de V?rus Respirat?rios, Instituto Oswaldo Cruz, Funda??o Oswaldo Cruz,Rio de Janeiro. Brazil. 2 Laborat?rio de S?ntese Org?nica, Programa de p?s-Gradua??o em Qu?mica, Departamento de Qu?mica Org?nica, Instituto de Qu?mica, Universidade Federal Fluminense, Niter?i, Rio de Janeiro. Brazil. 3 Instituto de Ci?ncias Biom?dicas, Centro de Ci?ncias da Sa?de, Universidade Federal do Rio de Janeiro, Rio de Janeiro. Brazil. 4 Laborat?rio de V?rus Respirat?rios, Instituto Oswaldo Cruz, Funda??o Oswaldo Cruz, Rio de Janeiro. Brazil.
[h=3]Abstract[/h] [h=4]BACKGROUND:[/h] Since 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 influenza virus. Therefore, novel compounds with anti-influenza activity are necessary.
[h=4]OBJECTIVE:[/h] To verify whether the NA from influenza A and B virus is susceptibility to the compound 4-(4-phenyl-1H-1,2,3-triazol-1-yl)-2,2,6,6-tetramethylpiperidine-1-oxyl (Tritempo).
[h=4]METHODS:[/h] 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 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.
[h=4]RESULTS/DISCUSSION:[/h] Indeed, tritempo inhibited the neuraminidase activity of WT and OST-resistant 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 ?M, along with very low cytotoxicity, CC50 > 2,000 ?M. When we passaged influenza A virus was 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.
[h=4]CONCLUSION:[/h] Our results suggest that Tritempo's chemical structure is a promising one to the development of novel antivirals against influenza.
Copyright? Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
[h=4]KEYWORDS:[/h] Influenza Virus; Neuraminidase; Nitroxide Radical; Oseltamivir-Resistant; Triazolic Compounds
PMID: 31880262 DOI: 10.2174/1568026620666191227142433
Sacramento CQ[SUP]1[/SUP], Jord?o AK[SUP]2[/SUP], Abrantes JL[SUP]3[/SUP], Alves CM[SUP]4[/SUP], Marttorelli A[SUP]4[/SUP], Fintelman-Rodrigues N[SUP]4[/SUP], de Freitas CS[SUP]4[/SUP], de Melo GR[SUP]4[/SUP], Cunha AC[SUP]2[/SUP], Ferreira VF[SUP]2[/SUP], Souza TML[SUP]4[/SUP].
[h=3]Author information[/h] 1 Laborat?rio de V?rus Respirat?rios, Instituto Oswaldo Cruz, Funda??o Oswaldo Cruz,Rio de Janeiro. Brazil. 2 Laborat?rio de S?ntese Org?nica, Programa de p?s-Gradua??o em Qu?mica, Departamento de Qu?mica Org?nica, Instituto de Qu?mica, Universidade Federal Fluminense, Niter?i, Rio de Janeiro. Brazil. 3 Instituto de Ci?ncias Biom?dicas, Centro de Ci?ncias da Sa?de, Universidade Federal do Rio de Janeiro, Rio de Janeiro. Brazil. 4 Laborat?rio de V?rus Respirat?rios, Instituto Oswaldo Cruz, Funda??o Oswaldo Cruz, Rio de Janeiro. Brazil.
[h=3]Abstract[/h] [h=4]BACKGROUND:[/h] Since 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 influenza virus. Therefore, novel compounds with anti-influenza activity are necessary.
[h=4]OBJECTIVE:[/h] To verify whether the NA from influenza A and B virus is susceptibility to the compound 4-(4-phenyl-1H-1,2,3-triazol-1-yl)-2,2,6,6-tetramethylpiperidine-1-oxyl (Tritempo).
[h=4]METHODS:[/h] 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 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.
[h=4]RESULTS/DISCUSSION:[/h] Indeed, tritempo inhibited the neuraminidase activity of WT and OST-resistant 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 ?M, along with very low cytotoxicity, CC50 > 2,000 ?M. When we passaged influenza A virus was 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.
[h=4]CONCLUSION:[/h] Our results suggest that Tritempo's chemical structure is a promising one to the development of novel antivirals against influenza.
Copyright? Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
[h=4]KEYWORDS:[/h] Influenza Virus; Neuraminidase; Nitroxide Radical; Oseltamivir-Resistant; Triazolic Compounds
PMID: 31880262 DOI: 10.2174/1568026620666191227142433