tetano
Editor, Senior Moderator
nt J Mol Sci. 2019 Dec 12;20(24). pii: E6261. doi: 10.3390/ijms20246261. [h=1]Antiviral Activity of Benzoic Acid Derivative NC-5 Against Influenza A Virus and Its Neuraminidase Inhibition.[/h]
Guo M[SUP]1[/SUP], Ni J[SUP]1[/SUP], Yu J[SUP]1[/SUP], Jin J[SUP]1[/SUP], Ma L[SUP]1[/SUP], Zhang H[SUP]2[/SUP], Wang D[SUP]2[/SUP], Zhang X[SUP]1[/SUP], Dou J[SUP]1[/SUP], Zhou C[SUP]1[/SUP].
[h=3]Author information[/h] 1 State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, Jiangsu, China. 2 Department of Organic Chemistry, School of Science, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, Jiangsu, China.
[h=3]Abstract[/h] The currently available drugs against influenza A virus primarily target neuraminidase (NA) or the matrix protein 2 (M2) ion channel. The emergence of drug-resistant viruses requires the development of new antiviral chemicals. Our study applied a cell-based approach to evaluate the antiviral activity of a series of newly synthesized benzoic acid derivatives, and 4-(2,2-Bis(hydroxymethyl)-5-oxopyrrolidin-l-yl)-3-(5-cyclohexyl-4H-1,2,4-triazol-3-yl)amino). benzoic acid, termed NC-5, was found to possess antiviral activity. NC-5 inhibited influenza A viruses A/FM/1/47 (H1N1), A/Beijing/32/92 (H3N2) and oseltamivir-resistant mutant A/FM/1/47-H275Y (H1N1-H275Y) in a dose-dependent manner. The 50% effective concentrations (EC[SUB]50[/SUB]) for H1N1 and H1N1-H275Y were 33.6 μM and 32.8 μM, respectively, which showed that NC-5 had a great advantage over oseltamivir in drug-resistant virus infections. The 50% cytotoxic concentration (CC[SUB]50[/SUB]) of NC-5 was greater than 640 μM. Orally administered NC-5 protected mice infected with H1N1 and H1N1-H275Y, conferring 80% and 60% survival at 100 mg/kg/d, reducing body weight loss, and alleviating virus-induced lung injury. NC-5 could suppress NP and M1 protein expression levels during the late stages of viral biosynthesis and inhibit NA activity, which may influence virus release. Our study proved that NC-5 has potent anti-influenza activity in vivo and in vitro, meaning that it could be regarded as a promising drug candidate to treat infection with influenza viruses, including oseltamivir-resistant viruses.
[h=4]KEYWORDS:[/h] antiviral activity; benzoic acid derivatives; neuraminidase inhibition; oseltamivir-resistant
PMID: 31842256 DOI: 10.3390/ijms20246261
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Guo M[SUP]1[/SUP], Ni J[SUP]1[/SUP], Yu J[SUP]1[/SUP], Jin J[SUP]1[/SUP], Ma L[SUP]1[/SUP], Zhang H[SUP]2[/SUP], Wang D[SUP]2[/SUP], Zhang X[SUP]1[/SUP], Dou J[SUP]1[/SUP], Zhou C[SUP]1[/SUP].
[h=3]Author information[/h] 1 State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, Jiangsu, China. 2 Department of Organic Chemistry, School of Science, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, Jiangsu, China.
[h=3]Abstract[/h] The currently available drugs against influenza A virus primarily target neuraminidase (NA) or the matrix protein 2 (M2) ion channel. The emergence of drug-resistant viruses requires the development of new antiviral chemicals. Our study applied a cell-based approach to evaluate the antiviral activity of a series of newly synthesized benzoic acid derivatives, and 4-(2,2-Bis(hydroxymethyl)-5-oxopyrrolidin-l-yl)-3-(5-cyclohexyl-4H-1,2,4-triazol-3-yl)amino). benzoic acid, termed NC-5, was found to possess antiviral activity. NC-5 inhibited influenza A viruses A/FM/1/47 (H1N1), A/Beijing/32/92 (H3N2) and oseltamivir-resistant mutant A/FM/1/47-H275Y (H1N1-H275Y) in a dose-dependent manner. The 50% effective concentrations (EC[SUB]50[/SUB]) for H1N1 and H1N1-H275Y were 33.6 μM and 32.8 μM, respectively, which showed that NC-5 had a great advantage over oseltamivir in drug-resistant virus infections. The 50% cytotoxic concentration (CC[SUB]50[/SUB]) of NC-5 was greater than 640 μM. Orally administered NC-5 protected mice infected with H1N1 and H1N1-H275Y, conferring 80% and 60% survival at 100 mg/kg/d, reducing body weight loss, and alleviating virus-induced lung injury. NC-5 could suppress NP and M1 protein expression levels during the late stages of viral biosynthesis and inhibit NA activity, which may influence virus release. Our study proved that NC-5 has potent anti-influenza activity in vivo and in vitro, meaning that it could be regarded as a promising drug candidate to treat infection with influenza viruses, including oseltamivir-resistant viruses.
[h=4]KEYWORDS:[/h] antiviral activity; benzoic acid derivatives; neuraminidase inhibition; oseltamivir-resistant
PMID: 31842256 DOI: 10.3390/ijms20246261
Free full text