tetano
Editor, Senior Moderator
Antiviral Res. 2015 Nov 21. pii: S0166-3542(15)30026-7. doi: 10.1016/j.antiviral.2015.11.005. [Epub ahead of print]
[h=1]Identification of a small-molecule inhibitor of influenza virus via disrupting the subunits interaction of the viral polymerase.[/h] Yuan S[SUP]1[/SUP], Chu H[SUP]1[/SUP], Zhao H[SUP]1[/SUP], Zhang K[SUP]1[/SUP], Singh K[SUP]2[/SUP], Chow BK[SUP]2[/SUP], Kao RY[SUP]1[/SUP], Zhou J[SUP]3[/SUP], Zheng BJ[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Assembly of the heterotrimeric influenza virus polymerase complex from the individual subunits PB1, PA, and PB2 is a prerequisite for viral replication, in which the interaction between the C terminal of PA (PA[SUB]C[/SUB]) and the N-terminal of PB1 (PB1[SUB]N[/SUB]) may be a desired target for antiviral development. In this study, we compared the feasibility of high throughput screening by enzyme-linked immunosorbent assay (ELISA) and fluorescence polarization assay. Among the two, ELISA was demonstrated to own broader dynamic range so that it was used for screening inhibitors that blocked PA[SUB]C[/SUB] and PB1[SUB]N[/SUB] interaction. Several binding inhibitors of PA[SUB]C[/SUB]-PB1[SUB]N[/SUB] were identified and subsequently tested for the antiviral efficacy. Apparently, 3-(2-chlorophenyl)-6-ethyl-7-methyl[1,2,4]triazolo[4,3-a]pyrimidin-5-ol, designated ANA-1, was found to be a strong inhibitor of viral polymerase activity and act as a potent antiviral agent against the infections of multiple subtypes of influenza A virus, including H1N1, H3N2, H5N1, H7N7, H7N9 and H9N2 subtypes, in cell cultures. Intranasal administration of ANA-1 protected mice from lethal challenge and reduced lung viral loads in H1N1 virus infected BALB/c mice. Docking analyses predicted that ANA-1 bound to an allosteric site of PA[SUB]C[/SUB], which might cause conformational changes thereby disrupting the PA[SUB]C[/SUB]-PB1[SUB]N[/SUB] interaction. Overall, our study has identified a novel compound with potential to be developed as an anti-influenza drug.
Copyright ? 2015. Published by Elsevier B.V.
PMID: 26593979 [PubMed - as supplied by publisher]
[h=1]Identification of a small-molecule inhibitor of influenza virus via disrupting the subunits interaction of the viral polymerase.[/h] Yuan S[SUP]1[/SUP], Chu H[SUP]1[/SUP], Zhao H[SUP]1[/SUP], Zhang K[SUP]1[/SUP], Singh K[SUP]2[/SUP], Chow BK[SUP]2[/SUP], Kao RY[SUP]1[/SUP], Zhou J[SUP]3[/SUP], Zheng BJ[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Assembly of the heterotrimeric influenza virus polymerase complex from the individual subunits PB1, PA, and PB2 is a prerequisite for viral replication, in which the interaction between the C terminal of PA (PA[SUB]C[/SUB]) and the N-terminal of PB1 (PB1[SUB]N[/SUB]) may be a desired target for antiviral development. In this study, we compared the feasibility of high throughput screening by enzyme-linked immunosorbent assay (ELISA) and fluorescence polarization assay. Among the two, ELISA was demonstrated to own broader dynamic range so that it was used for screening inhibitors that blocked PA[SUB]C[/SUB] and PB1[SUB]N[/SUB] interaction. Several binding inhibitors of PA[SUB]C[/SUB]-PB1[SUB]N[/SUB] were identified and subsequently tested for the antiviral efficacy. Apparently, 3-(2-chlorophenyl)-6-ethyl-7-methyl[1,2,4]triazolo[4,3-a]pyrimidin-5-ol, designated ANA-1, was found to be a strong inhibitor of viral polymerase activity and act as a potent antiviral agent against the infections of multiple subtypes of influenza A virus, including H1N1, H3N2, H5N1, H7N7, H7N9 and H9N2 subtypes, in cell cultures. Intranasal administration of ANA-1 protected mice from lethal challenge and reduced lung viral loads in H1N1 virus infected BALB/c mice. Docking analyses predicted that ANA-1 bound to an allosteric site of PA[SUB]C[/SUB], which might cause conformational changes thereby disrupting the PA[SUB]C[/SUB]-PB1[SUB]N[/SUB] interaction. Overall, our study has identified a novel compound with potential to be developed as an anti-influenza drug.
Copyright ? 2015. Published by Elsevier B.V.
PMID: 26593979 [PubMed - as supplied by publisher]