tetano
Editor, Senior Moderator
Antiviral Res. 2016 Nov 10. pii: S0166-3542(16)30372-2. doi: 10.1016/j.antiviral.2016.11.005. [Epub ahead of print]
[h=1]Identification of a novel small-molecule compound targeting the influenza A virus polymerase PB1-PB2 interface.[/h] Yuan S[SUP]1[/SUP], Chu H[SUP]1[/SUP], Ye J[SUP]1[/SUP], Singh K[SUP]2[/SUP], Ye Z[SUP]1[/SUP], Zhao H[SUP]1[/SUP], Kao RY[SUP]1[/SUP], Chow BK[SUP]2[/SUP], Zhou J[SUP]3[/SUP], Zheng BJ[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] The PB1 C-terminal domain and PB2 N-terminal domain interaction of the influenza A polymerase, which modulates the assembly of PB1 and PB2 subunits, may serve as a valuable target for the development of novel anti-influenza therapeutics. In this study, we performed a systematic screening of a chemical library, followed by the antiviral evaluation of primary hits and their analogues. Eventually, a novel small-molecule compound PP7 that abrogated the PB1-PB2 association and impaired viral polymerase activity was identified. PP7 exhibited antiviral activities against influenza virus subtypes A (H1N1)pdm09, A(H7N9) and A(H9N2) in cell cultures and partially protected mice against lethal challenge of mouse-adapted influenza A (H1N1)pdm09 virus. Surprisingly, a panel of other subtypes of influenza virus, including A(H5N1) and A(H7N7), showed various degrees of resistance to the compound. Biochemical studies revealed a similar pattern of resistance on the impairment of polymerase activity. Molecular docking analyses suggested a PP7-binding site that appeared to be completely conserved among the subtypes of the virus mentioned above. Thus, we propose that alternative/additional binding site (s) may exist for the regulation of PB1-PB2 subunits assembly of influenza A virus.
Copyright ? 2016. Published by Elsevier B.V.
PMID: 27840201 DOI: 10.1016/j.antiviral.2016.11.005
[PubMed - as supplied by publisher]
[h=1]Identification of a novel small-molecule compound targeting the influenza A virus polymerase PB1-PB2 interface.[/h] Yuan S[SUP]1[/SUP], Chu H[SUP]1[/SUP], Ye J[SUP]1[/SUP], Singh K[SUP]2[/SUP], Ye Z[SUP]1[/SUP], Zhao H[SUP]1[/SUP], Kao RY[SUP]1[/SUP], Chow BK[SUP]2[/SUP], Zhou J[SUP]3[/SUP], Zheng BJ[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] The PB1 C-terminal domain and PB2 N-terminal domain interaction of the influenza A polymerase, which modulates the assembly of PB1 and PB2 subunits, may serve as a valuable target for the development of novel anti-influenza therapeutics. In this study, we performed a systematic screening of a chemical library, followed by the antiviral evaluation of primary hits and their analogues. Eventually, a novel small-molecule compound PP7 that abrogated the PB1-PB2 association and impaired viral polymerase activity was identified. PP7 exhibited antiviral activities against influenza virus subtypes A (H1N1)pdm09, A(H7N9) and A(H9N2) in cell cultures and partially protected mice against lethal challenge of mouse-adapted influenza A (H1N1)pdm09 virus. Surprisingly, a panel of other subtypes of influenza virus, including A(H5N1) and A(H7N7), showed various degrees of resistance to the compound. Biochemical studies revealed a similar pattern of resistance on the impairment of polymerase activity. Molecular docking analyses suggested a PP7-binding site that appeared to be completely conserved among the subtypes of the virus mentioned above. Thus, we propose that alternative/additional binding site (s) may exist for the regulation of PB1-PB2 subunits assembly of influenza A virus.
Copyright ? 2016. Published by Elsevier B.V.
PMID: 27840201 DOI: 10.1016/j.antiviral.2016.11.005
[PubMed - as supplied by publisher]