Journal
ANTIVIRAL RESEARCH
Volume 125, Issue -, Pages 34-42Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.antiviral.2015.11.005
Keywords
Anti-influenza; Cross-protection; Polymerase assembly
Categories
Funding
- Innovation and Technology Commission, Government of Hong Kong SAR [UIM/278]
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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(C)) and the N-terminal of PB1 (PB1(N)) 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(C) and PB1(N) interaction. Several binding inhibitors of PA(C)-PB1(N) were identified and subsequently tested for the antiviral efficacy. Apparently, 3-(2-chloropheny1)-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(C), which might cause conformational changes thereby disrupting the PA(C)-PB1(N) interaction. Overall, our study has identified a novel compound with potential to be developed as an anti influenza drug. (C) 2015 Elsevier B.V. All rights reserved.
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