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Article: Identification of a small-molecule inhibitor of influenza virus via disrupting the subunits interaction of the viral polymerase

TitleIdentification of a small-molecule inhibitor of influenza virus via disrupting the subunits interaction of the viral polymerase
Authors
KeywordsAnti-influenza
Cross-protection
Polymerase assembly
Issue Date2016
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/antiviral
Citation
Antiviral Research, 2016, v. 125, p. 34-42 How to Cite?
AbstractAssembly 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 (PAC) and the N-terminal of PB1 (PB1N) 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 PAC and PB1N interaction. Several binding inhibitors of PAC-PB1N 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 PAC, which might cause conformational changes thereby disrupting the PAC-PB1N interaction. Overall, our study has identified a novel compound with potential to be developed as an anti-influenza drug.
Persistent Identifierhttp://hdl.handle.net/10722/232880
ISSN
2020 Impact Factor: 5.97
2020 SCImago Journal Rankings: 2.052
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYuan, S-
dc.contributor.authorChu, H-
dc.contributor.authorZhao, H-
dc.contributor.authorZhang, K-
dc.contributor.authorSingh, K-
dc.contributor.authorChow, BKC-
dc.contributor.authorKao, RYT-
dc.contributor.authorZhou, J-
dc.contributor.authorZheng, B-
dc.date.accessioned2016-09-20T05:33:07Z-
dc.date.available2016-09-20T05:33:07Z-
dc.date.issued2016-
dc.identifier.citationAntiviral Research, 2016, v. 125, p. 34-42-
dc.identifier.issn0166-3542-
dc.identifier.urihttp://hdl.handle.net/10722/232880-
dc.description.abstractAssembly 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 (PAC) and the N-terminal of PB1 (PB1N) 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 PAC and PB1N interaction. Several binding inhibitors of PAC-PB1N 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 PAC, which might cause conformational changes thereby disrupting the PAC-PB1N interaction. Overall, our study has identified a novel compound with potential to be developed as an anti-influenza drug.-
dc.languageeng-
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/antiviral-
dc.relation.ispartofAntiviral Research-
dc.subjectAnti-influenza-
dc.subjectCross-protection-
dc.subjectPolymerase assembly-
dc.titleIdentification of a small-molecule inhibitor of influenza virus via disrupting the subunits interaction of the viral polymerase-
dc.typeArticle-
dc.identifier.emailYuan, S: yuansf@hku.hk-
dc.identifier.emailChu, H: hinchu@hku.hk-
dc.identifier.emailZhao, H: hjzhao13@hku.hk-
dc.identifier.emailZhang, K: kezhang1@hku.hk-
dc.identifier.emailChow, BKC: bkcc@hku.hk-
dc.identifier.emailKao, RYT: rytkao@hkucc.hku.hk-
dc.identifier.emailZhou, J: jiezhou@hku.hk-
dc.identifier.emailZheng, B: bzheng@hkucc.hku.hk-
dc.identifier.authorityYuan, S=rp02640-
dc.identifier.authorityChu, H=rp02125-
dc.identifier.authorityChow, BKC=rp00681-
dc.identifier.authorityKao, RYT=rp00481-
dc.identifier.authorityZhou, J=rp01412-
dc.identifier.authorityZheng, B=rp00353-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.antiviral.2015.11.005-
dc.identifier.pmid26593979-
dc.identifier.scopuseid_2-s2.0-84948397146-
dc.identifier.hkuros263805-
dc.identifier.volume125-
dc.identifier.spage34-
dc.identifier.epage42-
dc.identifier.isiWOS:000369203900005-
dc.publisher.placeNetherlands-
dc.identifier.issnl0166-3542-

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