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Article: Identification of a novel small-molecule compound targeting the influenza A virus polymerase PB1-PB2 interface

TitleIdentification of a novel small-molecule compound targeting the influenza A virus polymerase PB1-PB2 interface
Authors
Issue Date2017
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/antiviral
Citation
Antiviral Research, 2017, v. 137, p. 58-66 How to Cite?
AbstractThe 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.
Persistent Identifierhttp://hdl.handle.net/10722/238681
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.authorYe, J-
dc.contributor.authorSingh, K-
dc.contributor.authorYe, Z-
dc.contributor.authorZhao, H-
dc.contributor.authorKao, RYT-
dc.contributor.authorChow, BKC-
dc.contributor.authorZhou, J-
dc.contributor.authorZheng, B-
dc.date.accessioned2017-02-20T01:24:41Z-
dc.date.available2017-02-20T01:24:41Z-
dc.date.issued2017-
dc.identifier.citationAntiviral Research, 2017, v. 137, p. 58-66-
dc.identifier.issn0166-3542-
dc.identifier.urihttp://hdl.handle.net/10722/238681-
dc.description.abstractThe 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.-
dc.languageeng-
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/antiviral-
dc.relation.ispartofAntiviral Research-
dc.titleIdentification of a novel small-molecule compound targeting the influenza A virus polymerase PB1-PB2 interface-
dc.typeArticle-
dc.identifier.emailYuan, S: yuansf@hku.hk-
dc.identifier.emailChu, H: hinchu@hku.hk-
dc.identifier.emailYe, J: yejiahui@hku.hk-
dc.identifier.emailYe, Z: zwye@hku.hk-
dc.identifier.emailZhao, H: hjzhao13@hku.hk-
dc.identifier.emailKao, RYT: rytkao@hkucc.hku.hk-
dc.identifier.emailChow, BKC: bkcc@hku.hk-
dc.identifier.emailZhou, J: jiezhou@hku.hk-
dc.identifier.emailZheng, B: bzheng@hkucc.hku.hk-
dc.identifier.authorityChu, H=rp02125-
dc.identifier.authorityKao, RYT=rp00481-
dc.identifier.authorityChow, BKC=rp00681-
dc.identifier.authorityZhou, J=rp01412-
dc.identifier.authorityZheng, B=rp00353-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.antiviral.2016.11.005-
dc.identifier.pmid27840201-
dc.identifier.scopuseid_2-s2.0-84995957135-
dc.identifier.hkuros271253-
dc.identifier.volume137-
dc.identifier.spage58-
dc.identifier.epage66-
dc.identifier.isiWOS:000393005300007-
dc.publisher.placeNetherlands-
dc.identifier.issnl0166-3542-

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