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Article: A novel small-molecule inhibitor of influenza A virus acts by suppressing PA endonuclease activity of the viral polymerase

TitleA novel small-molecule inhibitor of influenza A virus acts by suppressing PA endonuclease activity of the viral polymerase
Authors
Issue Date2016
PublisherNature Publishing Group: Open Access Journals. The Journal's web site is located at http://www.nature.com/srep/index.html
Citation
Scientific Reports, 2016, v. 6, article no. 22880 How to Cite?
AbstractThe RNA-dependent RNA polymerase of influenza A virus comprises conserved and independently-folded subdomains with defined functionalities. The N-terminal domain of the PA subunit (PAN) harbors the endonuclease function so that it can serve as a desired target for drug discovery. To identify a class of anti-influenza inhibitors that impedes PAN endonuclease activity, a screening approach that integrated the fluorescence resonance energy transfer based endonuclease inhibitory assay with the DNA gel-based endonuclease inhibitory assay was conducted, followed by the evaluation of antiviral efficacies and potential cytotoxicity of the primary hits in vitro and in vivo. A small-molecule compound ANA-0 was identified as a potent inhibitor against the replication of multiple subtypes of influenza A virus, including H1N1, H3N2, H5N1, H7N7, H7N9 and H9N2, in cell cultures. Combinational treatment of zanamivir and ANA-0 exerted synergistic anti-influenza effect in vitro. Intranasal administration of ANA-0 protected mice from lethal challenge and reduced lung viral loads in H1N1 virus infected BALB/c mice. In summary, ANA-0 shows potential to be developed to novel anti-influenza agents.
Persistent Identifierhttp://hdl.handle.net/10722/232881
ISSN
2020 Impact Factor: 4.379
2020 SCImago Journal Rankings: 1.240
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYuan, S-
dc.contributor.authorChu, H-
dc.contributor.authorSingh, K-
dc.contributor.authorZhao, H-
dc.contributor.authorZhang, K-
dc.contributor.authorKao, RYT-
dc.contributor.authorChow, BKC-
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.citationScientific Reports, 2016, v. 6, article no. 22880-
dc.identifier.issn2045-2322-
dc.identifier.urihttp://hdl.handle.net/10722/232881-
dc.description.abstractThe RNA-dependent RNA polymerase of influenza A virus comprises conserved and independently-folded subdomains with defined functionalities. The N-terminal domain of the PA subunit (PAN) harbors the endonuclease function so that it can serve as a desired target for drug discovery. To identify a class of anti-influenza inhibitors that impedes PAN endonuclease activity, a screening approach that integrated the fluorescence resonance energy transfer based endonuclease inhibitory assay with the DNA gel-based endonuclease inhibitory assay was conducted, followed by the evaluation of antiviral efficacies and potential cytotoxicity of the primary hits in vitro and in vivo. A small-molecule compound ANA-0 was identified as a potent inhibitor against the replication of multiple subtypes of influenza A virus, including H1N1, H3N2, H5N1, H7N7, H7N9 and H9N2, in cell cultures. Combinational treatment of zanamivir and ANA-0 exerted synergistic anti-influenza effect in vitro. Intranasal administration of ANA-0 protected mice from lethal challenge and reduced lung viral loads in H1N1 virus infected BALB/c mice. In summary, ANA-0 shows potential to be developed to novel anti-influenza agents.-
dc.languageeng-
dc.publisherNature Publishing Group: Open Access Journals. The Journal's web site is located at http://www.nature.com/srep/index.html-
dc.relation.ispartofScientific Reports-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleA novel small-molecule inhibitor of influenza A virus acts by suppressing PA endonuclease activity 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.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.authorityYuan, S=rp02640-
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.naturepublished_or_final_version-
dc.identifier.doi10.1038/srep22880-
dc.identifier.pmid26956222-
dc.identifier.pmcidPMC4783701-
dc.identifier.scopuseid_2-s2.0-84960487693-
dc.identifier.hkuros263807-
dc.identifier.volume6-
dc.identifier.spagearticle no. 22880-
dc.identifier.epagearticle no. 22880-
dc.identifier.isiWOS:000372025800001-
dc.publisher.placeUnited Kingdom-
dc.identifier.issnl2045-2322-

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