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Article: A novel small-molecule compound disrupts influenza A virus PB2 cap-binding and inhibits viral replication

TitleA novel small-molecule compound disrupts influenza A virus PB2 cap-binding and inhibits viral replication
Authors
Issue Date2016
PublisherOxford University Press. The Journal's web site is located at http://jac.oxfordjournals.org/
Citation
Journal of Antimicrobial Chemotherapy, 2016, v. 71 n. 9, p. 2489-2497 How to Cite?
AbstractObjectives: The conserved residues 318–483 in the PB2 subunit of influenza A polymerase is an independently folded cap-binding domain (PB2cap) that exhibits a distinct binding mode from other host cap-binding proteins, which suggests that PB2cap might be an ideal drug target. This study aimed to identify a new class of anti-influenza inhibitors that specifically disrupts the interaction between PB2cap and host cap structures. Methods: An innovative fluorescence polarization assay was established for primary screening, followed by cap-binding inhibitory activity, antiviral efficacy and cytotoxicity evaluations of the selected compounds. The best compound was characterized by multi-cycle virus growth assay, cross-protection test, synergism evaluation, mini-replicon assay, binding affinity analysis, docking simulation and mouse study. Results: Several PB2 cap-binding inhibitors were discovered. The compound 7-(4-hydroxy-2-oxo-2H-chromen-3-yl)-6H,7H,8H-chromeno[3′,4′:5,6]pyrano[3,2-c]chromene-6,8-dione, designated PB2-39, was identified as a potent inhibitor of replication of multiple subtypes of influenza A virus, including H1N1, H3N2, H5N1, H7N7, H7N9 and H9N2 in vitro and H1N1, H5N1 and H7N9 in vivo. Combinational treatment with the influenza virus release inhibitor zanamivir and PB2-39 exerted a synergistic anti-influenza effect. Mechanistic experiments supported that PB2-39 suppressed viral polymerase activity. Docking and binding affinity analyses demonstrated that PB2-39 interacted with the PB2 cap-binding pocket, suggesting its role as a cap-binding competitor. Conclusions: Our study provides new insights for the strategic development of novel cap-binding inhibitors of influenza A viruses.
Persistent Identifierhttp://hdl.handle.net/10722/232875
ISSN
2020 Impact Factor: 5.79
2020 SCImago Journal Rankings: 2.124
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYuan, S-
dc.contributor.authorChu, H-
dc.contributor.authorZhang, K-
dc.contributor.authorYe, J-
dc.contributor.authorSingh, K-
dc.contributor.authorKao, RYT-
dc.contributor.authorChow, BKC-
dc.contributor.authorZhou, J-
dc.contributor.authorZheng, B-
dc.date.accessioned2016-09-20T05:33:05Z-
dc.date.available2016-09-20T05:33:05Z-
dc.date.issued2016-
dc.identifier.citationJournal of Antimicrobial Chemotherapy, 2016, v. 71 n. 9, p. 2489-2497-
dc.identifier.issn0305-7453-
dc.identifier.urihttp://hdl.handle.net/10722/232875-
dc.description.abstractObjectives: The conserved residues 318–483 in the PB2 subunit of influenza A polymerase is an independently folded cap-binding domain (PB2cap) that exhibits a distinct binding mode from other host cap-binding proteins, which suggests that PB2cap might be an ideal drug target. This study aimed to identify a new class of anti-influenza inhibitors that specifically disrupts the interaction between PB2cap and host cap structures. Methods: An innovative fluorescence polarization assay was established for primary screening, followed by cap-binding inhibitory activity, antiviral efficacy and cytotoxicity evaluations of the selected compounds. The best compound was characterized by multi-cycle virus growth assay, cross-protection test, synergism evaluation, mini-replicon assay, binding affinity analysis, docking simulation and mouse study. Results: Several PB2 cap-binding inhibitors were discovered. The compound 7-(4-hydroxy-2-oxo-2H-chromen-3-yl)-6H,7H,8H-chromeno[3′,4′:5,6]pyrano[3,2-c]chromene-6,8-dione, designated PB2-39, was identified as a potent inhibitor of replication of multiple subtypes of influenza A virus, including H1N1, H3N2, H5N1, H7N7, H7N9 and H9N2 in vitro and H1N1, H5N1 and H7N9 in vivo. Combinational treatment with the influenza virus release inhibitor zanamivir and PB2-39 exerted a synergistic anti-influenza effect. Mechanistic experiments supported that PB2-39 suppressed viral polymerase activity. Docking and binding affinity analyses demonstrated that PB2-39 interacted with the PB2 cap-binding pocket, suggesting its role as a cap-binding competitor. Conclusions: Our study provides new insights for the strategic development of novel cap-binding inhibitors of influenza A viruses.-
dc.languageeng-
dc.publisherOxford University Press. The Journal's web site is located at http://jac.oxfordjournals.org/-
dc.relation.ispartofJournal of Antimicrobial Chemotherapy-
dc.titleA novel small-molecule compound disrupts influenza A virus PB2 cap-binding and inhibits viral replication-
dc.typeArticle-
dc.identifier.emailYuan, S: yuansf@hku.hk-
dc.identifier.emailChu, H: hinchu@hku.hk-
dc.identifier.emailZhang, K: kezhang1@hku.hk-
dc.identifier.emailYe, J: yejiahui@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.naturelink_to_OA_fulltext-
dc.identifier.doi10.1093/jac/dkw194-
dc.identifier.pmid27272726-
dc.identifier.scopuseid_2-s2.0-85017134531-
dc.identifier.hkuros263798-
dc.identifier.volume71-
dc.identifier.issue9-
dc.identifier.spage2489-
dc.identifier.epage2497-
dc.identifier.isiWOS:000383911600018-
dc.publisher.placeUnited Kingdom-
dc.identifier.issnl0305-7453-

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