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- Publisher Website: 10.1016/j.antiviral.2016.11.005
- Scopus: eid_2-s2.0-84995957135
- PMID: 27840201
- WOS: WOS:000393005300007
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Article: Identification of a novel small-molecule compound targeting the influenza A virus polymerase PB1-PB2 interface
Title | Identification of a novel small-molecule compound targeting the influenza A virus polymerase PB1-PB2 interface |
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Authors | |
Issue Date | 2017 |
Publisher | Elsevier 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? |
Abstract | The 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 Identifier | http://hdl.handle.net/10722/238681 |
ISSN | 2023 Impact Factor: 4.5 2023 SCImago Journal Rankings: 1.500 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Yuan, S | - |
dc.contributor.author | Chu, H | - |
dc.contributor.author | Ye, J | - |
dc.contributor.author | Singh, K | - |
dc.contributor.author | Ye, Z | - |
dc.contributor.author | Zhao, H | - |
dc.contributor.author | Kao, RYT | - |
dc.contributor.author | Chow, BKC | - |
dc.contributor.author | Zhou, J | - |
dc.contributor.author | Zheng, B | - |
dc.date.accessioned | 2017-02-20T01:24:41Z | - |
dc.date.available | 2017-02-20T01:24:41Z | - |
dc.date.issued | 2017 | - |
dc.identifier.citation | Antiviral Research, 2017, v. 137, p. 58-66 | - |
dc.identifier.issn | 0166-3542 | - |
dc.identifier.uri | http://hdl.handle.net/10722/238681 | - |
dc.description.abstract | The 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.language | eng | - |
dc.publisher | Elsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/antiviral | - |
dc.relation.ispartof | Antiviral Research | - |
dc.title | Identification of a novel small-molecule compound targeting the influenza A virus polymerase PB1-PB2 interface | - |
dc.type | Article | - |
dc.identifier.email | Yuan, S: yuansf@hku.hk | - |
dc.identifier.email | Chu, H: hinchu@hku.hk | - |
dc.identifier.email | Ye, J: yejiahui@hku.hk | - |
dc.identifier.email | Ye, Z: zwye@hku.hk | - |
dc.identifier.email | Zhao, H: hjzhao13@hku.hk | - |
dc.identifier.email | Kao, RYT: rytkao@hkucc.hku.hk | - |
dc.identifier.email | Chow, BKC: bkcc@hku.hk | - |
dc.identifier.email | Zhou, J: jiezhou@hku.hk | - |
dc.identifier.email | Zheng, B: bzheng@hkucc.hku.hk | - |
dc.identifier.authority | Chu, H=rp02125 | - |
dc.identifier.authority | Kao, RYT=rp00481 | - |
dc.identifier.authority | Chow, BKC=rp00681 | - |
dc.identifier.authority | Zhou, J=rp01412 | - |
dc.identifier.authority | Zheng, B=rp00353 | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1016/j.antiviral.2016.11.005 | - |
dc.identifier.pmid | 27840201 | - |
dc.identifier.pmcid | PMC7113721 | - |
dc.identifier.scopus | eid_2-s2.0-84995957135 | - |
dc.identifier.hkuros | 271253 | - |
dc.identifier.volume | 137 | - |
dc.identifier.spage | 58 | - |
dc.identifier.epage | 66 | - |
dc.identifier.isi | WOS:000393005300007 | - |
dc.publisher.place | Netherlands | - |
dc.identifier.issnl | 0166-3542 | - |