title: Identification of a novel small-molecule compound targeting the influenza A virus polymerase PB1-PB2 interface.
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.
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Shuofeng
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Hin
authors.initials: H
authors.lastname: Chu
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Ye
authors.affiliation: School of Biological Sciences, Faculty of Science, The University of Hong Kong, Hong Kong, China.
authors.forename: Kailash
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Hanjun
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Richard Y T
authors.initials: RY
authors.lastname: Kao
authors.affiliation: School of Biological Sciences, Faculty of Science, The University of Hong Kong, Hong Kong, China.
authors.forename: Billy K C
authors.initials: BK
authors.lastname: Chow
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. Electronic address: jiezhou@hku.hk.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. Electronic address: bzheng@hkucc.hku.hk.
authors.forename: Bo-Jian
authors.initials: BJ
authors.lastname: Zheng
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D002460:Cell Line; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects; D053126:Influenza A Virus, H7N7 Subtype / Q000187:drug effects; D064766:Influenza A Virus, H7N9 Subtype / Q000187:drug effects; D053127:Influenza A Virus, H9N2 Subtype / Q000187:drug effects; D009980:Influenza A virus / Q000737:chemistry* / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D062105:Molecular Docking Simulation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; C502893:PB2 protein, influenza virus; D054852:Small Molecule Libraries; D014764:Viral Proteins; C077346:influenza virus polymerase basic protein 1; D012324:RNA-Dependent RNA Polymerase