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

  • Antiviral Res. 2017 Jan;137:58-66. doi: 10.1016/j.antiviral.2016.11.005.
Shuofeng Yuan  1 ,  Hin Chu  1 ,  Jiahui Ye  1 ,  Kailash Singh  2 ,  Ziwei Ye  1 ,  Hanjun Zhao  1 ,  Richard Y T Kao  1 ,  Billy K C Chow  2 ,  Jie Zhou  3 ,  Bo-Jian Zheng  4
Affiliations
  • 1. Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 2. School of Biological Sciences, Faculty of Science, The University of Hong Kong, Hong Kong, China.
  • 3. Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. Electronic address: [email protected].
  • 4. Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. Electronic address: [email protected].
PMID: 27840201 DOI: 10.1016/j.antiviral.2016.11.005
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.

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