Discovery of a potent inhibitor targeting the cap-binding domain of the PB2 subunit of influenza RNA-dependent RNA polymerase

  • Biochem Biophys Res Commun. 2023 Oct 20:678:97-101. doi: 10.1016/j.bbrc.2023.08.027.
Weining Sun  1 ,  Ziling Zhang  2 ,  Mingxin Chen  1 ,  Xinlei Liu  1 ,  Yifei Wang  1 ,  Shaohua Yao  1 ,  Linli Li  3
Affiliations
  • 1. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2. Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
  • 3. Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 37625270 DOI: 10.1016/j.bbrc.2023.08.027
Abstract

Influenza pandemics have emerged as a significant global public health and security concern. PB2, a crucial subunit of the influenza RNA-dependent RNA polymerase (RdRP), has been identified as a promising target for influenza treatment. We herein report the discovery of a potent novel PB2 inhibitor, 7-51A, with a KD value of 1.64 nM as determined by ITC. The high activity of 7-51A was elucidated by the co-crystal structure of the PB2-7-51A complex, and comparative analysis revealed unique interactions that had never been observed before. The preliminary pharmacological evaluation indicated that 7-51A exhibited commendable cellular safety, hepatic microsomal metabolic safety and stability. Collectively, 7-51A was found to be an effective PB2 inhibitor and could be used as a lead compound for further studies.

Keywords
Crystal complex structure; Influenza A virus; PB2; Small molecule inhibitor.
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