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

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.