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 K_D 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.

流感大流行已成为全球重大公共卫生和安全问题。PB2 是流感 RNA 依赖性 RNA 聚合酶 (RdRP) 的一个重要亚基，已被确定为流感治疗的有希望的靶点。我们在此报告了一种有效的新型 PB2 抑制剂 7-51A 的发现，经 ITC 测定，其 KD_值为1.64 nM。PB2-7-51A复合物的共晶结构阐明了7-51A的高活性，比较分析揭示了以前从未观察到的独特相互作用。初步药理学评价表明7-51A表现出值得称赞的细胞安全性、肝微粒体代谢安全性和稳定性。总的来说，7-51A 被发现是一种有效的 PB2 抑制剂，可用作进一步研究的先导化合物。