PB2是流感RNA依赖的RNA聚合酶的一个重要亚基，在流感病毒基因组转录和复制过程中发挥着关键的调控作用。PB2在各种流感病毒亚型中高度保守，且宿主体内无同源蛋白。因此，PB2被认为是很有前景的新一代广谱抗流感药物治疗靶标。但到目前为止，还没有靶向PB2的上市药物，且其抑制剂的报道也较少。在前期研究中，我们使用药物分子设计和生物活性测试等方法，获得了4个具有新型骨架结构的苗头化合物（即Cpd01-Cpd04），但这些化合物的PB2抑制活性和选择性等都有待提高。本项目将在前期研究基础上，首先解析PB2-苗头化合物的复合物晶体结构，然后利用基于结构的先导化合物优化方法对这4个苗头化合物进行结构优化设计，开展化学合成和生物活性测试，探究其构效关系和体内外抗流感病毒活性，优化其成药性。期望最终获得新型高活性、高选择性并具有良好成药性的PB2抑制剂，为针对PB2的抗流感药物研发奠定坚实基础。

PB2 is an important subunit of RNA dependent RNA polymerase, which plays a key role in the transcription and replication of influenza virus genome. PB2 is highly conserved in various influenza virus subtypes, and there is no homologous protein in the host. Therefore, PB2 is considered to be a promising drug target for the new generation broad-spectrum anti-influenza. However, up to now, there are no listed PB2-targeting drugs in clinical, and just very few PB2 inhibitors have been reported. In early studies, we discovered four hit compounds (Cpd01-Cpd04) with novel chemical scaffolds by utilizing drug design and bioactivity evaluation. But their potency and selectivity are poor and need to be improved. In this project, we shall carry out structural optimization to these compounds. Crystal structures for the complexes of PB2 and hit compounds will be first dissolved. Then structure-based lead optimization design will be performed on the hit compounds. The generated compounds will be synthesized and tested for their bioactivities. The structure-activity relationship and anti-influenza virus activities both in vitro and in vivo will be studied. Finally the druggability of these compounds will be optimized as well. Collectively, we hope to obtain a number of new PB2 inhibitors with high potency, high selectivity, and good druggability, and to lay a solid foundation for the subsequent research and development of PB2-targeting anti-influenza drugs.