甲型流感的季节性传播和流行威胁着人类健康和社会稳定。神经氨酸酶（NA）是抗甲型流感的重要靶标，含有H274Y突变型NA的流感病毒对目前使用最广泛的神经氨酸酶抑制剂（NAI）奥司他韦产生了严重耐药性，亟需发展抗H274Y突变型NA的新型抑制剂。项目申请人前期建立了NAIs“设计-合成-生物活性评价”的研究平台，发现了若干个抗H274Y突变型的NAIs，并突破了NAIs高活性与高脂溶性不能兼得的困境。本项目拟基于前期的研究平台和成果，利用野生型和H274Y突变型NA在274位氨基酸附近的相同区域（暂定为区域X），寻找筛选作用于区域X的结构片段，与奥司他韦骨架拼接，随后引入改善脂溶性的片段，并经虚拟筛选酶抑制活性和成药性性质得到目标化合物。本项目争取获得至少一个具有高脂溶性的抗H274Y突变型NA的强效抑制剂，同时保持对野生型NA的高活性，为开发新型的抗耐药性甲型流感候选药物奠定基础。

Influenza A with the tendancy of seasonal transmission and epidemics threatens public health and social stability. Neuraminidase(NA) is an important target for influenza A, and mutant viruses containing H274Y-mutant NA exhibited serious resistance towards oseltamivir as the most widely used neuraminidase inhibitor (NAI). There is an urgent need for research and development of novel inhibitors of H274Y-mutant NAs. We previously established a research platform of “Design-Synthesis-Biological evaluation”, discovered several NAIs against H274Y-mutant NA and broke the dilemma that powerful activities of NAIs were inconsistent with satifactory lipid solubility. Based on the previous research platform and achievements, this project will intend to make full use of almost the same region X (tentatively called as “region X” ) around 274th amino acid both of wild-type and H274Y-mutant NAs, search and screen the fragments interacting with region X, associate the above fragments with OC skeleton and then obtain the target compounds after virtual screening of inhibitory activities and drug-like properties. This project strives to discover at least one inhibitor with high inhibitions on H274Y-mutant NAs and proper lipid solubility while maintaining powerful activities against wild-type NAs. This project will lay the foudation for research and development of novel drug candidate against drug-resistant influenza A.