HIV融合抑制剂具有可在HIV感染的最初阶段抑制病毒感染的活性，使其被国内外各大药企认为是最有潜力预防和治疗艾滋病的药物。然而，目前仍缺乏能口服且长效的融合抑制剂药物来持久抗击HIV，提高艾滋病患者的生存质量。本课题提出使用构象锁定和树状分子两种结构改造方法联用来提高HIV融合抑制的抗HIV活性和蛋白酶稳定性新策略，以期获得具有高抗HIV活性、长效性以及口服活性的融合抑制剂，从而为艾滋病的治疗提供新的候选药物分子。通过对兼具抗HIV-1和HIV-2活性的融合抑制剂2P23先进行螺旋构象锁定优化得到抗HIV活性和蛋白酶稳定性提升的构象锁定融合抑制剂。然后，再进行树状结构优化得到抗HIV活性和蛋白酶稳定性再次提升的长效树状构象锁定融合抑制剂。最后，利用结晶技术对树状构象锁定融合抑制剂与靶点复合物结构的确定，将为今后其它高活性抗HIV多肽药物设计提供结构基础。

HIV fusion inhibitors can inhibit viral infections in the initial stages of HIV infection, making them considered to be the most promising drugs for the prevention and treatment of AIDS, by major domestic and international pharmaceutical companies. However, currently there is still a lack of oral and long-acting fusion inhibitor drugs against HIV to improve the quality of AIDS patients’ life. This project proposes a new strategy to improve the anti-HIV activity and protease stability of HIV fusion inhibition using conformation lock and dendrimer structural modification methods, for obtaining fusion inhibitors with high activity, long-acting and oral activity. Thereby, new drug candidates will be generated for the treatment of AIDS by the above new strategy. The stapled fusion inhibitors with improved activity and protease stability will be obtained by locking helical conformation of 2P23, a fusion inhibitor against both HIV-1 and HIV-2. Then, the structure of stapled 2P23 will be optimized via dendritic strategy to yield a long-acting dendritic stapled fusion inhibitor with further improved activity and protease stability. Moreover, the study of the complex structure of the dendritic stapled fusion inhibitor and its target using the crystallization technique will provide a structural basis for the design of other anti-HIV peptide drugs with highly activity in the future.