Pu Chunlan, Luo Rong-Hua, Zhang Mengqi, Hou Xueyan, Yan Guoyi, Luo Jiang, Zheng Yong-Tang, Li Rui
Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041 Sichuan, PR China.
Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
Bioorg Med Chem Lett. 2017 Sep 1;27(17):4150-4155. doi: 10.1016/j.bmcl.2017.07.026. Epub 2017 Jul 10.
The crystal structure of viral infectivity factor (Vif) was reported recently, which makes it possible to design new inhibitors against Vif by structure-based drug design. Through analysis of the protein surface of Vif, the C2 pocket located in the N-terminal was found, which is suit for developing small molecular inhibitors. Then, in our article, fragment-based virtual screening (FBVS) was conducted and a series of fragments was obtained, among which, Zif-1 bearing indole scaffold and pyridine ring can form H-bonds with Tyr148 and Ile155. Subsequently, 19 derivatives of Zif-1 were synthesized. Through the immune-fluorescence staining and Western blot assays, Zif-15 shows potent activity in inhibiting Vif-mediated A3G degradation. Further docking experiment shows that Zif-15 form H-bond interactions with residues His139, Tyr148 and Ile155. Therefore, Zif-15 is a promising lead compound against Vif that can be used to treat AIDS.
病毒感染因子（Vif）的晶体结构最近已被报道，这使得通过基于结构的药物设计来设计针对Vif的新型抑制剂成为可能。通过对Vif蛋白质表面的分析，发现了位于N端的C2口袋，它适合于开发小分子抑制剂。然后，在我们的文章中，进行了基于片段的虚拟筛选（FBVS）并获得了一系列片段，其中，带有吲哚支架和吡啶环的Zif-1可与Tyr148和Ile155形成氢键。随后，合成了19种Zif-1的衍生物。通过免疫荧光染色和蛋白质印迹分析，Zif-15在抑制Vif介导的A3G降解方面显示出强效活性。进一步的对接实验表明，Zif-15与His139、Tyr148和Ile155残基形成氢键相互作用。因此，Zif-15是一种有前景的针对Vif的先导化合物，可用于治疗艾滋病。
