Design, synthesis and biological evaluation of indole derivatives as Vif inhibitors. Issue 17 (1st September 2017)

• Record Type: Journal Article
• Authors: Pu, Chunlan; Luo, Rong-Hua; Zhang, Mengqi; Hou, Xueyan; Yan, Guoyi; Luo, Jiang; Zheng, Yong-Tang; Li, Rui
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 17(2017)
• Page Start: 4150
• Page End: 4155
• Publication Date: 2017-09-01
• Subjects: APOBEC3G degradation -- Vif inhibitor -- FBVS -- Indole derivatives; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.07.026
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: FBVS was conducted against the C2 pocket of Vif, andZif-1 was selected for further optimization. Through the immune-fluorescence staining and western blot assays, Zif-15 shows potent activity in inhibiting Vif-mediated A3G degradation. Highlights: C2 pocket of Vif was found which is suit for developing small molecular inhibitors. FBVS was conducted against C2 pocket, and a series of fragments were obtained. Zif-15 shows potent activity in inhibiting Vif-mediated A3G degradation. Abstract: 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 ofZif-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 thatZif-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.