title: Design, synthesis and biological evaluation of indolizine derivatives as HIV-1 VIF-ElonginC interaction inhibitors.
abstract: The HIV-1 viral infectivity factor (VIF) protein is essential for viral replication. VIF recruits cellular ElonginB/C-Cullin5 E3 ubiquitin ligase to target the host antiviral protein APOBEC3G (A3G) for proteasomal degradation. Thus, the A3G-Vif-E3 complex represents an attractive target for the development of novel anti-HIV drugs. In this study, we describe the design and synthesis of indolizine derivatives as VIF inhibitors targeting the VIF-ElonginC interaction. Many of the synthesized compounds exhibited obvious inhibition activities of VIF-mediated A3G degradation, and 5 compounds showed improvement of activity compared to the known VIF inhibitor VEC-5 (1) with IC(50) values about 20 μM. The findings described here will be useful for the development of more potent VIF inhibitors.
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Wenlin
authors: W
authors: Huang
authors: Tao
authors: T
authors: Zuo
authors: Hongwei
authors: H
authors: Jin
authors: Zhenming
authors: Z
authors: Liu
authors: Zhenjun
authors: Z
authors: Yang
authors: Xianghui
authors: X
authors: Yu
authors: Liangren
authors: L
authors: Zhang
authors: Lihe
authors: L
authors: Zhang
mesh_terms: D000071480:APOBEC-3G Deaminase; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001426:Bacterial Proteins; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D044842:Cullin Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D000075065:Elongin; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000821:virology; D017930:Genes, Reporter; D057809:HEK293 Cells; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D054884:Host-Pathogen Interactions; D006801:Humans; D007212:Indolizines / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008164:Luminescent Proteins; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D014162:Transfection; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D001426:Bacterial Proteins; C496871:CUL5 protein, human; D044842:Cullin Proteins; D000075065:Elongin; D007212:Indolizines; D008164:Luminescent Proteins; D014157:Transcription Factors; D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; C054562:yellow fluorescent protein, Bacteria; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase
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