Design, synthesis and biological evaluation of indolizine derivatives as HIV-1 VIF–ElonginC interaction inhibitors

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• 作者：Wenlin Huang (1)
  Tao Zuo (2)
  Hongwei Jin (1)
  Zhenming Liu (1)
  Zhenjun Yang (1)
  Xianghui Yu (2) (3)
  Liangren Zhang (1)
  Lihe Zhang (1)
  
• 关键词：VIF–ElonginC interaction inhibition ; VEC ; 5 ; Anti ; HIV ; 1 ; Indolizine derivatives ; Structure ; activity relationship
• 刊名：Molecular Diversity
• 出版年：2013
• 出版时间：May 2013
• 年：2013
• 卷：17
• 期：2
• 页码：221-243
• 全文大小：829KB
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• 作者单位：Wenlin Huang (1)
  Tao Zuo (2)
  Hongwei Jin (1)
  Zhenming Liu (1)
  Zhenjun Yang (1)
  Xianghui Yu (2) (3)
  Liangren Zhang (1)
  Lihe Zhang (1)
  
  1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
  2. National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, Changchun, 130012, China
  3. Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University, Changchun, 130012, China
  
• ISSN：1573-501X

文摘

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 $\upmu $ M. The findings described here will be useful for the development of more potent VIF inhibitors.