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Design, synthesis and biological evaluation of indolizine derivatives as HIV-1 VIF-ElonginC interaction inhibitors. 2013

Wenlin Huang, and Tao Zuo, and Hongwei Jin, and Zhenming Liu, and Zhenjun Yang, and Xianghui Yu, and Liangren Zhang, and Lihe Zhang
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.

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.

UI MeSH Term Description Entries
D007212 Indolizines
D008164 Luminescent Proteins Proteins which are involved in the phenomenon of light emission in living systems. Included are the "enzymatic" and "non-enzymatic" types of system with or without the presence of oxygen or co-factors. Bioluminescent Protein,Bioluminescent Proteins,Luminescent Protein,Photoprotein,Photoproteins,Protein, Bioluminescent,Protein, Luminescent,Proteins, Bioluminescent,Proteins, Luminescent
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D002470 Cell Survival The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D003564 Cytidine Deaminase An enzyme that catalyzes the deamination of cytidine, forming uridine. EC 3.5.4.5. Cytidine Aminohydrolase,Aminohydrolase, Cytidine,Deaminase, Cytidine
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000071480 APOBEC-3G Deaminase An APOBEC deaminase that functions as an inhibitor of RETROVIRIDAE replication and inhibits the mobility of RETROTRANSPOSONS via deaminase-dependent and independent mechanisms. It is selective for SINGLE-STRANDED DNA and does not deaminate double-stranded DNA or single or DOUBLE-STRANDED RNA. It exhibits potent antiviral activity against VIF PROTEIN deficient HIV-1 through the creation of hypermutations in the VIRAL DNA. It also has anti-viral activity against SIMIAN IMMUNODEFICIENCY VIRUSES and HEPATITIS B VIRUS. APOBEC-3G Protein,APOBEC-3G dC-dU Editing Enzyme,APOBEC-Related Cytidine Deaminase,APOBEC-Related Protein,APOBEC3G Deaminase,APOBEC3G Protein,CEM15 Protein,APOBEC 3G Deaminase,APOBEC 3G Protein,APOBEC 3G dC dU Editing Enzyme,APOBEC Related Cytidine Deaminase,APOBEC Related Protein,Cytidine Deaminase, APOBEC-Related,Deaminase, APOBEC-3G,Deaminase, APOBEC3G
D000075065 Elongin A heterotrimeric protein complex composed of 110 kDa elongin A, 18 kDa elongin B, and 15 kDa elongin C subunits. It functions as a positive regulator of RNA POLYMERASE II, increasing its rate of transcriptional elongation by suppressing transient pausing along the DNA template. Elongin A is the transcriptionally active component; elongins B and C enhance its activity. EloA Protein,EloB Protein,EloC Protein,Elongin A,Elongin B,Elongin C,Elongin Complex,SIII Elongation Factor,TF-SIII,Transcription Factor SIII,Complex, Elongin,Elongation Factor, SIII,SIII, Transcription Factor
D001426 Bacterial Proteins Proteins found in any species of bacterium. Bacterial Gene Products,Bacterial Gene Proteins,Gene Products, Bacterial,Bacterial Gene Product,Bacterial Gene Protein,Bacterial Protein,Gene Product, Bacterial,Gene Protein, Bacterial,Gene Proteins, Bacterial,Protein, Bacterial,Proteins, Bacterial
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships

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