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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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APOBEC-3G Deaminase
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Anti-HIV Agents / chemical synthesis*
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Anti-HIV Agents / pharmacology
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Bacterial Proteins
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Cell Line
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Cell Survival / drug effects
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Cullin Proteins / antagonists & inhibitors
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Cullin Proteins / chemistry
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Cullin Proteins / metabolism
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Cytidine Deaminase / antagonists & inhibitors*
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Cytidine Deaminase / chemistry
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Cytidine Deaminase / metabolism
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Drug Design
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Elongin
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Embryonic Stem Cells / cytology
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Embryonic Stem Cells / drug effects
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Embryonic Stem Cells / virology
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Genes, Reporter
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HEK293 Cells
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HIV-1 / drug effects*
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HIV-1 / growth & development
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Host-Pathogen Interactions
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Humans
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Indolizines / chemical synthesis*
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Indolizines / pharmacology
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Inhibitory Concentration 50
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Luminescent Proteins
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Molecular Docking Simulation
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Structure-Activity Relationship
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / chemistry
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Transcription Factors / metabolism
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Transfection
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vif Gene Products, Human Immunodeficiency Virus / antagonists & inhibitors*
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vif Gene Products, Human Immunodeficiency Virus / chemistry
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vif Gene Products, Human Immunodeficiency Virus / metabolism
Substances
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Anti-HIV Agents
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Bacterial Proteins
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CUL5 protein, human
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Cullin Proteins
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Elongin
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Indolizines
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Luminescent Proteins
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Transcription Factors
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vif Gene Products, Human Immunodeficiency Virus
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vif protein, Human immunodeficiency virus 1
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yellow fluorescent protein, Bacteria
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APOBEC-3G Deaminase
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APOBEC3G protein, human
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Cytidine Deaminase