Identification of a novel HIV-1 inhibitor targeting Vif-dependent degradation of human APOBEC3G protein.

The Journal of Biological Chemistry
Erez PeryDana Gabuzda

Abstract

APOBEC3G (A3G) is a cellular cytidine deaminase that restricts HIV-1 replication by inducing G-to-A hypermutation in viral DNA and by deamination-independent mechanisms. HIV-1 Vif binds to A3G, resulting in its degradation via the 26 S proteasome. Therefore, this interaction represents a potential therapeutic target. To identify compounds that inhibit interaction between A3G and HIV-1 Vif in a high throughput format, we developed a homogeneous time-resolved fluorescence resonance energy transfer assay. A 307,520 compound library from the NIH Molecular Libraries Small Molecule Repository was screened. Secondary screens to evaluate dose-response performance and off-target effects, cell-based assays to identify compounds that attenuate Vif-dependent degradation of A3G, and assays testing antiviral activity in peripheral blood mononuclear cells and T cells were employed. One compound, N.41, showed potent antiviral activity in A3G(+) but not in A3G(-) T cells and had an IC50 as low as 8.4 μM and a TC50 of >100 μM when tested against HIV-1Ba-L replication in peripheral blood mononuclear cells. N.41 inhibited the Vif-A3G interaction and increased cellular A3G levels and incorporation of A3G into virions, thereby attenuating virus infe...Continue Reading

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Citations

Oct 29, 2015·Journal of Medicinal Chemistry·Peng ZhanXinyong Liu
Oct 16, 2016·Applied Microbiology and Biotechnology·Salwa Mansur AliNaveed Ahmed Khan
Feb 10, 2017·Biotechnology and Applied Biochemistry·Carlos A Duarte, Mickel Palomino
Jun 26, 2015·Viruses·Luc Willems, Nicolas Albert Gillet
Dec 7, 2017·International Reviews of Immunology·Faezeh BorzooeeMani Larijani
Feb 3, 2016·Antimicrobial Agents and Chemotherapy·Jonathan M O RawsonLouis M Mansky
Aug 19, 2015·Antimicrobial Agents and Chemotherapy·Jonathan M O RawsonLouis M Mansky
Jan 21, 2016·Proteomes·Haitham Sobhy
Dec 24, 2018·Frontiers in Immunology·Marta Colomer-LluchJulia G Prado
Dec 4, 2020·Microorganisms·Wendy Kaichun XuJaquelin P Dudley

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