Redoxal, an inhibitor of de novo pyrimidine biosynthesis, augments APOBEC3G antiviral activity against human immunodeficiency virus type 1

Abstract APOBEC3G (A3G) is a cytidine deaminase that restricts HIV-1 replication by inducing G-to-A hypermutation in viral DNA; deamination-independent mechanisms are also implicated. HIV-1 Vif protein counteracts A3G by inducing its proteasomal degradation. Thus, the Vif–A3G axis is a potential the...

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Bibliographic Details
Published in:Virology (New York, N.Y.) N.Y.), 2015-10, Vol.484, p.276-287
Main Authors: Pery, Erez, Sheehy, Ann, Miranda Nebane, N, Misra, Vikas, Mankowski, Marie K, Rasmussen, Lynn, Lucile White, E, Ptak, Roger G, Gabuzda, Dana
Format: Article
Language:English
Subjects:
Aminobiphenyl Compounds - metabolism
Antiviral
Antiviral Agents - metabolism
APOBEC-3G Deaminase
APOBEC3G
Cells, Cultured
Cytidine Deaminase - metabolism
Enzyme Inhibitors - metabolism
HIV-1
HIV-1 - immunology
HIV-1 - physiology
Humans
Infectious Disease
Leukocytes, Mononuclear - virology
Phenazines - metabolism
Pyrimidine synthesis
Pyrimidines - biosynthesis
Redoxal
Vif
Virus Replication
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Summary:Abstract APOBEC3G (A3G) is a cytidine deaminase that restricts HIV-1 replication by inducing G-to-A hypermutation in viral DNA; deamination-independent mechanisms are also implicated. HIV-1 Vif protein counteracts A3G by inducing its proteasomal degradation. Thus, the Vif–A3G axis is a potential therapeutic target. To identify compounds that inhibit Vif:A3G interaction, a 307,520 compound library was tested in a TR-FRET screen. Two identified compounds, redoxal and lomofungin, inhibited HIV-1 replication in peripheral blood mononuclear cells. Lomofungin activity was linked to A3G, but not pursued further due to cytotoxicity. Redoxal displayed A3G-dependent restriction, inhibiting viral replication by stabilizing A3G protein levels and increasing A3G in virions. A3G-independent activity was also detected. Treatment with uridine or orotate, intermediates of pyrimidine synthesis, diminished redoxal-induced stabilization of A3G and antiviral activity. These results identify redoxal as an inhibitor of HIV-1 replication and suggest its ability to inhibit pyrimidine biosynthesis suppresses viral replication by augmenting A3G antiviral activity.
ISSN:0042-6822
1096-0341
DOI:10.1016/j.virol.2015.06.014