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Virology. 2015 Oct;484:276-87. doi: 10.1016/j.virol.2015.06.014. Epub 2015 Jul 1.

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

Author information

1
Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA 02115, United States; Department of Pathology, Harvard Medical School, Boston, MA 02115, United States.
2
Department of Biology, College of the Holy Cross, Worcester, MA 01610, United States.
3
Southern Research Institute High Throughput Screening Center, Birmingham, AL 35205, United States.
4
Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA 02115, United States.
5
Southern Research Institute, Department of Infectious Disease Research, Frederick, MD 21701, United States.
6
Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA 02115, United States; Department of Neurology (Microbiology), Harvard Medical School, Boston, MA 02115, United States. Electronic address: dana_gabuzda@dfci.harvard.edu.

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.

KEYWORDS:

APOBEC3G; Antiviral; HIV-1; Pyrimidine synthesis; Redoxal; Vif

PMID:
26141568
PMCID:
PMC4567410
DOI:
10.1016/j.virol.2015.06.014
[Indexed for MEDLINE]
Free PMC Article
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