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

Virology. 2015 Oct:484:276-287. doi: 10.1016/j.virol.2015.06.014. Epub 2015 Jul 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 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • APOBEC-3G Deaminase
  • Aminobiphenyl Compounds / metabolism*
  • Antiviral Agents / metabolism*
  • Cells, Cultured
  • Cytidine Deaminase / metabolism*
  • Enzyme Inhibitors / metabolism
  • HIV-1 / immunology*
  • HIV-1 / physiology*
  • Humans
  • Leukocytes, Mononuclear / virology
  • Phenazines / metabolism
  • Pyrimidines / biosynthesis*
  • Virus Replication*

Substances

  • Aminobiphenyl Compounds
  • Antiviral Agents
  • Enzyme Inhibitors
  • Phenazines
  • Pyrimidines
  • lomofungin
  • 2,2'-((3,3'-dimethoxy(1,1'-biphenyl)-4,4'-diyl)diimino)bis-benzoic acid
  • APOBEC-3G Deaminase
  • APOBEC3G protein, human
  • Cytidine Deaminase
  • pyrimidine