title: 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 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.
authors.affiliation: 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.
authors.forename: Erez
authors.initials: E
authors.lastname: Pery
authors.affiliation: Department of Biology, College of the Holy Cross, Worcester, MA 01610, United States.
authors.forename: Ann
authors.initials: A
authors.lastname: Sheehy
authors.affiliation: Southern Research Institute High Throughput Screening Center, Birmingham, AL 35205, United States.
authors.forename: N
authors.initials: N
authors.lastname: Miranda Nebane
authors.affiliation: Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA 02115, United States.
authors.forename: Vikas
authors.initials: V
authors.lastname: Misra
authors.affiliation: Southern Research Institute, Department of Infectious Disease Research, Frederick, MD 21701, United States.
authors.forename: Marie K
authors.initials: MK
authors.lastname: Mankowski
authors.affiliation: Southern Research Institute High Throughput Screening Center, Birmingham, AL 35205, United States.
authors.forename: Lynn
authors.initials: L
authors.lastname: Rasmussen
authors.affiliation: Southern Research Institute High Throughput Screening Center, Birmingham, AL 35205, United States.
authors.forename: E
authors.initials: E
authors.lastname: Lucile White
authors.affiliation: Southern Research Institute, Department of Infectious Disease Research, Frederick, MD 21701, United States.
authors.forename: Roger G
authors.initials: RG
authors.lastname: Ptak
authors.affiliation: 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.
authors.forename: Dana
authors.initials: D
authors.lastname: Gabuzda
mesh_terms: D000071480:APOBEC-3G Deaminase; D000611:Aminobiphenyl Compounds / Q000378:metabolism*; D000998:Antiviral Agents / Q000378:metabolism*; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D010619:Phenazines / Q000378:metabolism; D011743:Pyrimidines / Q000096:biosynthesis*; D014779:Virus Replication
chemical_list: D000611:Aminobiphenyl Compounds; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D010619:Phenazines; D011743:Pyrimidines; C100203:lomofungin; C093361:2,2'-((3,3'-dimethoxy(1,1'-biphenyl)-4,4'-diyl)diimino)bis-benzoic acid; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase; C030986:pyrimidine
keywords: APOBEC3G; Antiviral; HIV-1; Pyrimidine synthesis; Redoxal; Vif