title: Small molecules that inhibit Vif-induced degradation of APOBEC3G.
abstract: BACKGROUND
  HIV-1 Vif is essential for virus replication in natural target cells such as T cells and macrophages. Vif recruits a ubiquitin ligase to degrade restrictive APOBEC3 proteins. APOBEC3G is one of the most potent retroviral restriction factors targeted by Vif and, as such, the Vif-APOBEC3G interaction has emerged as a promising HIV-1 therapeutic target.
  
  
  METHODS
  20,000 small molecules were used in live-cell screens for those that preserve EGFP-APOBEC3G fluorescence and luciferase-APOBEC3G luminescence in the presence of HIV-1 Vif.
  
  
  RESULTS
  2 compounds with similar core structures preserved APOBEC3G levels in the presence of Vif. 10 μM of compound restored APOBEC3G to levels sufficient for incorporation into vif-proficient virus particles and restriction of virus infectivity. Vif-dependent APOBEC3G polyubiquitination and general proteasomal activity were unaffected at the same concentration.
  
  
  CONCLUSIONS
  The small molecules described here preserve APOBEC3G levels and activity in the presence of Vif. These molecules are starting points for further development as antiretrovirals.
authors.forename: Masashi
authors.initials: M
authors.lastname: Matsui
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaracho, Sakyo-ku, Kyoto 606-8507, Japan. shind009@kuhp.kyoto-u.ac.jp.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shindo
authors.forename: Taisuke
authors.initials: T
authors.lastname: Izumi
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Io
authors.forename: Masanobu
authors.initials: M
authors.lastname: Shinohara
authors.forename: Jun
authors.initials: J
authors.lastname: Komano
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Kadowaki
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
authors.forename: Akifumi
authors.initials: A
authors.lastname: Takaori-Kondo
mesh_terms: D000071480:APOBEC-3G Deaminase; D000998:Antiviral Agents / Q000302:isolation & purification*; D003564:Cytidine Deaminase / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000302:isolation & purification*; D059748:Proteolysis / Q000187:drug effects; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase