Small molecules that inhibit Vif-induced degradation of APOBEC3G

Masashi Matsui, Keisuke Shindo, Taisuke Izumi, Katsuhiro Io, Masanobu Shinohara, Jun Komano, Masayuki Kobayashi, Norimitsu Kadowaki, Reuben S. Harris, Akifumi Takaori-Kondo

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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.

Original languageEnglish (US)
Article number122
JournalVirology journal
Volume11
Issue number1
DOIs
StatePublished - Jul 1 2014

Keywords

  • APOBEC3G
  • HIV-1
  • Small molecules
  • Vif

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