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Small molecules that inhibit Vif-induced degradation of APOBEC3G

Masashi Matsui1, Keisuke Shindo1*, Taisuke Izumi12, Katsuhiro Io1, Masanobu Shinohara1, Jun Komano3, Masayuki Kobayashi1, Norimitsu Kadowaki1, Reuben S Harris45 and Akifumi Takaori-Kondo1

Author Affiliations

1 Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaracho, Sakyo-ku, Kyoto 606-8507, Japan

2 Japanese Foundation for AIDS Prevention, Tokyo 101-0061, Japan

3 AIDS Research Center, National Institute of Infectious Diseases, Tokyo 162-8640, Japan

4 Department of Biochemistry, Molecular Biology and Biophysics, Minneapolis, USA

5 Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA

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Virology Journal 2014, 11:122  doi:10.1186/1743-422X-11-122

Published: 1 July 2014

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.

Keywords:
HIV-1; Vif; APOBEC3G; Small molecules