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J Biol Chem. 2010 May 28;285(22):16546-52. doi: 10.1074/jbc.M109.085308. Epub 2010 Apr 2.

Small molecular compounds inhibit HIV-1 replication through specifically stabilizing APOBEC3G.

Author information

1
Department of Virology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing 100050, China.

Abstract

APOBEC3G (hA3G) is a host inhibitor for human immunodeficiency virus, type 1 (HIV-1). However, HIV-1 Vif binds hA3G and induces its degradation. We have established a screening system to discover inhibitors that protect hA3G from Vif-mediated degradation. Through screening, compounds IMB-26 and IMB-35 were identified to be specific inhibitors for the degradation of hA3G by Vif. The inhibitors suppressed HIV-1 replication in hA3G-containing cells but not in those without hA3G. The anti-HIV effect correlated with the endogenous hA3G level. HIV-1 particles from hA3G(+) cells treated with IMB-26/35 contained a hA3G level higher than that from those without IMB-26/35 treatment and showed decreased infectivity. IMB-26/35 bound directly to the hA3G protein, suppressed Vif/hA3G interaction, and therefore protected hA3G from Vif-mediated degradation. The compounds were safe with an anti-HIV therapeutic index >200 in vitro. LD(50) of IMB-26 in mice was >1000 mg/kg (intraperitoneally). Therefore, IMB-26 and IMB-35 are novel anti-HIV leads working through specific stabilization of hA3G.

PMID:
20363737
PMCID:
PMC2878088
DOI:
10.1074/jbc.M109.085308
[Indexed for MEDLINE]
Free PMC Article

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