Small Molecular Compounds Inhibit HIV-1 Replication through Specifically Stabilizing APOBEC3G

被引：95

作者：

Cen, Shan ^{[2
,3
]}

Peng, Zong-Gen

Li, Xiao-Yu ^{[2
,3
]}

Li, Zhuo-Rong

Ma, Jing ^{[2
,3
]}

Wang, Yue-Ming

Fan, Bo

You, Xue-Fu

Wang, Yu-Ping ^{[1
]}

Liu, Fei ^{[1
]}

Shao, Rong-Guang ^{[1
]}

Zhao, Li-Xun ^{[1
]}

Yu, Liyan ^{[1
]}

Jiang, Jian-Dong ^{[1
]}

机构：

[1] Chinese Acad Med Sci, Inst Med Biotechnol, Dept Virol, Beijing 100050, Peoples R China

[2] McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada

[3] McGill Univ, Jewish Gen Hosp, McGill AIDS Ctr, Montreal, PQ H3T 1E2, Canada

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2010年 / 285卷 / 22期

基金：

加拿大健康研究院; 比尔及梅琳达.盖茨基金会; 中国国家自然科学基金;

关键词：

HUMAN-IMMUNODEFICIENCY-VIRUS; VIRAL VIF PROTEIN; SOR GENE; TYPE-1; VIF; LYMPHOCYTES; INFECTIVITY;

D O I：

10.1074/jbc.M109.085308

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. IMB26/35 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. LD50 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.

引用

页码：16546 / 16552

页数：7

共 20 条

[1] The interaction between HIV-1 Gag and APOBEC3G [J].