Small molecules that inhibit Vif-induced degradation of APOBEC3G.
Small molecules that inhibit Vif-induced degradation of APOBEC3G.
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DOI：
10.1186/1743-422x-11-122
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发表时间：
2014-07-01
期刊：
影响因子：
4.8
通讯作者：
Takaori-Kondo A
中科院分区：
文献类型：
--
作者：
Matsui M;Shindo K;Izumi T;Io K;Shinohara M;Komano J;Kobayashi M;Kadowaki N;Harris RS;Takaori-Kondo A
HIV-1 Vif是病毒在天然靶细胞如T细胞和巨噬细胞中复制所必需的。Vif招募泛素连接酶以降解限制性APOBEC 3蛋白。APOBEC 3G是Vif靶向的最有效的逆转录病毒限制性因子之一，因此，Vif-APOBEC 3G相互作用已成为有希望的HIV-1治疗靶点。在活细胞筛选中使用了20，000个小分子，用于在HIV-1 Vif存在下保留EGFP-APOBEC 3G荧光和荧光酶-APOBEC 3G发光的那些小分子。具有相似核心结构的2种化合物在Vif存在下保留了APOBEC 3G水平。10 μM化合物使APOBEC 3G恢复至足以掺入vif-活性病毒颗粒并限制病毒感染性的水平。在相同浓度下，VIF依赖性APOBEC 3G多聚泛素化和一般蛋白酶体活性不受影响。本文所述的小分子在Vif存在下保持APOBEC 3G水平和活性。这些分子是进一步开发抗逆转录病毒药物的起点。
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. 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. 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. 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.