Synthesis of a Vpr-Binding Derivative for Use as a Novel HIV-1 Inhibitor.
Synthesis of a Vpr-Binding Derivative for Use as a Novel HIV-1 Inhibitor.
复制标题
DOI：
10.1371/journal.pone.0145573
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Aida Y
中科院分区：
文献类型：
--
作者：
Hagiwara K;Ishii H;Murakami T;Takeshima SN;Chutiwitoonchai N;Kodama EN;Kawaji K;Kondoh Y;Honda K;Osada H;Tsunetsugu-Yokota Y;Suzuki M;Aida Y
多重耐药病毒的出现损害了抗人类免疫缺陷病毒1型（HIV-1）治疗的疗效，并限制了治疗选择。因此，需要确定可用于开发新型抗病毒药物的新靶点。我们之前发现了一种潜在的母体化合物苏木素，它通过Vpr-输入素α相互作用抑制HIV-1的核输入，并通过阻断整合前复合物的核输入以Vpr依赖性方式抑制HIV-1复制。但它并不稳定。在这里，我们合成了一种稳定的衍生物苏木素，结合特异性和稳定的Vpr和抑制HIV-1复制的巨噬细胞。此外，像苏木素，衍生物抑制核输入的Vpr在体外核输入试验，但对Vpr诱导的G2/M期细胞周期阻滞或半胱天冬酶活性没有影响。有趣的是，该衍生物与Vpr的C-末端α-螺旋结构域（αH3）内的氨基酸残基54-74强烈结合。这些残基在不同的HIV毒株中高度保守，表明该区域是耐药HIV-1感染的潜在靶点。因此，我们成功地开发了一种稳定的苏木素衍生物，直接结合到Vpr，这表明细胞和病毒辅助蛋白之间的相互作用的特异性抑制剂可能会提供一个新的策略，用于治疗HIV-1感染。
The emergence of multidrug-resistant viruses compromises the efficacy of anti-human immunodeficiency virus type 1 (HIV-1) therapy and limits treatment options. Therefore, new targets that can be used to develop novel antiviral agents need to be identified. We previously identified a potential parent compound, hematoxylin, which suppresses the nuclear import of HIV-1 via the Vpr-importin α interaction and inhibits HIV-1 replication in a Vpr-dependent manner by blocking nuclear import of the pre-integration complex. However, it was unstable. Here, we synthesized a stable derivative of hematoxylin that bound specifically and stably to Vpr and inhibited HIV-1 replication in macrophages. Furthermore, like hematoxylin, the derivative inhibited nuclear import of Vpr in an in vitro nuclear import assay, but had no effect on Vpr-induced G2/M phase cell cycle arrest or caspase activity. Interestingly, this derivative bound strongly to amino acid residues 54–74 within the C-terminal α-helical domain (αH3) of Vpr. These residues are highly conserved among different HIV strains, indicating that this region is a potential target for drug-resistant HIV-1 infection. Thus, we succeeded in developing a stable hematoxylin derivative that bound directly to Vpr, suggesting that specific inhibitors of the interaction between cells and viral accessory proteins may provide a new strategy for the treatment of HIV-1 infection.