2-thio-6-azauridine inhibits Vpu mediated BST-2 degradation.
2-thio-6-azauridine inhibits Vpu mediated BST-2 degradation.
复制标题
2-thio-6-azauridine 抑制 Vpu 介导的 BST-2 降解。
DOI：
10.1186/s12977-016-0247-z
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发表时间：
2016-03-02
期刊：
影响因子：
3.3
通讯作者：
Cen S
中科院分区：
文献类型：
--
作者：
Zhang Q;Mi Z;Huang Y;Ma L;Ding J;Wang J;Zhang Y;Chen Y;Zhou J;Guo F;Li X;Cen S
BST-2是一种干扰素诱导的宿主限制因子，通过物理捕获新形成的病毒粒子到宿主细胞表面，抑制多种哺乳动物包膜病毒从感染细胞中释放出来。人类免疫缺陷病毒-1 （HIV-1）编码一种辅助蛋白Vpu，通过从细胞表面下调BST-2来拮抗BST-2。利用基于细胞的ELISA筛选系统，我们发现了一种先导化合物，2-硫代-6-azauridine，在Vpu存在的情况下恢复细胞表面BST-2水平。该化合物对BST-2和Vpu的表达无影响，但抑制Vpu介导的BST-2下调，对Vpu诱导的CD4下调或KSHV K5蛋白诱导的BST-2下调无影响。2-硫代-6-氮脲以bst -2依赖的方式抑制HIV-1的产生。进一步的结果表明，2-硫代-6-偶氮嘧啶不会中断BST-2与Vpu和β-TrCP2的相互作用，但会降低BST-2的泛素化。我们的研究证明了利用小分子靶向Vpu功能并使野生型HIV-1对bst -2介导的宿主限制敏感的可行性。本文的在线版本（doi:10.1186/s12977-016-0247-z）包含补充材料，可供授权用户使用。
BST-2 is an interferon-induced host restriction factor that inhibits the release of diverse mammalian enveloped viruses from infected cells by physically trapping the newly formed virions onto the host cell surface. Human Immunodeficiency Virus-1 (HIV-1) encodes an accessory protein Vpu that antagonizes BST-2 by down-regulating BST-2 from the cell surface. Using a cell-based ELISA screening system, we have discovered a lead compound, 2-thio-6-azauridine, that restores cell surface BST-2 level in the presence of Vpu. This compound has no effect on the expression of BST-2 and Vpu, but inhibits Vpu-mediated BST-2 down-regulation and exerts no effect on Vpu-induced down-regulation of CD4 or KSHV K5 protein induced BST-2 down-regulation. 2-thio-6-azauridine suppresses HIV-1 production in a BST-2-dependent manner. Further results indicate that 2-thio-6-azauridine does not interrupt the interaction of BST-2 with Vpu and β-TrCP2, but decreases BST-2 ubiquitination. Our study demonstrates the feasibility of using small molecules to target Vpu function and sensitize wild type HIV-1 to BST-2-mediated host restriction. The online version of this article (doi:10.1186/s12977-016-0247-z) contains supplementary material, which is available to authorized users.