Inhibition of HIV-1 gene expression by Ciclopirox and Deferiprone, drugs that prevent hypusination of eukaryotic initiation factor 5A.
Inhibition of HIV-1 gene expression by Ciclopirox and Deferiprone, drugs that prevent hypusination of eukaryotic initiation factor 5A.
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环吡酮和去铁酮抑制 HIV-1 基因表达，这两种药物可防止真核起始因子 5A 的兴奋作用。
DOI：
10.1186/1742-4690-6-90
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发表时间：
2009-10-13
期刊：
影响因子：
3.3
通讯作者：
Mathews, Michael B.
中科院分区：
文献类型：
--
作者：
Hoque, Mainul;Hanauske-Abel, Hartmut M.;Palumbo, Paul;Saxena, Deepti;Gandolfi, Darlene D'Alliessi;Park, Myung Hee;Pe'ery, Tsafi;Mathews, Michael B.
真核翻译起始因子eIF5A与HIV-1复制有关。该蛋白含有明显独特的氨基酸hypusine，它是由脱氧hypusine合酶和脱氧hypusine羟化酶（DOHH）催化的赖氨酸残基的翻译后修饰形成的。两种临床使用的药物，局部杀菌剂环匹洛克斯和全身药用铁螯合剂去铁素可抑制DOHH活性。据报道，去铁蛋白可抑制HIV-1在组织培养中的复制。环匹罗和去铁酮阻断了pbmc中HIV-1的复制。为了研究潜在的机制，我们在模型系统中研究了药物对eIF5A修饰和HIV-1基因表达的作用。在药物暴露后的早期，两种药物都抑制底物与DOHH的结合，阻止成熟eIF5A的形成。来自HIV-1分子克隆的病毒基因表达在RNA水平上被抑制，与所有病毒基因无关。这种抑制作用是针对病毒启动子的，发生在HIV-1转录起始水平。通过siRNA部分敲低eIF5A-1导致HIV-1基因表达的抑制，这种抑制与药物作用无关。这些数据支持eIF5A和hypusine形成在HIV-1基因表达中的重要性。在临床相关浓度下，两种广泛使用的药物阻断了HIV-1的体外复制。它们在转录起始水平特异性地抑制HIV-1启动子的表达。两种药物都干扰了eIF5A hypusine修饰中的羟基化步骤。这些结果对这些药物作为抗逆转录病毒药物的潜在治疗用途和优化类似物的开发具有深远的意义。
Eukaryotic translation initiation factor eIF5A has been implicated in HIV-1 replication. This protein contains the apparently unique amino acid hypusine that is formed by the post-translational modification of a lysine residue catalyzed by deoxyhypusine synthase and deoxyhypusine hydroxylase (DOHH). DOHH activity is inhibited by two clinically used drugs, the topical fungicide ciclopirox and the systemic medicinal iron chelator deferiprone. Deferiprone has been reported to inhibit HIV-1 replication in tissue culture. Ciclopirox and deferiprone blocked HIV-1 replication in PBMCs. To examine the underlying mechanisms, we investigated the action of the drugs on eIF5A modification and HIV-1 gene expression in model systems. At early times after drug exposure, both drugs inhibited substrate binding to DOHH and prevented the formation of mature eIF5A. Viral gene expression from HIV-1 molecular clones was suppressed at the RNA level independently of all viral genes. The inhibition was specific for the viral promoter and occurred at the level of HIV-1 transcription initiation. Partial knockdown of eIF5A-1 by siRNA led to inhibition of HIV-1 gene expression that was non-additive with drug action. These data support the importance of eIF5A and hypusine formation in HIV-1 gene expression. At clinically relevant concentrations, two widely used drugs blocked HIV-1 replication ex vivo. They specifically inhibited expression from the HIV-1 promoter at the level of transcription initiation. Both drugs interfered with the hydroxylation step in the hypusine modification of eIF5A. These results have profound implications for the potential therapeutic use of these drugs as antiretrovirals and for the development of optimized analogs.
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影响因子：
5.4
作者：
Cano, Veridiana S. P.;Jeon, Geoung A.;Park, Myung Hee
通讯作者：
Park, Myung Hee
影响因子：
5.4
作者：
CHEN, BK;SAKSELA, K;BALTIMORE, D
通讯作者：
BALTIMORE, D
DOI：
10.1046/j.1432-1033.2003.03806.x
发表时间：
2003-11-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Clement, PMJ;Henderson, CA;Johansson, HE
通讯作者：
Johansson, HE
影响因子：
56.9
作者：
Emerman, M;Malim, MH
通讯作者：
Malim, MH
影响因子：
6.5
作者：
Chan, JCW;Chim, CS;Chan, V
通讯作者：
Chan, V