Inhibition of Human Immunodeficiency Virus Type 1 Replication by Blocking IκB Kinase with Noraristeromycin
Inhibition of Human Immunodeficiency Virus Type 1 Replication by Blocking IκB Kinase with Noraristeromycin
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DOI：
10.1093/jb/mvn104
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发表时间：
2008-11-01
影响因子：
2.7
通讯作者：
Okamoto, Takashi
中科院分区：
文献类型：
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作者：
Asamitsu, Kaori;Yamaguchi, Tsuyoshi;Okamoto, Takashi
核因子κ B（NF-κ B B）是人类免疫缺陷病毒（HIV）等病毒的炎症反应和复制中的关键转录因子之一。事实上，已经证明各种NF-κ B抑制剂可以阻断HIV复制。为了探索更有效的NF-κ B抑制剂，我们集中研究了已报道具有抗炎作用的碳环腺嘌呤核苷。我们合成了15个碳环腺嘌呤核苷化合物，并使用HEK 293细胞系检测了它们对NF-κ B依赖基因表达的影响。在这些化合物中，去甲红霉素（NAM）在非细胞毒性浓度下对NF-κ B活性表现出最强的抑制作用。在用肿瘤坏死因子-α（TNF-alpha）刺激细胞后，NAM抑制I kappa B α磷酸化和降解。此外，NAM阻止p65磷酸化。这些结果表明，I κ B激酶-α（IKK-α）和-β都是NAM的靶点。有趣的是，体外激酶测定显示，NAM抑制IKK-α的激酶活性比IKK-β更有效。当我们处理HIV-1潜伏和慢性感染的细胞系OM 10.1和Molt 4/IIIB时，我们发现NAM在TNF-α刺激下对HIV-1病毒复制具有强烈的抑制作用。
Nuclear factor kappa B (NF-kappa B) is one of the critical transcription factors in inflammatory responses and replication of viruses such as human immunodeficiency virus (HIV). In fact, it has been demonstrated that various NF-kappa B inhibitors could block HIV replication. To explore more potent NF-kappa B inhibitors, we focused on carbocyclic adenine nucleosides that had been reported to have anti-inflammatory effects. We synthesized 15 carbocyclic adenine nucleoside compounds and examined their effects on the NF-kappa B-dependent gene expression using HEK293 cell line. Among these compounds, noraristeromycin (NAM) exhibited the most potent inhibitory effect on the NF-kappa B activity under the non-cytotoxic concentrations. NAM-inhibited I kappa B alpha phosphorylation and degradation upon stimulation of cells with tumour necrosis factor-alpha (TNF-alpha). In addition, NAM prevented p65 phoshorylation. These findings suggested that both I kappa B kinase-alpha (IKK-alpha) and -beta were targeted by NAM. Interestingly, in vitro kinase assay revealed that NAM inhibited the kinase activity of IKK-alpha more potently than that of IKK-beta. When we treated the cell lines, OM10.1 and Molt4/IIIB, in which HIV-1 is latently and chronically infected, we found a strong suppressive effect of NAM on HIV-1 viral replication upon stimulation with TNF-alpha.