SJ23B, a jatrophane diterpene activates classical PKCs and displays strong activity against HIV in vitro
SJ23B, a jatrophane diterpene activates classical PKCs and displays strong activity against HIV in vitro
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DOI：
10.1016/j.bcp.2008.11.025
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发表时间：
2009-03-15
影响因子：
5.8
通讯作者：
Alcami, Jose
中科院分区：
文献类型：
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作者：
Bedoya, Luis M.;Marquez, Nieves;Alcami, Jose
病毒储存库的存在使得根除艾滋病毒感染极其困难。当前的药物疗法既不能消除这些病毒储存库，也不能阻止它们的形成。因此，需要新的策略来针对这些储存库，以减小其规模。我们分析了从欧洲大戟（Euphorbia hyberna）中分离出的一系列麻疯树烷型二萜，发现其中一种，SJ23B，可诱导艾滋病毒 - 1受体CD4、CXCR4和CCR5的内化，并在纳摩尔浓度范围内防止艾滋病毒R5和X4毒株在人原代T细胞中的感染。此外，SJ23B是艾滋病毒 - 1潜伏的强效拮抗剂。利用Jurkat - LAT - GFP细胞（一种艾滋病毒 - 1潜伏模型），我们发现佛波醇酯（prostratin）和SJ23B可激活艾滋病毒 - 1基因表达，且SJ23B的效力至少是佛波醇酯的10倍。SJ23B在NIH 3T3细胞中未引发转化灶活性，但通过体外激酶测定和细胞转位实验表明，它是蛋白激酶Cα和δ的强效激活剂。通过使用异构体特异性蛋白激酶C抑制剂，我们发现常规蛋白激酶C（cPKCs）对SJ23B诱导的艾滋病毒 - 1再激活至关重要。我们还表明，经典的蛋白激酶C抑制剂Go6976可抑制SJ23B诱导的IκBα降解和核因子 - κB（NF - κB）激活。相应地，SJ23B与离子霉素协同作用，将蛋白激酶Cα转位到质膜并激活核因子 - κB通路。此外，SJ23B在原代T细胞中激活核因子 - κB和Sp1依赖性转录活性。我们已经表明，麻疯树烷型二萜代表了一类新的抗艾滋病药物成员，可用于缓解艾滋病毒的再激活。（C）2008爱思唯尔公司。保留所有权利。
Existence of virus reservoirs makes the eradication of HIV infection extremely difficult. Current drug therapies neither eliminate these viral reservoirs nor prevent their formation. Consequently, new strategies are needed to target these reservoirs with the aim of decreasing their size. We analysed a series of jatrophane diterpenes isolated from Euphorbia hyberna and we found that one of them, SJ23B, induces the internalization of the HIV-1 receptors CD4, CXCR4 and CCR5 and prevents R5 and X4 viral infection in human primary T cells at the nanomolar range. Moreover, SJ23B is a potent antagonist of HIV-1 latency. Using Jurkat-LAT-GFP cells, a model for HIV-1 latency, we found that prostratin and SJ23B activate HIV-1 gene expression, with SJ23B being at least 10-fold more potent than prostratin. SJ23B did not elicit transforming foci activity in NIH 3T3 cells but is a potent activator of PKC alpha and delta as measured by in vitro kinase assays and by cellular translocation experiments. By using isoform-specific PKC inhibitors we found that cPKCs are critical for SJ23B-induced HIV-1 reactivation. We also showed that both SJ23B-induced I kappa B alpha degradation and NF-kappa B activation were inhibited by the classical PKC inhibitor, Go6976. Accordingly, SJ23B synergizes with ionomycin to translocate PKC alpha to the plasma membrane and to activate the NF-kappa B pathway. Moreover, SJ23B activates both NF-kappa B and Sp1-dependent transcriptional activities in primary T cells. We have shown that diterpene jatrophanes represent a new member of anti-AIDS agents that could be developed for mitigating HIV reactivation. (C) 2008 Elsevier Inc. All rights reserved.