Celastrol inhibits Tat-mediated human immunodeficiency virus (HIV) transcription and replication.
Celastrol inhibits Tat-mediated human immunodeficiency virus (HIV) transcription and replication.
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DOI：
10.1016/j.jmb.2011.04.013
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发表时间：
2011-07-29
影响因子：
5.6
通讯作者：
Prabhu KS
中科院分区：
文献类型：
--
作者：
Narayan V;Ravindra KC;Chiaro C;Cary D;Aggarwal BB;Henderson AJ;Prabhu KS
目前用于抗艾滋病毒的抗逆转录病毒疗法的药物具有狭窄的活性谱，并且除了产生耐药性之外，更经常地具有相关的毒性和严重的副作用。因此，有必要制定新的艾滋病毒/艾滋病治疗战略，以补充现有的战略。令人惊讶的是，达特，一种HIV基因组有效转录所需的早期病毒编码蛋白，尚未被开发为小分子治疗剂的靶标。我们先前已经描述了内源性迈克尔受体亲电体（MAE）15-脱氧-Δ 12，14-前列腺素J2（15 d-PGJ 2）通过靶向其富含半胱氨酸（Cys）的结构域来抑制Tat依赖性转录的能力。为了鉴定对HIV-1达特具有抑制活性的其他MAE，我们测试了一系列具有亲电子特性的植物衍生化合物，包括姜黄素、迷迭香酸和藤黄酸，以确定它们抑制达特的能力。南蛇藤酚（Celastrol，Cel）是从T. Wilfordii对达特的抑制活性最强。利用生物化学技术，我们证明了Cel通过共价修饰半胱氨酸巯基来抑制达特反式激活功能。利用圆二色性（CD）光谱，我们发现达特的烷基化引起了达特二级结构的改变，这种改变通过影响Tat-TAR相互作用以外的机制抑制了HIV前病毒基因组的转录延伸。我们的研究结果证明了植物源MAE抗逆转录病毒活性的潜在机制，并表明Cel可以作为开发新型抗病毒治疗药物的先导化合物。
Current drugs used for anti-retroviral therapy against HIV have a narrow spectrum of activity, and more often have associated toxicities and severe side effects in addition to developing resistance. Thus, there is a need to develop new therapeutic strategies against HIV/AIDS to complement the already existing ones. Surprisingly, Tat, an early virus encoded protein required for the efficient transcription of the HIV genome, has not been developed as a target for small molecular therapeutics. We have previously described the ability of an endogenous Michael acceptor electrophile (MAE), 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), to inhibit Tat-dependent transcription, by targeting its cysteine (Cys) rich domain. In an effort to identify other MAEs possessing inhibitory activity against HIV-1 Tat, we tested a collection of plant-derived compounds with electrophilic properties, including curcumin, rosmarinic acid, and gambogic acid, for their ability to inhibit Tat. Celastrol (Cel), a triterpenoid MAE isolated from T. wilfordii, exhibited the highest inhibitory activity against Tat. Using biochemical techniques, we demonstrate that Cel by covalently modifying the cysteine thiols inhibits Tat transactivation function. Using circular dichroism (CD) spectroscopy, we show that alklylation of Tat brought about a change in the secondary structure of Tat, which inhibited the transcription elongation of the HIV proviral genome by effecting mechanisms other than Tat-TAR interaction. Our results demonstrate the underlying mechanism of anti-retroviral activity of the plant-derived MAEs, and suggest that Cel could serve as a lead compound to develop novel anti-viral therapeutics.
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影响因子：
3.3
作者：
Agbottah, Emmanuel;Deng, Longwen;Dannenberg, Luke O.;Pumfery, Anne;Kashanchi, Fatah
通讯作者：
Kashanchi, Fatah
影响因子：
11
作者：
Emiliani, Stephane;Coudronniere, Nolwenn;Devaux, Christian
通讯作者：
Devaux, Christian
影响因子：
64.8
作者：
KAO, SY;CALMAN, AF;PETERLIN, BM
通讯作者：
PETERLIN, BM
影响因子：
1.6
作者：
Kirsch, T;Boehm, M;Rosch, P
通讯作者：
Rosch, P
DOI：
10.1101/sqb.1998.63.371
发表时间：
1998-01-01
期刊：
COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY
影响因子：
--
作者：
Garber, ME;Wei, P;Jones, KA
通讯作者：
Jones, KA