The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IκB kinase
The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IκB kinase
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DOI：
10.1016/s1074-5521(01)00049-7
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发表时间：
2001-08-01
影响因子：
--
通讯作者：
Crews, CM
中科院分区：
文献类型：
--
作者：
Kwok, BHB;Koh, B;Crews, CM
背景：具有生物活性的天然产物在探索和控制细胞内信号传导过程中仍然是有用的。例如，来自抗炎草药Feverfew（Tanacetum parthenium）的倍半萜内酯partheneutic似乎抑制促炎信号传导途径。然而，Parthenoptera的直接分子靶点仍然未知。我们着手确定的分子机制，小白菊的抗炎activity.Results：一个小白菊亲和试剂的合成，并显示直接结合和抑制I κ B激酶β（IKK β）的激酶亚基已知发挥关键作用，在姜黄素介导的信号。IKK β激活环中的半胱氨酸179突变消除了对孤雌激素的敏感性。此外，我们表明，小白菊的在体外和体内的抗炎活性是通过α-亚甲基γ-内酯部分共享的其他倍半萜lactones.Conclusions：近年来，多亚基IKK复合物已被证明是负责参与炎症的基因，并因此代表了一个有吸引力的药物干预的目标介导。我们的发现，孤雌菊靶向这种激酶复合物提供了一个可能的分子基础的抗炎特性的孤雌菊。此外，这些结果可能有助于开发其他抗炎药。(C)2001爱思唯尔科技有限公司版权所有。
Background: Biologically active natural products continue to be useful in the exploration and control of intracellular signaling processes. For example, the sesquiterpene lactone parthenolide from the anti-inflammatory medicinal herb Feverfew (Tanacetum parthenium) appears to inhibit the pro-inflammatory signaling pathway. Parthenolide's direct molecular target, however, remains unknown. We set out to identify the molecular mechanisms of parthenolide's anti-inflammatory activity.Results: A parthenolide affinity reagent was synthesized and shown to bind directly to and inhibit I kappaB kinase beta (IKK beta) the kinase subunit known to play a critical role in cytokine-mediated signaling. Mutation of cysteine 179 in the activation loop of IKK beta abolished sensitivity towards parthenolide. Moreover, we showed that parthenolide's in vitro and in vivo anti-inflammatory activity is mediated through the alpha -methylene gamma -lactone moiety shared by other sesquiterpene lactones.Conclusions: In recent years, the multi-subunit IKK complex has been shown to be responsible for cytokine-mediated stimulation of genes involved in inflammation and as such represents an attractive target for pharmaceutical intervention. Our finding that parthenolide targets this kinase complex provides a possible molecular basis for the anti-inflammatory properties of parthenolide. In addition, these results may be useful in the development of additional anti-inflammatory agents. (C) 2001 Elsevier Science Ltd. All rights reserved.