Binding Mechanism of the Farnesoid X Receptor Marine Antagonist Suvanine Reveals a Strategy To Forestall Drug Modulation on Nuclear Receptors. Design, Synthesis, and Biological Evaluation of Novel Ligands
Binding Mechanism of the Farnesoid X Receptor Marine Antagonist Suvanine Reveals a Strategy To Forestall Drug Modulation on Nuclear Receptors. Design, Synthesis, and Biological Evaluation of Novel Ligands
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DOI：
10.1021/jm400419e
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发表时间：
2013-06-13
影响因子：
7.3
通讯作者：
Fiorucci, Stefano
中科院分区：
文献类型：
--
作者：
Di Leva, Francesco Saverio;Festa, Carmen;Fiorucci, Stefano
在这里，我们报道了一种海洋海绵七萜类化合物苏瓦宁，它是哺乳动物胆汁酸感受器法尼西德-X受体(FXR)的拮抗剂。以Suvanine为模板，我们阐明了FXR拮抗作用的分子基础，确定了导致从激动剂向拮抗剂转变的基本构象变化。核辅阻遏子NCoR和辅活化子Src-1的分子特征表明，受体构象的变化与这些辅因子募集到FXR调节基因OSTα启动子的特定动态有关。利用苏瓦宁作为一种新的热门药物，已经设计和制备了一个半合成衍生物库，导致了对FXR从兴奋到拮抗的一系列药理特征。深入的药理评价表明，衍生物19代表了一种新的FXR调节剂的化学类型，而乙醇6具有简化的分子支架，具有良好的拮抗活性。
Here, we report suvanine, a marine sponge sesterterpene, as an antagonist of the mammalian bile acid sensor farnesoid-X-receptor (FXR). Using suvanine as a template, we shed light on the molecular bases of FXR antagonism, identifying the essential conformational changes responsible for the transition from the agonist to the antagonist form. Molecular characterization of the nuclear corepressor NCoR and coactivator Src-1 revealed that receptor conformational changes are associated with a specific dynamic of recruitment of these cofactors to the promoter of OST alpha, a FXR regulated gene. Using suvanine as a novel hit, a library of semisynthetic derivatives has been designed and prepared, leading to pharmacological profiles ranging from agonism to antagonism toward FXR. Deep pharmacological evaluation demonstrated that derivative 19 represents a new chemotype of FXR modulator, whereas alcohol 6, with a simplified molecular scaffold, exhibits excellent antagonistic activity.