Cholestenoic acid analogues as inverse agonists of the liver X receptors.,The Journal of Steroid Biochemistry and Molecular Biology

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Cholestenoic acid analogues as inverse agonists of the liver X receptors.
The Journal of Steroid Biochemistry and Molecular Biology ( IF 2.7 ) Pub Date : 2020-01-10 , DOI: 10.1016/j.jsbmb.2020.105585
Lautaro D Alvarez ₁ , María V Dansey ₁ , María F Ogara ₂ , Carina I Peña ₃ , René Houtman ₄ , Adriana S Veleiro ₅ , Adali Pecci ₆ , Gerardo Burton ₃

Affiliation

Liver X Receptors (LXRs) are ligand dependent transcription factors activated by oxidized cholesterol metabolites (oxysterols) that play fundamental roles in the transcriptional control of lipid metabolism, cholesterol transport and modulation of inflammatory responses. In the last decade, LXRs have become attractive pharmacological targets for intervention in human metabolic diseases and thus, several efforts have concentrated on the development of synthetic analogues able to modulate LXR transcriptional response. In this sense, we have previously found that cholestenoic acid analogues with a modified side chain behave as LXR inverse agonists. To further investigate the structure-activity relationships and to explore how cholestenoic acid derivatives interact with the LXRs, we evaluated the LXR biological activity of new analogues containing a C24-C25 double bond. Furthermore, a microarray assay was performed to evaluate the recruitment of coregulators to recombinant LXR LBD upon ligand binding. Also, conventional and accelerated molecular dynamics simulations were applied to gain insight on the molecular determinants involved in the inverse agonism. As LXR inverse agonists emerge as very promising candidates to control LXR activity, the cholestenoic acid analogues here depicted constitute a new relevant steroidal scaffold to inhibit LXR action.

中文翻译：

胆甾酸类似物作为肝X受体的反向激动剂。

肝X受体（LXR）是被氧化的胆固醇代谢物（氧固醇）激活的依赖配体的转录因子，在脂质代谢的转录控制，胆固醇的运输和炎症反应的调节中起基本作用。在过去的十年中，LXR已成为干预人类代谢疾病的有吸引力的药理学靶标，因此，数项工作集中在开发能够调节LXR转录反应的合成类似物上。从这个意义上讲，我们以前已经发现具有修饰的侧链的胆甾烯酸类似物具有LXR反向激动剂的作用。为了进一步研究构效关系，并探讨胆甾烯酸衍生物如何与LXR相互作用，我们评估了含有C24-C25双键的新类似物的LXR生物活性。此外，进行微阵列分析以评估配体结合后共调节剂募集至重组LXR LBD。同样，常规的和加速的分子动力学模拟被用于获得有关逆激动作用的分子决定簇的见解。由于LXR反向激动剂成为控制LXR活性的非常有前途的候选者，此处所示的胆甾烯酸类似物构成了抑制LXR作用的新的相关甾体支架。应用常规和加速的分子动力学模拟来获得有关逆激动作用中分子决定因素的见解。由于LXR反向激动剂成为控制LXR活性的非常有前途的候选者，此处所示的胆甾烯酸类似物构成了抑制LXR作用的新的相关甾体支架。应用常规和加速的分子动力学模拟来获得有关逆激动作用中分子决定因素的见解。由于LXR反向激动剂成为控制LXR活性的非常有前途的候选者，此处所示的胆甾烯酸类似物构成了抑制LXR作用的新的相关甾体支架。

更新日期：2020-01-11

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