针对替代维生素E代谢物结合部位使非正规的PPARγ调节成为可能
Silvia Arifi1, Julian A Marschner2, Julius Pollinger1
1Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, D-60438 Frankfurt, Germany.
Journal of the American Chemical Society
|June 29, 2023
概括
研究人员发现了一种通过向第二个结合部位来调节转录因子PPARγ的新方法. 这一发现表明了超越传统PPARγ激活的新疗法.
科学领域:
- 生物化学
- 分子生物学
- 药理学
背景情况:
- 氧酶增殖器激活受体马 (PPARγ) 是抗糖尿病药物如 thiazolidinediones (TZDs) 的关键标.
- PPARγ有两个不同的联结位点;正规位点与TZDs结合,而第二个位点与氧化维生素E代谢物和酸结合.
- 这第二个结合位点的功能意义及其非正规PPARγ调节的潜力在很大程度上尚未被探索.
研究的目的:
- 研究第二个联结位点对PPARγ活性的作用.
- 为这种替代结合点开发选择性连接体,以探测其功能.
- 了解双重PPARγ结合介导的不同调节机制.
主要方法:
- 开发一种选择性的PPARγ结合位的配体.
- 检测正确位子和替代位子的同时结合.
- 使用选择性配体对PPARγ辅助因子相互作用的分析.
- 差异性基因表达分析以评估PPARγ信号.
- 对FOXO信号通路的影响评估.
主要成果:
- 确定了一种模仿双维生素E代谢物结合的激动剂.
- 开发了第二个PPARγ结合点的选择性连接体,显示出非正规的调节.
- 替代部位的结合可以与正联体同时发生,从而改变PPARγ辅因子的相互作用.
- 这种替代结合缺乏TZDs的亲脂效应,并且不激活经典的PPAR信号.
- 值得注意的是,替代部位绑定显著降低了FOXO信号.
结论:
- 通过其两个连接位介导,PPARγ具有不同的调节机制.
- 针对替代结合位提供了一种独立于经典途径的PPARγ活性调节的新方法.
- 观察到的FOXO信号调节表明对代谢和其他疾病的潜在治疗应用.
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