ERR-alpha 小分子激动剂及其对糖脂代谢调控的机理研究

项目名称： ERR-alpha 小分子激动剂及其对糖脂代谢调控的机理研究

项目编号： No.21272235

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 数理科学和化学

项目作者： 丁克

作者单位： 中国科学院广州生物医药与健康研究院

项目金额： 80万元

中文摘要： ERRa在线粒体生物合成，氧化磷酸化等糖脂代谢过程中发挥重要的调节作用，选择性ERRa小分子激动剂有可能成为治疗Ⅱ型糖尿病等代谢性疾病的新策略。我们已世界首次报道了嘧啶酮类和喹唑啉酮类化合物可有效地选择性提高ERRa的转录活性，促进氧化磷酸化调节基因的转录和表达，并改善肌肉细胞对葡萄糖和脂肪酸的摄取。其中候选药物DK3表现出很好的动物体内降糖活性。但是，化合物调节ERRa转录功能和能量代谢的具体机制尚不清楚。本项目将利用分子标记，基因沉默等化学生学方法，深入研究化合物对ERRa调节的作用机制,考察化合物对糖脂代谢调节作用是否依赖于其对ERRa转录功能的调节，为进一步阐明ERRa的功能及其作为药物开发有效性靶点等奠定基础。同时，我们将进一步设计和合成具有不同分子骨架的新型选择性ERRa调节剂，为ERRa激动剂类抗代谢疾病药物开发提供backup分子.

中文关键词： 雌激素相关受体；激动剂；反向激动剂；代谢；设计

英文摘要： The Estrogen-Related Receptor a(ERRa) plays a central role in the regulation of expression of the genes involved in mitochondrial biogenesis and oxidative metabolism. Therefore, ERR has been considered a novel potential drug target and selective ERRa agonists might be developed as new therapeutic agents for the treatment of type II diabetes and other metabolic disorders. We have argurably reported the first class of small molecular ERRa agonists with pyrido[1,2-a]pyrimidin-4-one or quinazolin-4(3H)-one chemical scaffolds. The compounds potently enhanced the transcription of ERRa downstream target genes and improved the glucose and fatty acid uptake in C2C12 muscle cells. One of the most promising candidates DK3 effectively alleviated glucose intolerance and hepatosteatosis in both high-fat-diet (HFD) induced and ob/ob mouse models. However, the precise mechanism remains elusive. In this proposal, we will extensively study the mechanism of regulating functions and other ERR? modulators by using both chemical biology approaches and ERRa gene knockout (or knockdown) models. Furthermore, we will also design and synthesis novel ERRa modulators with different chemical scaffolds to provide new backup molecules for the further development of DK3. Our results may provide an interesting basis for further understanding th

英文关键词： estrogen-related receptor；agonist；inverse agonist；metabolism；design