以糖皮质激素受体α为新靶点的抗肥胖症惕各烷型二萜的发现与研究

肥胖症是一系列代谢性疾病的重要诱因，已成为全球第五大致死疾病。目前上市药物在靶点或机制存上存在一定缺陷，限制了其临床应用。前期研究中我们从中药小狼毒根部发现了一类结构新颖的惕各烷型二萜(5/7/6/3环系碳骨架)。该类化合物在细胞（EC50 = 0.32μM）和动物水平（小鼠减重27%）显示出良好的降脂活性，且毒性较低。机制研究表明该类化合物的潜在作用靶点可能为糖皮质激素受体α（GRα）：与GRα结合，抑制GRα蛋白转位入核，下调GRα-Dexras1轴相关基因及蛋白表达水平，将脂肪细胞分化成脂过程阻滞在早期。本项目拟在上述基础上，通过提取分离和化学合成构建结构多样性的惕各烷型二萜小分子库，筛选出具有高降脂活性的选择性GRα抑制剂，阐明其分子作用模式、构效关系；并通过深入的体内外机制、药效学研究及早期成药性评价，为基于GRα为新靶点的抗肥胖症药物研发奠定基础。

Obesity is the major inducement of a series of metabolic diseases, and is listed as the fifth leading cause of death worldwide. The targets and mechanisms of current anti-obesity drugs exist drawbacks, restricting their clinical use. In our early research, a series of tigliane-tpye diterpenoids (5/7/6/3 carbon ring system) were isolated from the roots of a traditional Chinese medicine Euphorbia prolifera. These tiglianes exhibited remarkable lipid-lowering activity in vitro （EC50 = 0.32 μM）and in vivo （reduce the mice weight by 27%）without apparent cytotoxicity. Mechanistic study suggested that these tiglianes may target the glucocorticoid receptor α (GRα), inhibiting the translocation of GRα and then down-regulate the GRα-Dexras 1 axis, which finally lead to the retardation of adipocyte differentiation at the early stage. .In this proposal, we are aiming to construct a structurally diverse tigliane library via natural product chemistry and synthetic chemistry methods; obtain the potent lipid-lowering agents via systematically screening of this library; illustrate the structure−activity relationship and molecular interaction mechanism of the active tiglianes with GRα; explore the in vitro/vivo mechanism, efficacy, and potential druggability of the active tiglianes. The above research will hopefully pave the way for GRα-based anti-obesity drug development.