基于GLUT4和SGLT2双靶点的槐属药用植物抗糖尿药效物质基础及作用机制研究

Type 2 diabetes mellitus is a metabolic disorder of the endocrine system associated with a variety of enzymes and receptors. But at present antidiabetic agents acting on single target can’t get good therapeutic results. So to develop multi-target antidiabetic agents is a new approach for discovery of new drugs. We previously demonstrated that lavandulyl flavonoids from Sophora flavescens displayed both GLUT4 translocation and SGLT2 inhibitory activity, and fraction rich in lavandulyl flavonoids exhibited in vivo significant antidiabetic effects, suggesting that lavandulyl flavonoids may be the main antidiabetic effective substances of Sophora medicinal plants. We will screen five Sophora medicinal plants with making use of the bioassay method based on double targets of GLUT4 and SGLT2, isolate and purify targetedly the lavandulyl flavonoids by bioassay and MS direction, investigate on the structure-activity relationship of in vitro antidiabetic activities of lavandulyl flavonoids and their interactions with targeted proteins, and evaluate in vivo antidiabetic effects of lavandulyl flavonoids in two type 2 diabetes animal models as wells as elucidate antidiabetic mechanisms on molecular, cellular and animal levels with molecular biological techniques in this study. Important theoretical basis for the prevention and treatment of diabete and developing Sophora medicinal plants will be provided by this study.

Ⅱ型糖尿病是一种与多种酶和受体相关的代谢性疾病，但目前针对单靶点的抗糖尿病药物还达不到理想疗效，因而开发作用于多靶点的抗糖尿病新药是药物研究的新方向。我们研究发现苦参Lavandulyl黄酮具有GLUT4转膜和SGLT2抑制的双重活性，且富含这类成分的部位具有明显的体内降糖效果，揭示Lavandulyl黄酮可能是槐属药用植物的主要抗糖尿病药效物质。本研究将利用基于GLUT4和SGLT2双靶点的筛选方法筛选5种槐属药用植物，运用基于HPLC的活性导向和质谱导向分离技术制备分离Lavandulyl黄酮，以计算机辅助药物设计研究Lavandulyl黄酮的抗糖尿病活性构效关系及与靶蛋白的相互作用，采用两种Ⅱ型糖尿病动物模型评价Lavandulyl黄酮的体内抗糖尿病效果，运用分子生物学技术从分子-细胞-动物水平上阐明Lavandulyl黄酮的抗糖尿病作用机制，为糖尿病防治和槐属药用植物开发提供依据。

Ⅱ型糖尿病是一种与多种酶和受体相关的代谢性疾病，但目前针对单靶点的抗糖尿病药物 还达不到理想疗效，因而开发作用于多靶点的抗糖尿病新药是药物研究的新方向。前期研究发现槐属植物含有的Lavandulyl黄酮具有GLUT4转膜和SGLT2抑制的双重活性，且富含这类成分的部位具有明显的体内降糖效果，揭示Lavandulyl黄酮可能是槐属药用植物的主要抗糖尿病药效物质。本研究利用基于GLUT4和SGLT2双靶点的筛选方法筛选槐属药用植物，综合运用各种柱层析技术，特别是基于HPLC的活性导向和质谱导向分离技术分离纯化128个单体化合物，其中52个有良好的促GLUT4转膜活性，15个具有SGLT2抑制活性。我们以计算机辅助药物设计研究部分Lavandulyl黄酮的体外抗糖尿病活性和GLUT4蛋白的构效关系。我们采用多种Ⅱ型糖尿病动物模型评价了4种槐属药用植物活性部位的体内糖尿活性，运用分子生物学技术从分子-细胞-动物水平上初步阐明了4种槐属药用植物的抗糖尿病作用机制。本项目的研究结果将为糖尿病防治和槐属药用植物开发提供依据。依托于本基金项目，发表相关科研学术论文22篇，其中SCI论文20篇，申报发明专利9项，授权4项，获得省部级二等奖奖项3项。