口服新型降糖多肽ODA的设计及其口服降糖活性  

Design and oral hypoglycemic activity of novel oral hypoglycemic peptide ODA

作　　者：安东贤 姚文兵[1] 高向东[1] 田浤[1] AN Dongxian;YAO Wenbing;GAO Xiangdong;TIAN Hong(Jiangsu Provincial Key Laboratory of Druggability of Biopharmaceuticals,School of Life Science and Technology,China Pharmaceuti-cal University,Nanjing 211198,China)

机构地区：[1]中国药科大学生命科学与技术学院、江苏省生物药物成药性研究重点实验室,南京211198

出　　处：《中国药科大学学报》2023年第4期511-518,共8页Journal of China Pharmaceutical University

基　　金：新疆维吾尔自治区重点研发计划项目资助(No.2020B03003)。

摘　　要：肠促胰岛素分泌肽胰高血糖素样肽-1(GLP-1)和葡萄糖依赖性促胰岛素释放多肽(GIP)能通过血糖依赖机制促进胰岛素分泌,其特异性结合受体GLP-1R和GIPR是治疗2型糖尿病的良好靶点。以本实验室前期设计的口服降糖多肽OHP2为基础,设计了可口服的新型降糖多肽——ODA。ODA较OHP2的亲脂性提高,在Caco-2细胞中的胞吞能力及跨细胞转运能力更强。ODA保留了OHP2对GLP-1R的激活能力,增强了与GIPR的结合能力。口服低剂量ODA(0.53 mg/kg)即可达到与口服OHP2(1.06 mg/kg)相当的降糖水平。研究结果显示,ODA是治疗2型糖尿病极具潜力的口服药物。Incretin promotes insulin secretion through a glucose-dependent mechanism,involving glucagon-like peptide-1(GLP-1)and glucose-dependent insulinotropic peptide(GIP).Therefore,their correspondingly specific receptors GLP-1R and GIPR are suitable targets for the treatment of type 2 diabetes.Based on the oral hypogly⁃cemic peptide OHP2 designed by our team,we further designed a new oral hypoglycemic peptide,ODA to reduce glucose.Compared with OHP2,ODA exhibited better lipophilicity as well as the enhanced endocytosis and trans⁃cytosis in Caco-2 cells.In addition,ODA remained the ability to activate GLP-1R and enhanced the binding abil⁃ity to GIPR.The hypoglycemic efficacy of the low-dose ODA(0.53 mg/kg)is comparable to that of OHP2(1.06 mg/kg).These results indicated that ODA could be a new oral drug with potential for the treatment of type 2 dia⁃betes.

关 键 词：肠促胰岛素分泌肽 胰高血糖素样肽-1 葡萄糖依赖性促胰岛素释放多肽 2型糖尿病 口服降糖活性 

分 类 号：TQ936[化学工程]