基于GLP-1代谢片段的新型减肥降糖多肽的分子构建及生物活性研究

胰高血糖素样肽-1（GLP-1）是一种减肥降糖多肽，但半衰期较短，减肥作用有限。本项目着眼于GLP-1代谢片段针对肥胖2型糖尿病相关生物活性研究，拟首先采用“序列漫步”策略，筛寻具有减肥降糖双重作用的GLP-1活性代谢片段，接着对其进行结构优化和生物活性测试，通过构效关系研究筛选出减肥降糖活性较好的GLP-1活性代谢片段类似物。然后，优选片段类似物再进行长效化修饰，得到目标缀合肽。最后对缀合肽进行稳定性研究、短期给药生物活性研究以及作用机制研究，并通过长期给药来系统性评价优选缀合肽的生物活性。本项目的完成既能为肥胖2型糖尿病治疗药物的研发提供理想的先导化合物，又能通过深入研究GLP-1代谢片段减肥降糖作用的构效关系，为研发治疗肥胖2型糖尿病的新型多肽药物提供理论依据。

Glucagon-like peptide-1 (GLP-1) is a polypeptide with weight lowering and hypoglycemic activities, but its half-life is short and weight lowering effect is limited. In this study, we focus on the biological activity assessment of GLP-1 metabolites in treatment of type 2 diabetes with obesity. The proposed project will firstly screen GLP-1 active metabolic fragments with weight lowering and hypoglycemic activities using the "sequence walk" strategy. By using novel GLP-1 fragment as a starting point, structure modification will be conducted and the enzymatic stability and biological activity tests will be carried out to explore the structure-activity relationship. The derivatives with favorable antidiabetic and antiobesity activity will then be conjugated with small molecules with strong affinity to human serum albumin to prolong the duration of action. Then, the pharmacokinetic profile, hypoglycemic and body weight lowering effects of the conjugates will be comprehensively studied to discover novel long-acting conjugates with favorable antidiabetic and antiobesity activity. It is anticipated that the completion of this project will provide an ideal lead compound for the treatment of type 2 diabetes with obesity, and in-depth study the structure-activity relationship of GLP-1 metabolites on hypoglycemic and weight lowering activities, provide a theoretical basis for the development of the new long-acting peptides to treat type 2 diabetes with obesity.