糖尿病具有血糖与脂质代谢异常的特征，胃泌酸调节素（OXM）具有GLP-1R和GCGR双重激动活性，可同时调控血糖、脂质代谢异常。但OXM对GLP-1R激动活性相对较弱，易被酶降解，半衰期短。本项目拟针对糖尿病发病机制设计合成长效化的特异性地提高GLP-1R激动活性，同时保持适度GCGR激动活性的OXM类似物，以期获得既具降糖效果又具调节脂质代谢异常（控制血糖代谢异常的重要因素）的候选活性肽。采用单模微波辅助固相合成技术，结合氨基酸位点扫描和优化肽链二级构象等方法，快速合成系列OXM类似物；分别进行受体激动活性和动物降糖调脂活性评价，筛选出GLP-1R/GCGR激动活性最优的多肽，再进行长效化修饰，以及深入的细胞分子水平的作用机制研究。最终总结分析OXM肽链序列变化及二级结构变化与GLP-1R/GCGR选择性及活性之间的相互关系，通过作用机制探索，力求在糖尿病药物治疗的基础研究方面有所突破。

Gastric intestinal peptide hormone - oxyntomodulin (OXM), a dual-acting GCGR and GLP-1R agonist, has become hot spot of the diabetes treatment drug research. However, the relatively weaker agonism of OXM on GLP-1R results in the less thypoglycemic activity when compare to GLP-1. Moreover, the half-life of OXM was short due to its susceptibility to rapid enzymatic degradation. In order to obtain candidates with favorable or moderate agonist activity on GLP-1R and GCGR respectively, a series of OXM analogs will be synthesized. Single-mode microwave-assisted solid-phase synthesis technology and the methods of amino acid sites scan and optimize peptide conformation will be applied in this study. Following rceptor activation assay in vitro and hypoglycemic activity assessment in vivo render us active polypeptides exhibiting favorable hypoglycemic effect and regulating lipid metabolic abnormalities. To prolong action duration of preferred polypeptides, long-acting modification strategies are employed to develop dual-acting GCGR and GLP-1R agonists with prolonged in vivo half-lives and then the cellular and molecular mechanisms of the prolonged agonist are explored. In conclusion, the candidates obtained is expected to possess better hypoglycemic activity than OXM. The relationships between the amino acid sequence and secondary structure changes and selectivity and activity on GLP-1R/GCGR will be revealed, and the mechanism exploration wil be strived to hold a promising breakthrough in the basic research on the diabetes medication.