Glucagon-like peptide-1(GLP-1) receptor agonists as an effective approach for type 2 diabetes mellitus(T2DM) has been explored extensively, multi agonists based on GLP-1 may have better clinical benefits on obesity, Nonalcoholic steatohepatitis (NASH) and other metabolic diseases. To get multi agonists based on GLP-1, 15 conjugates were designed, synthesized, and tested for biological activity. GLP-1/glucagon dual receptor agonist E1 showed moderate long-acting hypoglycemic effect, CY-5 and CY-16 with GLP-1/GIP dual receptor agonistic activity exhibited longer duration of continuous blood glucose stabilization. The long-acting hypoglycemic effect was equal to that of semaglutide. Although they have lost the agonistic activity on glucagon receptor, chronic in vivo studies on T2DM mice and diet-induced obesity (DIO) mice showed that CY-5 can effectively reduce food intake, inhibit body weight gain, repair islets damage and improve the glucose tolerance. One month treatment on NASH mice showed that CY-5 can significantly lower the TG, TC, AST, ALT and LDL-C and increase the HDL-C. CY-5 can also improve the liver vacuolation, reduce fat accumulation and delay the process of the fibrosis. The liver protection effect is better than that of semaglutide. In summary, CY-5 is a promising candidate for the treatment of metabolic diseases and worthy for further development.

胰高血糖素样肽-1（GLP-1）受体激动剂作为治疗 2 型糖尿病（T2DM）的有效方法已被广泛探索，基于 GLP-1 的多效激动剂可能对肥胖、非酒精性脂肪性肝炎（NASH）有更好的临床益处和其他代谢疾病。为了获得基于 GLP-1 的多激动剂，我们设计、合成了 15 种偶联物并测试了其生物活性。GLP-1/胰高血糖素双重受体激动剂E1显示出中度长效降血糖作用，具有GLP-1/GIP双重受体激动活性的CY-5和CY-16表现出更长的持续血糖稳定持续时间。长效降血糖作用与司美鲁肽相同。虽然它们已经失去了对胰高血糖素受体的激动活性，对 T2DM 小鼠和饮食诱导肥胖 (DIO) 小鼠的慢性体内研究表明，CY-5 可有效减少食物摄入、抑制体重增加、修复胰岛损伤并提高糖耐量。对 NASH 小鼠进行 1 个月的治疗表明，CY-5 可以显着降低 TG、TC、AST、ALT 和 LDL-C，并增加 HDL-C。CY-5还可以改善肝脏空泡化，减少脂肪堆积，延缓纤维化进程。保肝效果优于司美鲁肽。综上所述，CY-5 是治疗代谢性疾病的有前景的候选者，值得进一步开发。ALT 和 LDL-C 并增加 HDL-C。CY-5还可以改善肝脏空泡化，减少脂肪堆积，延缓纤维化进程。保肝效果优于司美鲁肽。综上所述，CY-5 是治疗代谢性疾病的有前景的候选者，值得进一步开发。ALT 和 LDL-C 并增加 HDL-C。CY-5还可以改善肝脏空泡化，减少脂肪堆积，延缓纤维化进程。保肝效果优于司美鲁肽。综上所述，CY-5 是治疗代谢性疾病的有前景的候选者，值得进一步开发。