Discovery of a novel GLP-1/GIP dual receptor agonist CY-5 as long-acting hypoglycemic, anti-obesity agent
Discovery of a novel GLP-1/GIP dual receptor agonist CY-5 as long-acting hypoglycemic, anti-obesity agent
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发现新型 GLP-1/GIP 双受体激动剂 CY-5 作为长效降血糖、抗肥胖剂
DOI：
10.1016/j.bioorg.2020.104492
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发表时间：
2021
影响因子：
5.1
通讯作者：
Wenjie Zhang
中科院分区：
文献类型：
--
作者：
Chunxia Liu;Chengye Li;Xingguang Cai;Yuxing Zou;Jiaxian Mo;Bin Chen;Yan Cai;Ting Han;Wenlong Huang;Hai Qian;Wenjie Zhang
胰高血糖素样肽-1（GLP-1）受体激动剂作为治疗2型糖尿病（T2 DM）的有效手段已被广泛研究，以GLP-1为基础的多种受体激动剂对肥胖、非酒精性脂肪性肝炎（NASH）等代谢性疾病可能有更好的临床疗效。为了得到基于GLP-1的多激动剂，设计、合成了15种缀合物，并进行了生物活性测试。GLP-1/胰高血糖素双受体激动剂E1表现出中等的长效降血糖作用，具有GLP-1/GIP双受体激动剂活性的CY-5和CY-16表现出较长的持续血糖稳定持续时间。长效降血糖作用与Semaglutide相同。虽然CY-5已经失去了对胰高血糖素受体的激动活性，但对T2 DM小鼠和饮食诱导的肥胖（DIO）小鼠的长期体内研究表明，CY-5可以有效地减少食物摄入，抑制体重增加，修复胰岛损伤，改善葡萄糖耐量。对NASH小鼠治疗1个月后，CY-5能显著降低TG、TC、AST、ALT和LDL-C，升高HDL-C。CY-5还能改善肝空泡形成，减少脂肪堆积，延缓肝纤维化进程。保肝作用优于Semaglutide。综上所述，CY-5是治疗代谢性疾病的有希望的候选物，值得进一步开发。
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.