Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, P. R. China.
School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, P. R. China.
J Med Chem. 2022 Oct 27;65(20):14201-14220. doi: 10.1021/acs.jmedchem.2c01385. Epub 2022 Oct 10.
GLP-1 receptor (GLP-1R) and neuropeptide Y receptor (YR) dual agonists have shown great potential to treat obesity and type 2 diabetes (T2DM). We developed a multitarget strategy to design monomeric agonists based on GLP-1 (xGLP-1) and PYY analogues with dual activation activities on GLP-1R and YR. A novel peptide, , was obtained via stepwise structure optimization and receptor screens. In / and diet-induced obesity (DIO) mice, produced greater effects on long-term glycemic control and body weight reduction than GLP-1R and YR monoagonist counterparts. Notably, in high-fat diet-induced nonalcoholic steatohepatitis (NASH) mice, treatment significantly reduced hepatic triglyceride and total cholesterol levels and reversed hepatic steatosis compared with GLP-1R monoagonist (liraglutide) treatment. Collectively, these data support the therapeutic potential of our GLP-1R/YR dual agonist as a novel antidiabetic, antiobesity, and antisteatotic agent.
GLP-1 受体 (GLP-1R) 和神经肽 Y 受体 (YR) 双重激动剂在治疗肥胖症和 2 型糖尿病 (T2DM) 方面显示出巨大的潜力。我们开发了一种多靶点策略，基于 GLP-1 (xGLP-1) 和 PYY 类似物，设计具有 GLP-1R 和 YR 双重激活活性的单体激动剂。通过逐步结构优化和受体筛选，获得了一种新型肽 。在 和饮食诱导肥胖 (DIO) 小鼠中， 对长期血糖控制和体重减轻的效果优于 GLP-1R 和 YR 单激动剂对应物。值得注意的是，在高脂肪饮食诱导的非酒精性脂肪性肝炎 (NASH) 小鼠中， 治疗可显著降低肝甘油三酯和总胆固醇水平，并与 GLP-1R 单激动剂 (利拉鲁肽) 治疗相比，逆转肝脂肪变性。总之，这些数据支持我们的 GLP-1R/YR 双重激动剂 作为一种新型抗糖尿病、抗肥胖和抗脂肪变性药物的治疗潜力。
