Exenatide is known as the first marketed GLP-1 agonist for antidiabetic treatment, but it need twice injection a day because of its fast clearance. This work aims to prolong the half-life of exenatide by modified with novel lipid chain. Four optimized exenatide analogs named as Cys12-Exenatide (1–39)-NH₂, Cys40-Exenatide (1–39)-NH₂, Cys12-Tyr22-Gln24-Glu28-Arg35-Exenatide (1–39)-NH₂ and Tyr22-Gln24-Glu28-Arg35-Cys40-Exenatide (1–39)-NH₂ were selected and applied for conjugation. Then a series of evaluations including GLP-1R activation assay were conducted, conjugation C2 was selected for further investigation. Glucoregulatory and insulin secretion assay and hypoglycemic duration test were accessed and showed that C2 was capable of comparable insulinotropic activities and glucose-lowering abilities with those of liraglutide and exenatide. Cell protective effects in INS-1 cells confirmed that C2 had relatively protection effects. Meanwhile, once daily injection of C2 to STZ-induced diabetic mice achieved long-term beneficial effects on glucose tolerance, body weight and blood chemistry. Acute feeding studies were evaluated in DIO mice. These results suggested that C2 is a promising agent for further investigation of its potential to treat diabetes patients with obese.

艾塞那肽是第一个上市的用于抗糖尿病治疗的GLP-1激动剂，但由于其清除速度快，因此每天需要注射两次。这项工作旨在通过新型脂质链修饰来延长艾塞那肽的半衰期。四个优化的艾塞那肽类似物，分别称为Cys12-艾塞那肽（1-39）-NH ₂，Cys40-艾塞那肽（1-39）-NH ₂，Cys12-Tyr22-Gln24-Glu28-Arg35-艾塞那肽（1-39）-NH ₂和选择Tyr22-Gln24-Glu28-Arg35-Cys40-艾塞那肽（1-39）-NH ₂并用于缀合。然后进行了包括GLP-1R激活测定在内的一系列评估，共轭C2被选中进行进一步调查。进行了调糖和胰岛素分泌测定以及降糖持续时间测试，结果表明C2具有与利拉鲁肽和艾塞那肽相当的促胰岛素活性和降糖能力。在INS-1细胞中的细胞保护作用证实C2具有相对的保护作用。同时，每天一次向STZ诱导的糖尿病小鼠注射C2对葡萄糖耐量，体重和血液化学具有长期有益的作用。在DIO小鼠中评估了急性喂养研究。这些结果表明，C2是用于进一步研究其治疗肥胖型糖尿病患者潜力的有前途的药物。