Abstract：
Tirzepatide, the first approved dual GLP-1/GIP receptor agonist (RA), has achieved better clinical outcomes than other GLP-1RAs. However, it is an imbalanced dual GIP/GLP-1 RA, and it remains unclear whether the degree of imbalance is optimal. Here, we present a novel long-acting dual GLP-1/GIP RA that exhibits better activity than tirzepatide toward GLP-1R. A candidate conjugate, D314, identified via peptide design, synthesis, conjugation, and experimentation, was evaluated using chronic studies in db/db and diet induced obese (DIO) mice. D314 achieved favorable blood glucose and body weight-lowering effects, equal to those of tirzepatide. Its half-life in dogs (T1/2: 78.3 ± 14.01 h) reveals its suitability for once-weekly administration in humans. This preclinical study suggests the potential role of D314 as an effective agent for treating T2DM and obesity.
摘要：
Tirzepatide,第一个批准的双重GLP-1/GIP受体激动剂（RA），取得了比其他GLP-1RA更好的临床结果。然而,它是一种不平衡的双重GIP/GLP-1RA，目前尚不清楚失衡的程度是否最优。这里,我们提出了一种新型的长效双重GLP-1/GIPRA,其对GLP-1R的活性优于替利西肽。候选缀合物,D314，通过肽设计鉴定，合成，共轭，和实验，在db/db和饮食诱导的肥胖（DIO）小鼠中使用慢性研究进行评估。D314取得了良好的血糖和体重降低效果，等于那些的tirzepatide。其在狗中的半衰期（T1/2：78.3±14.01h）表明其适合每周一次在人类中给药。这项临床前研究表明D314作为治疗T2DM和肥胖症的有效药物的潜在作用。
