Design of a novel long-acting dual GLP-1/GIP receptor agonist.

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. Copyright © 2024 Elsevier Ltd. All rights reserved.

Citation

Yuanzhen Dong, Jinhua Zhang, Hongjiang Xu, Hengqiao Shen, Qin Lu, Jun Feng, Zhengyan Cai. Design of a novel long-acting dual GLP-1/GIP receptor agonist. Bioorganic & medicinal chemistry. 2024 Feb 15;100:117630

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PMID: 38330849

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