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

Bioorg Med Chem. 2024 Feb 3;100:117630. doi: 10.1016/j.bmc.2024.117630. Online ahead of print.ABSTRACTTirzepatide, 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.PMID:38330849 | DOI:10.1016/j.bmc.2024.117630
Source: Bioorganic and Medicinal Chemistry - Category: Chemistry Authors: Source Type: research