Strategic Design of Triple GLP-1R/GCGR/GIPR Agonists with Varied Receptor Potency: Achieving Comparable Glycemic and Weight Reduction Effects.

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-09-16 DOI:10.1021/acs.jmedchem.5c02032

Shuang Wang,Yun Liu,Zhiming Yan,Xianxian Huang,Yonghe Liao,Chunli Tang,Lin Jing,Zhongbo Zhou,Jing Han,Weizhong Tang,Neng Jiang

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Abstract

Triple activation of the glucagon-like peptide 1 receptor (GLP-1R), the GIP receptor (GIPR), and the glucagon receptor (GCGR) is an innovative strategy for treating obesity and diabetes. We report the rational design of triple GLP-1R/GCGR/GIPR agonists, featuring potent GLP-1R and GCGR activity with weaker GIPR activation. Using sequence analysis, molecular dynamics simulations, docking, and amino acid optimization, we developed xGLP-1-based triagonists, with xGLP/GCG/GIP-32 exhibiting a unique activation profile. It shows superior weight loss effects compared to tirzepatide and similar metabolic efficacy to retatrutide, despite significantly less potent GIPR activity. Preliminary mechanistic studies revealed that xGLP/GCG/GIP-32 exhibits biased agonism toward the GIPR and GCGR. These activity data suggest it may not be imperative to focus solely on potent activation of all three receptors. Especially for triple agonists with receptor-biased agonism, there may be room to explore optimal receptor activation ratios.

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具有不同受体效力的三重GLP-1R/GCGR/GIPR激动剂的策略设计：实现可比的降糖和减肥效果。

胰高血糖素样肽1受体（GLP-1R）、胰高血糖素受体（GIPR）和胰高血糖素受体（GCGR）的三重激活是治疗肥胖和糖尿病的一种创新策略。我们报告了三重GLP-1R/GCGR/GIPR激动剂的合理设计，具有强大的GLP-1R和GCGR活性，而GIPR活性较弱。通过序列分析、分子动力学模拟、对接和氨基酸优化，我们开发了基于xGLP-1的三角拮抗剂，其中xGLP/GCG/GIP-32具有独特的激活谱。与替西帕肽相比，它的减肥效果更好，代谢效果与利特鲁肽相似，尽管GIPR活性明显较弱。初步的机制研究表明，xGLP/GCG/GIP-32对GIPR和GCGR表现出偏激作用。这些活性数据表明，可能没有必要仅仅关注这三种受体的有效激活。特别是对于具有受体偏向激动作用的三重激动剂，可能有探索最佳受体激活比的空间。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.