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Structural basis for the therapeutic advantage of dual and triple agonists at the human GIP, GLP-1 or GCG receptors

By Fenghui Zhao, Qingtong Zhou, Zhaotong Cong, Kaini Hang, Xinyu Zou, Chao Zhang, Yan Chen, Antao Dai, Anyi Liang, Qianqian Ming, Mu Wang, Linan Chen, Peiyu Xu, Rulue Chang, Wenbo Feng, Tian Xia, Yan Zhang, Beili Wu, Dehua Yang, Lihua Zhao, H. Eric Xu, Ming-Wei Wang

Posted 30 Jul 2021
bioRxiv DOI: 10.1101/2021.07.29.454286

Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists at GIPR, GLP-1R or GCGR, developed to maximize metabolic benefits with reduced side-effects, are in clinical trials to treat type 2 diabetes and obesity. To elucidate the molecular mechanisms by which tirzepatide, a GIPR/GLP-1R dualagonist, and peptide 20, a GIPR/GLP-1R/GCGR triagonist, manifest their superior efficacies over monoagonist such as semaglutide, we determined cryo-electron microscopy structures of tirzepatide-bound GIPR and GLP-1R as well as peptide 20-bound GIPR, GLP-1R and GCGR The structures reveal both common and unique features for the dual and triple agonism by illustrating key interactions of clinical relevance at the atomic level. Retention of glucagon function is required to achieve such an advantage over GLP-1 monotherapy. Our findings provide valuable insights into the structural basis of functional versatility and therapeutic supremacy of tirzepatide and peptide 20.

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