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

Abstract

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.

Designing a Dual GLP-1R/GIPR Agonist from Tirzepatide: Comparing Residues Between Tirzepatide, GLP-1, and GIP

“…Tirzepatide Lys 16 may have a stacking interaction with GIPR Phe 127 . 8 In CY-5 experiments, if Ser 16 from GCG was changed to Lys from GIP, the GLP-1 activity decreased while the GIP activity increased. 16 Surprisingly, replacing GIP Lys 16 with Ala promotes the insulinotropic effect of GIP.…”

“… 62 Tirzepatide is also biased toward cAMP activation and the activity of β-arrestin recruitment is lower than that of native GLP-1 for GLP-1R. 8 , 56 , 63 After binding with a ligand for a certain period, the receptor will trigger the inward sinking of the membrane, forming an endosomal compartment, which is called agonist-induced receptor internalization. 64 Some of these endosomal compartments return to the membrane, while others fuse with lysosomes.…”

“…Tirzepatide has an obviously lower affinity with GIPR than GIP does (pIC 50 : 6.70 vs 7.87), and its cAMP activity is approximately equal to that of GIP. 6 , 8 …”