Discovery of a potent GIPR peptide antagonist that is effective in rodent and human systems

• Published in: Molecular metabolism (Germany) 2022-12, Vol.66, p.101638-101638, Article 101638
• Main Authors: Yang, Bin, Gelfanov, Vasily M, El, Kimberley, Chen, Alex, Rohlfs, Rebecca, DuBois, Barent, Kruse Hansen, Ann Maria, Perez-Tilve, Diego, Knerr, Patrick J, D'Alessio, David, Campbell, Jonathan E, Douros, Jonathan D, Finan, Brian
• Format: Article
• Language: English
• Subjects: Animals; Diabetes; Gastric Inhibitory Polypeptide - antagonists & inhibitors; Gastric Inhibitory Polypeptide - metabolism; GIP/GIPR; GLP-1/GLP-1R; Glucagon-Like Peptide 1 - metabolism; Glucagon-Like Peptide-1 Receptor - metabolism; Humans; Mice; Mice, Obese; Obesity; Original; Peptide antagonist; Peptides - chemistry; Peptides - pharmacology; Receptors, Gastrointestinal Hormone - antagonists & inhibitors; Rodentia - metabolism; Weight Loss
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2022.101638

Glucose-dependent insulinotropic polypeptide (GIP) is one of the two major incretin factors that regulate metabolic homeostasis. Genetic ablation of its receptor (GIPR) in mice confers protection against diet-induced obesity (DIO), while GIPR neutralizing antibodies produce additive weight reduction when combined with GLP-1R agonists in preclinical models and clinical trials. Conversely, GIPR agonists have been shown to promote weight loss in rodents, while dual GLP-1R/GIPR agonists have proven superior to GLP-1R monoagonists for weight reduction in clinical trials. We sought to develop a long-acting, specific GIPR peptide antagonist as a tool compound suitable for investigating GIPR pharmacology in both rodent and human systems. We report a structure-activity relationship of GIPR peptide antagonists based on the human and mouse GIP sequences with fatty acid-based protraction. We assessed these compounds in vitro, in vivo in DIO mice, and ex vivo in islets from human donors. We report the discovery of a GIP palmitoylated analogue, [N -Ac, L14, R18, E21] hGIP -K11 (γE-C16), which potently inhibits in vitro GIP-mediated cAMP generation at both the hGIPR and mGIPR. In vivo, this peptide effectively blocks GIP-mediated reductions in glycemia in response to exogenous and endogenous GIP and displays a circulating pharmacokinetic profile amenable for once-daily dosing in rodents. Co-administration with the GLP-1R agonist semaglutide and this GIPR peptide antagonist potentiates weight loss compared to semaglutide alone. Finally, this antagonist inhibits GIP- but not GLP-1-stimulated insulin secretion in intact human islets. Our work demonstrates the discovery of a potent, specific, and long-acting GIPR peptide antagonist that effectively blocks GIP action in vitro, ex vivo in human islets, and in vivo in mice while producing additive weight-loss when combined with a GLP-1R agonist in DIO mice.