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

• Main Authors: Bin Yang (Author), Vasily M. Gelfanov (Author), Kimberley El (Author), Alex Chen (Author), Rebecca Rohlfs (Author), Barent DuBois (Author), Ann Maria Kruse Hansen (Author), Diego Perez-Tilve (Author), Patrick J. Knerr (Author), David D'Alessio (Author), Jonathan E. Campbell (Author), Jonathan D. Douros (Author), Brian Finan (Author)
• Format: Book
• Published: Elsevier, 2022-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 2212-8778; 10.1016/j.molmet.2022.101638
• Keywords: Peptide antagonist; GIP/GIPR; GLP-1/GLP-1R; Obesity; Diabetes; Internal medicine; RC31-1245
• Source: Molecular Metabolism, Vol 66, Iss , Pp 101638- (2022)

Objective: 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. Methods: 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. Results: We report the discovery of a GIP(5-31) palmitoylated analogue, [Nα-Ac, L14, R18, E21] hGIP(5-31)-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. Conclusions: 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.