biostudies-literatureUnknown66Yang B<h4>Objective</h4> 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. <h4>Methods</h4> 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. <h4>Results</h4> 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. <h4>Conclusions</h4> 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. Highlights • [Nα-Ac, L14, R18, E21] hGIP(5-31) - K11 (γE-C16) is a potent and specific GIPR peptide antagonist.• Protraction chemistry and location influences pharmacology, not simply PK profile.• The lead peptide displays a PK profile amenable for once-daily dosing in rodents.• The lead antagonist potentiates GLP-1R agonist mediated weight loss in rodents.• GIP, not GLP-1, action is diminished by the lead antagonist in intact human islets.Molecular metabolismhttps://www.ebi.ac.uk/biostudies/studies/S-EPMC9719863biostudies-literatureDiscovery of a potent GIPR peptide antagonist that is effective in rodent and human systemsPMC9719863Gelfanov VPerez-Tilve DD'Alessio DFinan BYang BRohlfs REl KChen ACampbell JDouros JKruse Hansen ADuBois BKnerr PfalseDiscovery of a potent GIPR peptide antagonist that is effective in rodent and human systems<h4>Objective</h4> 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. <h4>Methods</h4> 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. <h4>Results</h4> 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. <h4>Conclusions</h4> 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. Highlights • [Nα-Ac, L14, R18, E21] hGIP(5-31) - K11 (γE-C16) is a potent and specific GIPR peptide antagonist.• Protraction chemistry and location influences pharmacology, not simply PK profile.• The lead peptide displays a PK profile amenable for once-daily dosing in rodents.• The lead antagonist potentiates GLP-1R agonist mediated weight loss in rodents.• GIP, not GLP-1, action is diminished by the lead antagonist in intact human islets.2022-01-01T00:00:00Z2022 Nov2025-06-01T01:20:46.963Z2025-06-01T01:20:46.963ZS-EPMC9719863