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

ABSTRACT:

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. 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.

SUBMITTER: Yang B 

PROVIDER: S-EPMC9719863 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature