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

Nov 18, 2022Molecular metabolism

Identification of a strong peptide blocker of the GIP receptor effective in both rodent and human systems

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Abstract

The GIP palmitoylated analogue [N-Ac, L14, R18, E21] hGIP-K11 (γE-C16) effectively blocks GIP action and promotes weight loss when combined with a GLP-1R agonist in mice.

This peptide antagonist potently inhibits GIP-mediated cAMP generation in both human and mouse receptors.
It effectively blocks GIP-mediated reductions in blood sugar levels in response to GIP.
The pharmacokinetic profile of the peptide allows for once-daily dosing in rodents.
Combining this GIPR antagonist with the GLP-1R agonist semaglutide enhances weight loss compared to semaglutide alone.
The antagonist specifically inhibits GIP-stimulated insulin secretion in human islets without affecting GLP-1 stimulation.

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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 GIPpalmitoylated 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. (5-31) (5-31) α

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.

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

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