Disconnect between signalling potency and in vivo efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists
| Autor: | Philip Pickford, Guy A. Rutter, Alejandra Tomas, Stephen R. Bloom, James Minnion, Ben Jones, Katja Schoeneberg, Stavroula Bitsi, Jan Ungewiss, Maria Lucey |
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| Přispěvatelé: | Medical Research Council (MRC), The Academy of Medical Sciences, Society for Endocrinology, European Foundation for the Study of Diabetes |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Acylation GLP-1RA glucagon-like peptide-1 receptor agonist Pharmacology 0601 Biochemistry and Cell Biology law.invention Mice 0302 clinical medicine n.c. not calculable law Glucagon-Like Peptide 1 Receptors Glucagon Receptor TR-FRET time-resolved Förster resonance energy transfer Trafficking Chemistry Type 2 diabetes Ligand (biochemistry) Glucagon-like peptide-1 3. Good health cAMP cyclic adenosine monophosphate FITC fluorescein isothiocyanate Signal Transduction lcsh:Internal medicine PBS phosphate-buffered saline 030209 endocrinology & metabolism T2D type 2 diabetes AUC area under curve Brief Communication SEM standard error of the mean Glucagon-Like Peptide-1 Receptor 03 medical and health sciences Pharmacokinetics Confocal microscopy In vivo Potency Animals Humans HTRF homogenous time-resolved fluorescence lcsh:RC31-1245 HBSS Hank's buffered salt solution Molecular Biology Biased signalling Dose-Response Relationship Drug Exendin-4 Cell Biology DIO diet-induced obesity LC/MSMS liquid chromatography/tandem mass spectrometry 0606 Physiology Peptide Fragments 030104 developmental biology Glucose HEK293 Cells Exenatide Blood sugar regulation BSA bovine serum albumin Peptides |
| Zdroj: | Molecular Metabolism Molecular Metabolism, Vol 37, Iss, Pp 100991-(2020) |
| ISSN: | 2212-8778 |
| Popis: | Objective The objective of this study was to determine how pharmacokinetically advantageous acylation impacts on glucagon-like peptide-1 receptor (GLP-1R) signal bias, trafficking, anti-hyperglycaemic efficacy, and appetite suppression. Methods In vitro signalling responses were measured using biochemical and biosensor assays. GLP-1R trafficking was determined by confocal microscopy and diffusion-enhanced resonance energy transfer. Pharmacokinetics, glucoregulatory effects, and appetite suppression were measured in acute, sub-chronic, and chronic settings in mice. Results A C-terminally acylated ligand, [F1,G40,K41.C16 diacid]exendin-4, was identified that showed undetectable β-arrestin recruitment and GLP-1R internalisation. Depending on the cellular system used, this molecule was up to 1000-fold less potent than the comparator [D3,G40,K41.C16 diacid]exendin-4 for cyclic AMP signalling, yet was considerably more effective in vivo, particularly for glucose regulation. Conclusions C-terminal acylation of biased GLP-1R agonists increases their degree of signal bias in favour of cAMP production and improves their therapeutic potential. Highlights • Programming of GLP-1R agonists for selective signalling. • Signal bias allows “low efficacy” agonists to be highly effective in vivo. • GLP-1R endocytosis does not affect pharmacokinetics. |
| Databáze: | OpenAIRE |
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