%0 Journal Article %T Disconnect between signalling potency and in vivo efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists %V 37 %P 100991 %U https://www.sciencedirect.com/science/article/pii/S221287782030065X %X 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. %G en %J Molecular Metabolism %A Lucey, Maria %A Pickford, Philip %A Bitsi, Stavroula %A Minnion, James %A Ungewiss, Jan %A Schoeneberg, Katja %A Rutter, Guy A. %A Bloom, Stephen R. %A Tomas, Alejandra %A Jones, Ben %D July 1, 2020 %K Biased signalling Exendin-4 Glucagon-like peptide-1 receptor Trafficking Type 2 diabetes WP4