TY - JOUR T1 - Disconnect between signalling potency and <em>in vivo</em> efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists JF - bioRxiv DO - 10.1101/855874 SP - 855874 AU - Maria Lucey AU - Philip Pickford AU - James Minnion AU - Jan Ungewiss AU - Katja Schoeneberg AU - Guy A Rutter AU - Stephen R Bloom AU - Alejandra Tomas AU - Ben Jones Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/11/26/855874.abstract N2 - Objective 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-1 receptor 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, exendin-phe1-C16, was identified with 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 exendin-asp-3-C16 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. ER -