@article{lucey_disconnect_2020, title = {Disconnect between signalling potency and in vivo efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists}, volume = {37}, issn = {2212-8778}, url = {https://www.sciencedirect.com/science/article/pii/S221287782030065X}, doi = {10.1016/j.molmet.2020.100991}, abstract = {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.}, language = {en}, urldate = {2021-02-05}, journal = {Molecular Metabolism}, author = {Lucey, Maria and Pickford, Philip and Bitsi, Stavroula and Minnion, James and Ungewiss, Jan and Schoeneberg, Katja and Rutter, Guy A. and Bloom, Stephen R. and Tomas, Alejandra and Jones, Ben}, month = jul, year = {2020}, keywords = {Biased signalling, Exendin-4, Glucagon-like peptide-1 receptor, Trafficking, Type 2 diabetes, WP4}, pages = {100991}, }