Disconnect between signalling potency and in vivo efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists

Lucey, M.; Pickford, P.; Minnion, J.; Ungewiss, J.; Schoeneberg, K.; Rutter, G. A.; Bloom, S. R.; Tomas, A.; Jones, B.

doi:10.1101/855874

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bioRxiv · 10.1101/855874

Disconnect between signalling potency and in vivo efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists

Lucey, M.·Pickford, P.·Minnion, J.·Ungewiss, J.·Schoeneberg, K.·Rutter, G. A.·Bloom, S. R.·Tomas, A.·Jones, B.

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Abstract

ObjectiveTo determine how pharmacokinetically advantageous acylation impacts on glucagon-like peptide-1 receptor (GLP-1R) signal bias, trafficking, anti-hyperglycaemic efficacy and appetite suppression. MethodsIn 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. ResultsA C-terminally acylated ligand, exendin-phe1-C16, was identified with undetectable {beta}-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. ConclusionsC-terminal acylation of biased GLP-1R agonists increases their degree of signal bias in favour of cAMP production and improves their therapeutic potential.

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Lucey, M., Pickford, P., Minnion, J., Ungewiss, J., Schoeneberg, K., Rutter, G. A., Bloom, S. R., Tomas, A., Jones, B.. 2019-11-26. Disconnect between signalling potency and in vivo efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists. https://doi.org/10.1101/855874

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