Abstract
ObjectiveThe 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. MethodsIn 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. ResultsA 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. ConclusionsC-terminal acylation of biased GLP-1R agonists increases their degree of signal bias in favour of cAMP production and improves their therapeutic potential.
Highlights
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective agents for the treatment of type 2 diabetes (T2D) and obesity [1]
C-terminal acylation of biased glucagon-like peptide-1 receptor (GLP-1R) agonists increases their degree of signal bias in favour of cyclic adenosine monophosphate (cAMP) production and improves their therapeutic potential
An updated view of GLP-1R pharmacology highlights the roles of membrane trafficking [7,8] and additional effector proteins such as the β-arrestins [9,10] in the control of amplitude, duration and subcellular localisation of signalling events to regulate insulin secretion, in the pharmacological setting
Summary
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective agents for the treatment of type 2 diabetes (T2D) and obesity [1]. Their therapeutic effects derive mainly from potentiation of glucosestimulated insulin secretion and suppression of appetite leading to weight loss, respectively mediated by GLP-1Rs expressed in pancreatic beta cells and anorectic neurons. “biased” GLP-1RAs which retain full efficacy for cAMP production, but reduced β-arrestin recruitment and endocytic uptake, are able to avoid GLP-1R desensitisation and downregulation which ordinarily attenuate glucoregulatory responses in vivo
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
