| Title: |
Evaluation of efficacy- versus affinity-driven agonism with biased GLP-1R ligands P5 and exendin-F1 |
| Authors: |
Marzook, A; Chen, S; Pickford, P; Lucey, M; Wang, Y; Corrêa Jr, IR; Broichhagen, J; Hodson, DJ; Salem, V; Rutter, GA; Tan, TM; Bloom, SR; Tomas, A; Jones, B |
| Contributors: |
Imperial College Healthcare NHS Trust- BRC Funding; Medical Research Council (MRC); The Academy of Medical Sciences; Society for Endocrinology; European Foundation for the Study of Diabetes; British Society for Neuroendocrinology; MRC Programme Grant; Wellcome Trust |
| Source: |
12 ; 1 |
| Publisher Information: |
Elsevier BV |
| Publication Year: |
2021 |
| Collection: |
Imperial College London: Spiral |
| Subject Terms: |
Biased agonism; Endocytosis; Exendin-4; GLP-1R; β-arrestin; Pharmacology & Pharmacy; 0601 Biochemistry and Cell Biology; 1115 Pharmacology and Pharmaceutical Sciences |
| Description: |
The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of glucose homeostasis and has been successfully targeted for the treatment of type 2 diabetes. Recently described biased GLP-1R agonists with selective reductions in β-arrestin versus G protein coupling show improved metabolic actions in vivo. However, two prototypical G protein-favouring GLP-1R agonists, P5 and exendin-F1, are reported to show divergent effects on insulin secretion. In this study we aimed to resolve this discrepancy by performing a side-by-side characterisation of these two ligands across a variety of in vitro and in vivo assays. Exendin-F1 showed reduced acute efficacy versus P5 for several readouts, including recruitment of mini-G proteins, G protein-coupled receptor kinases (GRKs) and β-arrestin-2. Maximal responses were also lower for both GLP-1R internalisation and the presence of active GLP-1R-mini-Gs complexes in early endosomes with exendin-F1 treatment. In contrast, prolonged insulin secretion in vitro and sustained anti-hyperglycaemic efficacy in mice were both greater with exendin-F1 than with P5. We conclude that the particularly low acute efficacy of exendin-F1 and associated reductions in GLP-1R downregulation appear to be more important than preservation of endosomal signalling to allow sustained insulin secretion responses. This has implications for the ongoing development of affinity- versus efficacy-driven biased GLP-1R agonists as treatments for metabolic disease. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
Biochemical Pharmacology; http://hdl.handle.net/10044/1/89686; RDA05 79560; MR/R010676/1; RDA29; RDC04; N/A; 98102; MR/R022259/1; 212625/Z/18/Z |
| DOI: |
10.1016/j.bcp.2021.114656 |
| Availability: |
http://hdl.handle.net/10044/1/89686; https://doi.org/10.1016/j.bcp.2021.114656 |
| Rights: |
© 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). ; http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.71DF11B2 |
| Database: |
BASE |