The influence of peptide context on signalling and trafficking of glucagon-like peptide-1 receptor biased agonists

Zijan Fang; Shiqian Chen; Philip Pickford; Johannes Broichhagen; David Hodson; Ivan R Corrêa; Sunil Kumar; Frederik Gorlitz; Christopher Dunsby; Paul  French; Guy Rutter; Tricia M. Tan; Stephen R. Bloom; Alejandra Tomas; Ben  Jones

doi:10.1021/acsptsci.0c00022

The influence of peptide context on signalling and trafficking of glucagon-like peptide-1 receptor biased agonists

Zijan Fang, Shiqian Chen, Philip Pickford, Johannes Broichhagen, David Hodson, Ivan R Corrêa, Sunil Kumar, Frederik Gorlitz, Christopher Dunsby, Paul French, Guy Rutter, Tricia M. Tan, Stephen R. Bloom, Alejandra Tomas, Ben Jones

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Abstract

Signal bias and membrane trafficking have recently emerged as important considerations in the therapeutic targeting of the glucagon-like peptide-1 receptor (GLP-1R) in type 2 diabetes and obesity. In the present study, we have evaluated a peptide series with varying sequence homology between native GLP-1 and exendin-4, the archetypal ligands on which approved GLP-1R agonists are based. We find notable differences in agonist-mediated cyclic AMP signaling, recruitment of β-arrestins, endocytosis, and recycling, dependent both on the introduction of a His → Phe switch at position 1 and the specific midpeptide helical regions and C-termini of the two agonists. These observations were linked to insulin secretion in a beta cell model and provide insights into how ligand factors influence GLP-1R function at the cellular level.

Original language	English
Pages (from-to)	345–360
Number of pages	16
Journal	ACS Pharmacology & Translational Science
Volume	3
Issue number	2
Early online date	17 Mar 2020
DOIs	https://doi.org/10.1021/acsptsci.0c00022
Publication status	Published - 10 Apr 2020

Keywords

GLP-1R
biased signaling
endocytosis
exendin-4
membrane trafficking
recycling

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acsptsci.0c00022Licence: None: All rights reserved

Fang_et_al_The_influence_of_peptide_context_on_signalling_ACS_Pharmacol_Transl_Sci_2020
This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Pharmacology & Translational Science, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acsptsci.0c00022
Accepted author manuscript, 12.5 MBLicence: None: All rights reserved

https://pubs.acs.org/doi/10.1021/acsptsci.0c00022Licence: None: All rights reserved

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Fang, Z., Chen, S., Pickford, P., Broichhagen, J., Hodson, D., Corrêa, I. R., Kumar, S., Gorlitz, F., Dunsby, C., French, P., Rutter, G., Tan, T. M., Bloom, S. R., Tomas, A., & Jones, B. (2020). The influence of peptide context on signalling and trafficking of glucagon-like peptide-1 receptor biased agonists. ACS Pharmacology & Translational Science, 3(2), 345–360. https://doi.org/10.1021/acsptsci.0c00022

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abstract = "Signal bias and membrane trafficking have recently emerged as important considerations in the therapeutic targeting of the glucagon-like peptide-1 receptor (GLP-1R) in type 2 diabetes and obesity. In the present study, we have evaluated a peptide series with varying sequence homology between native GLP-1 and exendin-4, the archetypal ligands on which approved GLP-1R agonists are based. We find notable differences in agonist-mediated cyclic AMP signaling, recruitment of β-arrestins, endocytosis, and recycling, dependent both on the introduction of a His → Phe switch at position 1 and the specific midpeptide helical regions and C-termini of the two agonists. These observations were linked to insulin secretion in a beta cell model and provide insights into how ligand factors influence GLP-1R function at the cellular level.",

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Fang, Z, Chen, S, Pickford, P, Broichhagen, J, Hodson, D, Corrêa, IR, Kumar, S, Gorlitz, F, Dunsby, C, French, P, Rutter, G, Tan, TM, Bloom, SR, Tomas, A & Jones, B 2020, 'The influence of peptide context on signalling and trafficking of glucagon-like peptide-1 receptor biased agonists', ACS Pharmacology & Translational Science, vol. 3, no. 2, pp. 345–360. https://doi.org/10.1021/acsptsci.0c00022

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AU - Fang, Zijan

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AU - Hodson, David

AU - Corrêa, Ivan R

AU - Kumar, Sunil

AU - Gorlitz, Frederik

AU - Dunsby, Christopher

AU - French, Paul

AU - Rutter, Guy

AU - Tan, Tricia M.

AU - Bloom, Stephen R.

AU - Tomas, Alejandra

AU - Jones, Ben

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AB - Signal bias and membrane trafficking have recently emerged as important considerations in the therapeutic targeting of the glucagon-like peptide-1 receptor (GLP-1R) in type 2 diabetes and obesity. In the present study, we have evaluated a peptide series with varying sequence homology between native GLP-1 and exendin-4, the archetypal ligands on which approved GLP-1R agonists are based. We find notable differences in agonist-mediated cyclic AMP signaling, recruitment of β-arrestins, endocytosis, and recycling, dependent both on the introduction of a His → Phe switch at position 1 and the specific midpeptide helical regions and C-termini of the two agonists. These observations were linked to insulin secretion in a beta cell model and provide insights into how ligand factors influence GLP-1R function at the cellular level.

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The influence of peptide context on signalling and trafficking of glucagon-like peptide-1 receptor biased agonists

Abstract

Keywords

UN SDGs

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