Imperial College London
Alternate

DrDavidHodson

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Honorary Senior Lecturer (non-clinical)
 
 
 
//

Contact

 

+44 (0)20 7594 1713d.hodson Website

 
 
//

Location

 

329ICTEM buildingHammersmith Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Podewin:2018:10.1021/acscentsci.7b00237,
author = {Podewin, T and Ast, J and Broichhagen, J and Fine, N and Nasteska, D and Leippe, P and Gailer, M and Buenaventura, T and Kanda, N and Jones, B and M'Kadmi, C and Baneres, J-L and Marie, J and Tomas, Catala A and Trauner, D and Hoffmann-Röder, A and Hodson, D},
doi = {10.1021/acscentsci.7b00237},
journal = {ACS Central Science},
pages = {166--179},
title = {Conditional and reversible activation of class A and B G protein-coupled receptors using tethered pharmacology},
url = {http://dx.doi.org/10.1021/acscentsci.7b00237},
volume = {4},
year = {2018}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Understanding the activation and internalization of G protein-coupled receptors (GPCRs) using conditional approaches is paramount to developing new therapeutic strategies. Here, we describe the design, synthesis, and testing of ExONatide, a benzylguanine-linked peptide agonist of the glucagon-like peptide-1 receptor (GLP-1R), a class B GPCR required for maintenance of glucose levels in humans. ExONatide covalently binds to SNAP-tagged GLP-1R-expressing cells, leading to prolonged cAMP generation, Ca2+ rises, and intracellular retention of the receptor. These effects were readily switched OFF following cleavage of the introduced disulfide bridge using the cell-permeable reducing agent beta-mercaptoethanol (BME). A similar approach could be extended to a class A GPCR using GhrelON, a benzylguanine-linked peptide agonist of the growth hormone secretagogue receptor 1a (GHS-R1a), which is involved in food intake and growth. Thus, ExONatide and GhrelON allow SNAP-tag-directed activation of class A and B GPCRs involved in gut hormone signaling in a reversible manner. This tactic, termed reductively cleavable agONist (RECON), may be useful for understanding GLP-1R and GHS-R1a function both in vitro and in vivo, with applicability across GPCRs.
AU  - Podewin,T
AU  - Ast,J
AU  - Broichhagen,J
AU  - Fine,N
AU  - Nasteska,D
AU  - Leippe,P
AU  - Gailer,M
AU  - Buenaventura,T
AU  - Kanda,N
AU  - Jones,B
AU  - M'Kadmi,C
AU  - Baneres,J-L
AU  - Marie,J
AU  - Tomas,Catala A
AU  - Trauner,D
AU  - Hoffmann-Röder,A
AU  - Hodson,D
DO  - 10.1021/acscentsci.7b00237
EP  - 179
PY  - 2018///
SN  - 2374-7943
SP  - 166
TI  - Conditional and reversible activation of class A and B G protein-coupled receptors using tethered pharmacology
T2  - ACS Central Science
UR  - http://dx.doi.org/10.1021/acscentsci.7b00237
UR  - http://hdl.handle.net/10044/1/56227
VL  - 4
ER  -
Download