Conditional and reversible activation of class A and B G protein-coupled receptors using tethered pharmacology

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Conditional and reversible activation of class A and B G protein-coupled receptors using tethered pharmacology. / Podewin, Tom; Ast, Julia; Broichhagen, Johannes; Fine, Nicholas; Nasteska, Daniela; Leippe, Philipp; Gailer, Manuel; Buenaventura, Teresa; Kanda, Nisha; Jones, Ben; N'Kadmi, Celine; Baneres, Jean-Louis; Marie, Jacky ; Tomas, Alejandra; Trauner, Dirk; Hoffmann-Roder, Anja; Hodson, David.

In: ACS Central Science, Vol. 4, No. 2, 28.02.2018, p. 166-179.

Research output: Contribution to journalArticlepeer-review

Harvard

Podewin, T, Ast, J, Broichhagen, J, Fine, N, Nasteska, D, Leippe, P, Gailer, M, Buenaventura, T, Kanda, N, Jones, B, N'Kadmi, C, Baneres, J-L, Marie, J, Tomas, A, Trauner, D, Hoffmann-Roder, A & Hodson, D 2018, 'Conditional and reversible activation of class A and B G protein-coupled receptors using tethered pharmacology', ACS Central Science, vol. 4, no. 2, pp. 166-179. https://doi.org/10.1021/acscentsci.7b00237

APA

Podewin, T., Ast, J., Broichhagen, J., Fine, N., Nasteska, D., Leippe, P., Gailer, M., Buenaventura, T., Kanda, N., Jones, B., N'Kadmi, C., Baneres, J-L., Marie, J., Tomas, A., Trauner, D., Hoffmann-Roder, A., & Hodson, D. (2018). Conditional and reversible activation of class A and B G protein-coupled receptors using tethered pharmacology. ACS Central Science, 4(2), 166-179. https://doi.org/10.1021/acscentsci.7b00237

Vancouver

Author

Podewin, Tom ; Ast, Julia ; Broichhagen, Johannes ; Fine, Nicholas ; Nasteska, Daniela ; Leippe, Philipp ; Gailer, Manuel ; Buenaventura, Teresa ; Kanda, Nisha ; Jones, Ben ; N'Kadmi, Celine ; Baneres, Jean-Louis ; Marie, Jacky ; Tomas, Alejandra ; Trauner, Dirk ; Hoffmann-Roder, Anja ; Hodson, David. / Conditional and reversible activation of class A and B G protein-coupled receptors using tethered pharmacology. In: ACS Central Science. 2018 ; Vol. 4, No. 2. pp. 166-179.

Bibtex

@article{b9c7b21ff78e48bd822b8e962cfd8c63,
title = "Conditional and reversible activation of class A and B G protein-coupled receptors using tethered pharmacology",
abstract = "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 a cell-permeable reducing agent. 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.",
author = "Tom Podewin and Julia Ast and Johannes Broichhagen and Nicholas Fine and Daniela Nasteska and Philipp Leippe and Manuel Gailer and Teresa Buenaventura and Nisha Kanda and Ben Jones and Celine N'Kadmi and Jean-Louis Baneres and Jacky Marie and Alejandra Tomas and Dirk Trauner and Anja Hoffmann-Roder and David Hodson",
year = "2018",
month = feb,
day = "28",
doi = "10.1021/acscentsci.7b00237",
language = "English",
volume = "4",
pages = "166--179",
journal = "ACS Central Science",
issn = "2374-7951",
publisher = "American Chemical Society",
number = "2",

}

RIS

TY - JOUR

T1 - Conditional and reversible activation of class A and B G protein-coupled receptors using tethered pharmacology

AU - Podewin, Tom

AU - Ast, Julia

AU - Broichhagen, Johannes

AU - Fine, Nicholas

AU - Nasteska, Daniela

AU - Leippe, Philipp

AU - Gailer, Manuel

AU - Buenaventura, Teresa

AU - Kanda, Nisha

AU - Jones, Ben

AU - N'Kadmi, Celine

AU - Baneres, Jean-Louis

AU - Marie, Jacky

AU - Tomas, Alejandra

AU - Trauner, Dirk

AU - Hoffmann-Roder, Anja

AU - Hodson, David

PY - 2018/2/28

Y1 - 2018/2/28

N2 - 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 a cell-permeable reducing agent. 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.

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 a cell-permeable reducing agent. 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.

U2 - 10.1021/acscentsci.7b00237

DO - 10.1021/acscentsci.7b00237

M3 - Article

VL - 4

SP - 166

EP - 179

JO - ACS Central Science

JF - ACS Central Science

SN - 2374-7951

IS - 2

ER -