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ACS Cent Sci. 2018 Feb 28;4(2):166-179. doi: 10.1021/acscentsci.7b00237. Epub 2018 Jan 16.

Conditional and Reversible Activation of Class A and B G Protein-Coupled Receptors Using Tethered Pharmacology.

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Department of Chemistry and Center for Integrated Protein Science, LMU Munich, 81377 Munich, Germany.
Institute of Metabolism and Systems Research (IMSR), University of Birmingham, B15 2TT, Birmingham, United Kingdom.
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, United Kingdom, and COMPARE University of Birmingham and University of Nottingham Midlands.
Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, W12 0NN, United Kingdom.
Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, W12 0NN, United Kingdom.
Institut des Biomolécules Max Mousseron, UMR 5247 CNRS-Université Montpellier-ENSCM, Faculté de Pharmacie, 15 Avenue Charles Flahault, BP 14491, 34093 Montpellier Cedex 05, France.


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.

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