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Podewin, Tom; Ast, Julia; Broichhagen, Johannes; Fine, Nicholas H. F.; Nasteska, Daniela; Leippe, Philipp; Gailer, Manuel; Buenaventura, Teresa; Kanda, Nisha; Jones, Ben J.; M'Kadmi, Celine; Baneres, Jean-Louis; Marie, Jacky; Tomas, Alejandra; Trauner, Dirk; Hoffmann-Röder, Anja; Hodson, David J. (2018): Conditional and Reversible Activation of Class A and B G Protein-Coupled Receptors Using Tethered Pharmacology. In: ACS Central Science, Vol. 4, No. 2: pp. 166-179
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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.