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

Research output: Contribution to journalArticlepeer-review


  • Tom Podewin
  • Johannes Broichhagen
  • Nicholas Fine
  • Philipp Leippe
  • Manuel Gailer
  • Teresa Buenaventura
  • Nisha Kanda
  • Ben Jones
  • Celine N'Kadmi
  • Jean-Louis Baneres
  • Jacky Marie
  • Alejandra Tomas
  • Dirk Trauner
  • Anja Hoffmann-Roder

Colleges, School and Institutes

External organisations

  • Department of Chemistry and Center for Integrated Protein Science, LMU Munich
  • Max Planck Institute for Medical Research, Department of Chemical Biology
  • Imperial College London
  • Institut des Biomolécules Max Mousseron, UMR 5247 CNRS-Université Montpellier-ENSCM
  • Department of Chemistry, Silver Center for Arts and Science, New York University


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.


Original languageEnglish
Pages (from-to)166-179
Number of pages14
JournalACS Central Science
Issue number2
Early online date16 Jan 2018
Publication statusPublished - 28 Feb 2018