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

Tom Podewin, Julia Ast, Johannes Broichhagen, Nicholas H.F. Fine, Daniela Nasteska, Philipp Leippe, Manuel Gailer, Teresa Buenaventura, Nisha Kanda, Ben J. Jones, Celine M'Kadmi, Jean Louis Baneres, Jacky Marie, Alejandra Tomas, Dirk Trauner, Anja Hoffmann-Röder, David J. Hodson

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)166-179
Number of pages14
JournalACS Central Science
Volume4
Issue number2
DOIs
StatePublished - Feb 28 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

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