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

Tom Podewin, Julia Ast, Johannes Broichhagen, Nicholas Fine, Daniela Nasteska, 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, David Hodson

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)
155 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)166-179
Number of pages14
JournalACS Central Science
Volume4
Issue number2
Early online date16 Jan 2018
DOIs
Publication statusPublished - 28 Feb 2018

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