Conditional and reversible activation of class A and B G protein-coupled receptors using tethered pharmacology
Research output: Contribution to journal › Article › peer-review
Authors
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
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.
Details
Original language | English |
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Pages (from-to) | 166-179 |
Number of pages | 14 |
Journal | ACS Central Science |
Volume | 4 |
Issue number | 2 |
Early online date | 16 Jan 2018 |
Publication status | Published - 28 Feb 2018 |