Conditional and reversible activation of class A and B G protein-coupled receptors using tethered pharmacology
| Autor: | Philipp Leippe, Julia Ast, Nicholas H. F. Fine, Teresa Buenaventura, Ben Jones, Daniela Nasteska, Anja Hoffmann-Röder, Dirk Trauner, Alejandra Tomas, David J. Hodson, Céline M'Kadmi, Jean Louis Banères, Johannes Broichhagen, N Kanda, Tom Podewin, Jacky Marie, Manuel Gailer |
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| Přispěvatelé: | Medical Research Council |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Agonist Reducing agent medicine.drug_class General Chemical Engineering media_common.quotation_subject Growth hormone secretagogue receptor Peptide Cleavage (embryo) 01 natural sciences 03 medical and health sciences medicine Receptor Internalization QD1-999 media_common G protein-coupled receptor chemistry.chemical_classification 010405 organic chemistry General Chemistry 0104 chemical sciences 3. Good health Cell biology Chemistry 030104 developmental biology chemistry hormones hormone substitutes and hormone antagonists Research Article |
| Zdroj: | ACS Central Science ACS Central Science, Vol 4, Iss 2, Pp 166-179 (2018) |
| Popis: | 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. SNAP-tag-directed activation of class A and B G protein-coupled receptors can be achieved in a conditional and reversible manner using peptidic reductively cleavable agONists (RECONs). |
| Databáze: | OpenAIRE |
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