Dataset Information

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

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.

SUBMITTER: Podewin T

PROVIDER: S-EPMC5832994 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Podewin Tom T Ast Julia J Broichhagen Johannes J Fine Nicholas H F NHF Nasteska Daniela D Leippe Philipp P Gailer Manuel M Buenaventura Teresa T Kanda Nisha N Jones Ben J BJ M'Kadmi Celine C Baneres Jean-Louis JL Marie Jacky J Tomas Alejandra A Trauner Dirk D Hoffmann-Röder Anja A Hodson David J DJ

ACS central science 20180116 2

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 <b>ExONatide</b>, 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. <b>ExONatide</b> covalently binds to SNAP-tagged GLP-1R-expressing cells, leading to prolonged c ...[more]

PMID: 29532016

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Project description:Asthma is a heterogeneous inflammatory disease of the airways that is associated with airway hyperresponsiveness and airflow limitation. Although asthma was once simply categorized as atopic or nonatopic, emerging analyses over the last few decades have revealed a variety of asthma endotypes that are attributed to numerous pathophysiological mechanisms. The classification of asthma by endotype is primarily routed in different profiles of airway inflammation that contribute to bronchoconstriction. Many asthma therapeutics target G protein-coupled receptors (GPCRs), which either enhance bronchodilation or prevent bronchoconstriction. Short-acting and long-acting β 2-agonists are widely used bronchodilators that signal through the activation of the β 2-adrenergic receptor. Short-acting and long-acting antagonists of muscarinic acetylcholine receptors are used to reduce bronchoconstriction by blocking the action of acetylcholine. Leukotriene antagonists that block the signaling of cysteinyl leukotriene receptor 1 are used as an add-on therapy to reduce bronchoconstriction and inflammation induced by cysteinyl leukotrienes. A number of GPCR-targeting asthma drug candidates are also in different stages of development. Among them, antagonists of prostaglandin D2 receptor 2 have advanced into phase III clinical trials. Others, including antagonists of the adenosine A2B receptor and the histamine H4 receptor, are in early stages of clinical investigation. In the past decade, significant research advancements in pharmacology, cell biology, structural biology, and molecular physiology have greatly deepened our understanding of the therapeutic roles of GPCRs in asthma and drug action on these GPCRs. This review summarizes our current understanding of GPCR signaling and pharmacology in the context of asthma treatment. SIGNIFICANCE STATEMENT: Although current treatment methods for asthma are effective for a majority of asthma patients, there are still a large number of patients with poorly controlled asthma who may experience asthma exacerbations. This review summarizes current asthma treatment methods and our understanding of signaling and pharmacology of G protein-coupled receptors (GPCRs) in asthma therapy, and discusses controversies regarding the use of GPCR drugs and new opportunities in developing GPCR-targeting therapeutics for the treatment of asthma.

Dataset Information

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

Publications

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

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