Characterization and Development of Gs-biased ligands of Beta2-Adrenergic Receptor

Beta2-肾上腺素能受体 Gs 偏向配体的表征和开发

• 批准号: 9763337
• 负责人: Michael Ippolito
• 金额: $ 4.5万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763337
• 关键词: Address; Adopted; Adrenergic Receptor; Adverse effects; Agonist; Allosteric Site; Area; Arrestins; Asthma; Attenuated; Binding; Biochemical; Biological Models; Biology; Bronchoconstriction; Chemicals; Chronic Disease; Complement; Complex; Computer Simulation; Cyclic AMP; Development; Disease; Docking; Drug Design; Drug Targeting; Drug usage; Extracellular Domain; Face; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Goals; Human; In Vitro; Inflammatory; Inflammatory Response; Isoproterenol; Ligands; Lung; Mediating; Medical; Methods; Molecular Conformation; Mus; Muscle Contraction; Mutagenesis; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Physiological; Process; Production; Property; Proteins; Regulation; Relaxation; Risk; Role; Signal Pathway; Signal Transduction; Site; Slice; Smooth Muscle; Smooth Muscle Myocytes; Specificity; Structure; Structure-Activity Relationship; Sudden Death; System; Testing; Therapeutic; Therapeutic Effect; Translations; Transmembrane Domain; Validation; Vestibule; Work; X-Ray Crystallography; airway inflammation; asthma exacerbation; beta-2 Adrenergic Receptors; clinical development; constriction; desensitization; design; drug development; extracellular; functional group; improved; insight; molecular dynamics; novel strategies; physiologic model; receptor; recruit; respiratory smooth muscle; response; screening; treatment response

Project Summary/Abstract Asthma is a common, chronic disorder characterized by airway inflammation and airway smooth muscle (ASM) contraction leading to airway constriction. The β2-adrenergic receptor (β2AR) is a G protein coupled receptor (GPCR) that promotes the reversal of airway constriction when activated, and is a critical drug target for asthma therapeutics. β-agonists have been cornerstone therapies for asthma but long-term use of these drugs leads to desensitization of therapeutic response. This can cause severe adverse effects and an increased risk of sudden death during an asthma attack. Canonically, β2AR signaling is mediated by initial interaction with the Gs protein followed by receptor phosphorylation and arrestin recruitment. Evidence shows that signaling through the Gs pathway promotes the relaxation of ASM, while arrestin binding promotes β2AR internalization, desensitization of receptor response to β-agonists, and pro-inflammatory signaling. Balanced agonists, like current β- agonist drugs, activate both of these pathways, resulting in concurrent therapeutic and harmful effects. Studies from our lab and others indicate that biased agonists can differentially activate these pathways toward discrete physiological responses. It is our hypothesis that molecules that selectively promote signaling through the Gs pathway, while antagonizing arrestin recruitment would attenuate the adverse effects associated with β-agonists currently prescribed for asthma. Gs-biased agonists and allosteric modulators of β2AR will be characterized by cAMP production through the Gs pathway and arrestin recruitment to the receptor, and the downstream processes of receptor phosphorylation and internalization will be evaluated. The effects of Gs-biased β2AR signaling on key contributors to the negative effects of β-agonism, desensitization of cAMP production / airway contractility and inflammatory response, will be thoroughly assessed in vitro and in physiological models. The proposed work is designed to take advantage of recent insights into GPCR biology with the goal of developing Gs-biased β2AR ligands with improved therapeutic properties.

项目总结/摘要 哮喘是一种常见的慢性疾病，其特征是气道炎症和气道光滑 肌肉（ASM）收缩导致气道收缩。β2-肾上腺素能受体（β 2-adrenergic receptor，β2AR）是一种G 蛋白偶联受体（GPCR），其在激活时促进气道收缩的逆转， 并且是哮喘治疗的关键药物靶点。β受体激动剂已成为 哮喘，但长期使用这些药物会导致治疗反应的脱敏。这可以 会导致严重的不良反应，并增加哮喘发作时猝死的风险。 典型地，β 2 AR信号传导通过与Gs蛋白的初始相互作用介导，随后通过受体介导。 磷酸化和抑制蛋白募集。有证据表明，通过Gs通路的信号传导 促进平滑肌松弛，而arrestin结合促进β 2 AR内化、脱敏 受体对β-激动剂的反应，以及促炎信号。平衡激动剂，如目前的β- 激动剂药物，激活这两个途径，导致同时治疗和有害的 方面的影响.我们实验室和其他实验室的研究表明，有偏见的激动剂可以不同地激活这些 通向离散生理反应的途径。我们的假设是， 通过Gs通路促进信号传导，而拮抗arrestin募集将减弱 与目前用于哮喘的β-受体激动剂相关的不良反应。GS偏性激动剂 β 2 AR的变构调节剂将通过Gs途径产生cAMP来表征 以及受体磷酸化的下游过程 和内在化将被评估。Gs-biased β2AR信号转导对关键因素的影响， β-激动剂的负面作用，cAMP产生/气道收缩的脱敏， 炎症反应，将在体外和生理模型中彻底评估。的 拟议的工作旨在利用GPCR生物学的最新见解，目标是 开发具有改善的治疗特性的Gs-biased β2AR配体。