Project 3 - Biased Targeting of beta 2AR Signaling in Airway Disease

项目 3 - 气道疾病中 β2AR 信号传导的偏向靶向

• 批准号: 10238023
• 负责人: Jeffrey L Benovic
• 金额: $ 32.49万
• 依托单位: RUTGERS BIOMEDICAL/HEALTH SCIENCES-RBHS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238023
• 关键词: Address; Adrenal Cortex Hormones; Adverse effects; Affect; Agonist; Airway Disease; Arrestins; Asthma; Binding; Binding Sites; Bronchoconstriction; Bronchodilation; Cells; Cessation of life; Complex; Coupled; Coupling; Cyclic AMP; Development; Disease; Drug usage; Electrons; Epithelial Cells; Fluorescence Spectroscopy; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Grant; Human; Inflammation; Inflammatory; Inflammatory Response; Lead; Lung; Mediating; Molecular; Molecular Conformation; Morbidity - disease rate; Muscarinic Acetylcholine Receptor M3; Muscle Contraction; Muscle relaxation phase; Nature; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Play; Population; Process; Production; Property; Regulation; Relaxation; Research; Risk; Role; Salmeterol; Signal Transduction; Slice; Smooth Muscle Myocytes; Spectrum Analysis; Structure; Testing; Time; X-Ray Crystallography; airway inflammation; asthma model; asthmatic; beta-2 Adrenergic Receptors; beta-arrestin; biophysical techniques; cell type; constriction; cysteinyl-leukotriene; desensitization; drug development; formoterol; human disease; human model; improved; insight; molecular modeling; mortality; nanobodies; novel; novel therapeutics; receptor; respiratory smooth muscle; screening; side effect

Project Summary Asthma is a complex disease that results in airway smooth muscle (ASM) contraction and subsequent airway constriction. The major drugs used to treat asthma include β-agonists that promote ASM relaxation, Gq- coupled receptor antagonists that inhibit bronchoconstriction, and corticosteroids that reduce inflammation. Recent studies suggest that long acting β-agonists increase the risk of having a severe asthmatic attack that can result in death. While the mechanisms whereby β-agonists cause such severe side effects are poorly understood, β2-adrenergic receptor (β2AR) desensitization and β-arrestin-mediated signaling appear to contribute to this process. We hypothesize that biased agonists that selectively promote β2AR interaction with Gs will serve as an effective way of treating asthma. To test this hypothesis, we will characterize lead compounds that we have developed as well as additional compounds, for their ability to provide superior inhibition of ASM contraction by virtue of their ability to promote Gs-biased β2AR signaling. In aim 1, we will develop compounds that mediate Gs-biased signaling through the β2AR. We have identified two broad classes of compounds that bias Gs signaling through the β2AR, arrestin-biased negative allosteric modulators (NAMs), that effectively inhibit β2AR interaction with arrestins, and Gs-biased agonists. The lead compounds will be further characterized and then optimized using molecular modeling, structure activity analysis, and medicinal chemistry to improve the potency, bias and drug-like properties. In aim 2, we will identify the molecular basis of Gs-biased signaling using structural and biophysical approaches to study the interaction of arrestin-biased NAMs and Gs-biased agonists with the β2AR. In aim 3, we will characterize the ability of Gs-biased agonists and arrestin-biased NAMs to promote human airway smooth muscle relaxation as compared to β-agonists currently used to treat asthma. Overall, our development of Gs-biased β2AR agonists and allosteric modulators will provide a structural framework for better understanding the mechanistic basis of β2AR biased signaling, which should ultimately lead to novel drugs for a wide range of airway diseases.

项目摘要 哮喘是一种复杂的疾病，其导致气道平滑肌（ASM）收缩，随后导致气道炎症。 收缩。用于治疗哮喘的主要药物包括促进ASM松弛的β-激动剂、Gq- 抑制支气管收缩的偶联受体拮抗剂和减轻炎症的皮质类固醇。 最近的研究表明，长效β受体激动剂增加了严重哮喘发作的风险， 会导致死亡虽然β受体激动剂引起如此严重副作用的机制尚不清楚， 据了解，β2-肾上腺素能受体（β2AR）脱敏和β-抑制蛋白介导的信号似乎 为这一进程做出贡献。我们假设，选择性促进β 2 AR与 GS将成为治疗哮喘的有效方法。为了验证这一假设，我们将描述铅 我们开发的化合物以及其他化合物，因为它们能够提供上级 通过其促进Gs-biased β2AR信号传导的能力抑制ASM收缩。在目标1中， 开发通过β2AR介导Gs偏置信号的化合物。我们已经确定了两大类 通过β2AR偏置Gs信号传导的化合物，抑制蛋白偏置的负变构调节剂（NAM）， 有效抑制β2AR与抑制蛋白和Gs-偏向激动剂的相互作用。先导化合物将是 使用分子建模、结构活性分析和药物分析进一步表征并优化 化学来改善效力、偏差和药物样性质。在目标2中，我们将确定 使用结构和生物物理方法研究抑制蛋白偏性信号传导与抑制蛋白的相互作用 NAM和GS偏性激动剂与β2AR。在目标3中，我们将描述Gs-偏向激动剂的能力， 与β-激动剂相比，抑制蛋白偏向的NAM促进人气道平滑肌松弛 目前用于治疗哮喘。总之，我们开发的Gs-偏向的β2AR激动剂和变构调节剂， 将为更好地理解β2AR偏置信号传导的机制基础提供结构框架， 这最终应该会导致治疗多种呼吸道疾病的新药的出现。