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

基本信息

批准号：
10683130
负责人：
Jeffrey L Benovic
金额：
$ 32.49万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10683130
关键词：
Address Adrenal Cortex Hormones Adrenergic Agonists Adverse effects Affect Agonist Airway Disease Arrestins Asthma Binding Binding Sites Bronchoconstriction Bronchodilation Cells Cessation of life Complex Coupled 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 Receptor Signaling Regulation Relaxation Research Risk Role Salmeterol Signal Transduction Slice Smooth Muscle Myocytes Spectrum Analysis Structure Testing Time X-Ray Crystallography airway inflammation antagonist asthma exacerbation 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 receptor coupling respiratory smooth muscle screening side effect

项目摘要

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.

项目概要哮喘是一种复杂的疾病，会导致气道平滑肌 (ASM) 收缩和随后的气道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少炎症的皮质类固醇。最近的研究表明，长效β受体激动剂会增加严重哮喘发作的风险，虽然β-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传导似乎我们勇敢地使用选择性促进 β2AR 相互作用的偏向激动剂。 Gs 将成为治疗哮喘的有效方法为了检验这一假设，我们将表征铅。我们开发的化合物以及其他化合物，因为它们能够提供卓越的性能通过促进 Gs 偏向的 β2AR 信号传导来抑制 ASM 收缩在目标 1 中，我们将。开发通过 β2AR 介导 Gs 偏向信号传导的化合物我们已经确定了两大类。通过 β2AR 偏向 Gs 信号传导的化合物，抑制蛋白偏向的负变构调节剂 (NAM)，有效抑制 β2AR 与抑制蛋白和 Gs 偏向激动剂的相互作用。使用分子建模、结构活性分析和药物进一步表征并优化在目标 2 中，我们将确定其分子基础。使用结构和生物物理方法研究抑制蛋白偏向的相互作用的 Gs 偏向信号传导 NAM 和 β2AR 偏向 Gs 的激动剂在目标 3 中，我们将表征偏向 Gs 的激动剂的能力。与 β 激动剂相比，偏向抑制蛋白的 NAM 可以促进人气道平滑肌松弛总体而言，我们开发的 Gs 偏向 β2AR 激动剂和变构调节剂。将为更好地理解β2AR偏向信号传导的机制基础提供一个结构框架，这最终将带来治疗多种气道疾病的新药。