Novel Biased Beta2-AR Ligands as Asthma Therapeutics

新型偏向 Beta2-AR 配体作为哮喘治疗药物

• 批准号: 10372196
• 负责人: RICHARD Agustin BOND
• 金额: $ 61.53万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10372196
• 关键词: Ablation; Address; Adrenal Cortex Hormones; Adrenergic Receptor; Agonist; Allergens; Allergic; Arrestins; Asthma; Basic Science; Biology; Bronchodilation; Cell physiology; Cells; Clinic; Clinical Research; Collaborations; Complex; Deterioration; Disease; Disease model; Epithelial; Epithelial Cells; Failure; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Genes; Genetic; Hand; Human; Inflammation; Inflammatory; Interleukin-13; Knock-out; Knockout Mice; Ligands; Lung; Mechanics; Mediating; Modeling; Molecular; Mucous body substance; Mus; Muscle Contraction; NIH Program Announcements; Pathology; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Physiology; Prophylactic treatment; Public Health; Pulmonary Inflammation; Research; Safety; Series; Signal Pathway; Signal Transduction; Signaling Protein; System; Tachyphylaxis; Testing; Therapeutic; Translational Research; Universities; Work; airway epithelium; airway hyperresponsiveness; airway inflammation; arrestin 2; asthma model; asthmatic; base; beta-2 Adrenergic Receptors; beta-arrestin; cell type; cytokine; desensitization; drug discovery; epidemiology study; genetic regulatory protein; human subject; immunoregulation; improved; in vivo; mortality; mouse model; novel; pre-clinical; protective effect; receptor function; respiratory smooth muscle; scaffold

Agonists of the beta-2-adrenoceptor (b2AR), commonly referred to as b-agonists, have been a cornerstone of asthma treatment for nearly half a century. Despite their utility, b-agonists used in asthma management have problems, including functional tachyphylaxis, deterioration of asthma control, and mortality concerns. Moreover, lingering safety concerns regarding long-acting b-agonists necessitate the concomitant use of corticosteroids. The inability to understand why such problems exist and the failure to significantly improve b2AR pharmacology is reflected by over 2 decades of NIH Program announcements declaring the need for safer, more efficacious alternatives to asthma treatment. Over the last 2 decades our team has employed a robust combination of genetic and molecular approaches to convincingly demonstrate that both endogenous and exogenous b-agonist promote the asthma phenotype, and that the b2AR regulatory protein, b-arrestin-2 is critical to the limited efficacy, and safety issues, associated with b-agonist use in asthma. Despite our work to date which constitutes compelling proof of principle, a corrective pharmacological approach sufficiently feasible to advance has been unavailable until now. In collaboration with colleagues at Thomas Jefferson University we have characterized a novel b2AR agonist as well as b2AR allosteric modulator (AM) that provide the therapeutic signaling of b-agonists yet allow the b2AR to avoid (pathology-inducing) engagement of b-arrestins. These compounds are the first b2AR ligands/AMs capable of “biasing” b2AR to increase Gs protein signaling. We propose to use our preclinical in vivo and cell-based models to: 1) establish that these novel compounds are superior to current b-agonists with respect to mitigating the central features of asthma (airway inflammation and hyperresponsiveness (AHR)) while maintaining bronchodilation function, 2) determine the specific cell type(s) through which these drugs work and 3) address a fundamental conundrum in the field of GPCR biology - do b-arrestins impact function and disease by generating their own signal, or are their effects due to their inhibition of canonical b2AR signaling? In Aim 1 we will establish the ability of novel b2AR-biasing compounds to mitigate the asthma phenotype in in vivo and cell-based models. In Aim 2 we will use using genetic and pharmacological approaches to establish epithelial cell b2AR-arrestin biasing as critical to the permissive effect of b-agonist in promoting the asthma phenotype. Finally, in Aim 3 we will establish the mechanisms by which novel b2AR biasing compounds regulate airway cell functions that contribute to the asthma phenotype.

β-2-肾上腺素能受体（b2 AR）的激动剂，通常称为β-激动剂，已经成为β-肾上腺素能受体激动剂的基石。 哮喘治疗已经有将近半个世纪的历史了。尽管它们的效用，用于哮喘管理的b-激动剂， 问题，包括功能性快速耐受、哮喘控制恶化和死亡率问题。此外，委员会认为， 关于长效β-激动剂的挥之不去的安全性问题需要伴随使用皮质类固醇。 无法理解为什么存在这样的问题，以及未能显着改善b2 AR药理学 20多年来，NIH计划宣布需要更安全、更有效的 哮喘治疗的替代品。在过去的20年里，我们的团队采用了一种强大的基因组合， 和分子方法来令人信服地证明内源性和外源性B-激动剂都促进 哮喘表型，以及b2 AR调节蛋白，b-arrestin-2对有限的疗效至关重要， 安全性问题，与哮喘中使用b-激动剂有关。尽管我们迄今为止的工作 原则证明，尚未获得足够可行的纠正药理学方法来推进 到现在在与托马斯杰斐逊大学的同事合作中，我们描述了一种新的b2 AR 激动剂以及b2 AR变构调节剂（AM），其提供b-激动剂的治疗信号传导， b2 AR以避免b-抑制蛋白的（病理诱导的）接合。这些化合物是第一个b2 AR 能够“偏置”b2 AR以增加Gs蛋白信号传导的配体/AM。我们建议使用我们的临床前体内 和基于细胞的模型，以：1）确定这些新化合物在以下方面上级当前的β-激动剂： 缓解哮喘的主要特征（气道炎症和高反应性（AHR））， 维持支气管扩张功能，2）确定这些药物起作用的特定细胞类型， 3)解决了GPCR生物学领域的一个基本难题-b-抑制蛋白影响功能和疾病吗 通过产生自己的信号，还是由于它们抑制经典的b2 AR信号？目标1 我们将建立新的b2 AR偏性化合物在体内减轻哮喘表型的能力， 细胞模型在目标2中，我们将使用遗传和药理学方法建立上皮细胞 细胞b2 AR-抑制蛋白偏向性对促进哮喘表型的b-激动剂的容许效应至关重要。 最后，在目的3中，我们将建立新型b2 AR偏性化合物调节气道细胞的机制。 导致哮喘表型的功能。