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Novel Biased Beta2-AR Ligands as Asthma Therapeutics

新型偏向 Beta2-AR 配体作为哮喘治疗药物

基本信息

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
项目类别：
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

项目摘要

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.

β2-肾上腺素受体 (b2AR) 激动剂，通常称为 b-激动剂，是哮喘治疗已有近半个世纪的历史。尽管 B 受体激动剂具有实用性，但用于哮喘治疗的问题，包括功能性快速耐受、哮喘控制恶化和死亡问题。而且，由于长效β受体激动剂长期存在的安全问题，需要同时使用皮质类固醇。无法理解为什么存在此类问题并且未能显着改善b2AR药理学 20 多年来 NIH 计划的公告都反映了这一点，这些公告宣布需要更安全、更有效的药物哮喘治疗的替代方案。在过去的 20 年里，我们的团队采用了强大的遗传组合和分子方法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，并且 b2AR 调节蛋白 b-arrestin-2 对于有限的疗效至关重要，并且与哮喘中使用 b 激动剂相关的安全问题。尽管我们迄今为止的工作令人信服原理证明，目前还没有足够可行的纠正药理学方法来推进到目前为止。我们与托马斯·杰斐逊大学的同事合作，描述了一种新颖的 b2AR 激动剂以及 b2AR 变构调节剂 (AM)，提供 b 激动剂的治疗信号，但允许 b2AR 以避免（病理诱导）与 b-抑制蛋白的结合。这些化合物是第一个b2AR 配体/AM能够“偏向”b2AR以增加Gs蛋白信号传导。我们建议使用我们的临床前体内和基于细胞的模型：1) 确定这些新型化合物在以下方面优于当前的 b-激动剂减轻哮喘的主要特征（气道炎症和高反应性（AHR）），同时维持支气管扩张功能，2) 确定这些药物发挥作用的特定细胞类型，以及 3) 解决 GPCR 生物学领域的一个基本难题 - b-抑制蛋白是否影响功能和疾病是通过产生它们自己的信号，还是它们的影响是由于它们对典型 b2AR 信号传导的抑制？目标 1 我们将建立新型 b2AR 偏向化合物在体内减轻哮喘表型的能力，基于细胞的模型。在目标 2 中，我们将使用遗传和药理学方法来建立上皮细胞细胞b2AR-抑制蛋白偏向对于b-激动剂促进哮喘表型的许可作用至关重要。最后，在目标 3 中，我们将建立新型 b2AR 偏向化合物调节气道细胞的机制有助于哮喘表型的功能。