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：
10581573
负责人：
RICHARD Agustin BOND
金额：
$ 62.99万
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/10581573
关键词：
ARRB2 Ablation Address Adrenal Cortex Hormones Agonist Allergens Allergic Arrestins Asthma Basic Science Biology Bronchodilation Cell physiology Cells Clinic Clinical Research Collaborations Complex Deterioration Disease Disease model Epithelial Cells Epithelium Failure G-Protein-Coupled Receptors 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 asthma model asthmatic 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 permissiveness pharmacologic 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.

通常称为B-激动剂的Beta-2-肾上腺素受体（B2AR）的激动剂一直是近半个世纪的哮喘治疗。尽管有实用性，但用于哮喘管理的B-激动剂已经问题，包括功能性速度，哮喘控制恶化和死亡率问题。而且，关于长效B-激动剂的安全性问题持续的安全性有必要同时使用皮质类固醇。无法理解为什么存在此类问题以及无法显着改善B2AR药理学的原因超过20年的NIH计划公告反映了宣布需要安全，更高效的需求哮喘治疗的替代方案。在过去的20年中令人信服的分子方法表明，内源性和外源性B-激动剂均促进哮喘表型和B2AR调节蛋白B-arrestin-2对于有限的效率至关重要，并且安全问题，与B-激动剂在哮喘中使用相关。尽管我们迄今为止的工作构成了引人注目的原则证明，不可用的纠正式药物方法是适当可行的到目前为止。在与托马斯·杰斐逊大学（Thomas Jefferson University）的同事合作中，我们描述了一本小说B2AR 激动剂以及B2AR变构调节剂（AM），可提供B-激动剂的治疗信号 B2AR避免B-arrestins的（病理诱导）参与。这些化合物是第一个B2AR 配体/AMS能够“偏置” B2AR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优于当前的B-激动剂减轻哮喘的中心特征（气道注射和反应性（AHR）），而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GPCR生物学领域的基本难题 - b -arrestins撞击功能和疾病通过产生自己的信号，还是由于抑制规范B2AR信号的抑制而产生的影响？在目标1中我们将建立新型B2AR偏见化合物减轻体内哮喘表型的能力基于细胞的模型。在AIM 2中，我们将使用遗传和药物方法来建立上皮细胞B2AR - arrestin对B-激动剂在促进哮喘表型中的允许作用至关重要。最后，在AIM 3中，我们将建立新型B2AR偏置化合物调节气道细胞的机制有助于哮喘表型的功能。