Characterization of biased airway smooth muscle TAS2R agonists for treating asthma

偏向气道平滑肌 TAS2R 激动剂治疗哮喘的表征

• 批准号: 10543121
• 负责人: Stephen B Liggett
• 金额: $ 53.51万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543121
• 关键词: Affect; Affinity; Age; Agonist; Air Movements; Arrestins; Asthma; Back; Binding; Binding Sites; Biochemical; Biology; Bronchial Spasm; Bronchodilation; Bronchodilator Agents; Cell model; Cells; Characteristics; Clinical; Collection; Complex; Coupling; Cytometry; Data; Disease; Docking; Dose; Engineering; Ethnic Origin; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic Engineering; Human; Intervention; Learning; Libraries; Ligand Binding; Ligands; Lung; Magnetism; Methods; Modality; Modeling; Molecular Conformation; Morbidity - disease rate; Obstruction; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Prevention; Process; Property; Public Health; Relaxation; Resistance; Signal Transduction; Slice; Smooth Muscle Myocytes; Structure; System; Tachyphylaxis; Taste Buds; Techniques; Therapeutic; Time; Transfection; Translations; Work; airway obstruction; asthmatic; attenuation; beta-arrestin; cell type; constriction; desensitization; disorder control; drug action; experience; experimental study; in silico; interest; models and simulation; molecular modeling; mortality; novel; pharmacologic; pharmacophore; predictive modeling; prevent; receptor; recruit; respiratory smooth muscle; response; simulation; three dimensional structure; treatment optimization; virtual; virtual screening

Asthma remains a major public health issue worldwide, affecting all ages and ethnicities, with 50% of patients experiencing inadequate control of the disease. Constricted airways from contraction of airway smooth muscle is the major cause of airflow obstruction, and morbidity and mortality, in asthma. Despite this key point for intervention, only one class of direct bronchodilators (-agonists) are available for treatment, and they are suboptimal for many patients. We have discovered bitter taste receptors (TAS2Rs) on human airway smooth muscle (HASM) cells which signal by a unique mechanism. When activated, TAS2Rs markedly relax HASM and relieve airway obstruction that is otherwise resistant to -agonists. However, the known TAS2R agonists have low affinity and evoke desensitization (tachyphylaxis) of the relaxation response over time via -arrestin mechanisms. The overarching hypothesis is that TAS2R agonists with novel structures can be highly effective in relaxing airways in an asthmatic milieu and yet not evoke tachyphylaxis. The broad long-term objectives are to determine the 3D structures and binding sites of two TAS2Rs expressed on HASM (R5 and R14) and then use these structures to perform virtual docking of an agnostic ultra-large compound library to identify potential ligands. These hits will be examined in engineered model cells, but will be most intensely studied within the context of the physiology of HASM cells, and human airways, under asthmatic conditions to delineate novel ways to engage the receptor that are biased towards relaxation and away from desensitization. Aim 1 will computationally determine the structures and binding sites for R5 and R14 using methods that include 13 trillion combinations of the residues to determine favorable energy conformations of inactive and active states. The structures will be used to dock compounds from a highly diverse library. These will be studied in Aim 2 to determine potency and efficacy in genetically engineered model cells and in HASM cells from nonasthmatic and asthmatic lungs. In Aim 3, the most favorable compounds will be studied to ascertain -arrestin engagement and biasing away from desensitization in model cells, HASM cells, and human lungs under asthmatic conditions. Results from Aims2/3 will be fed back into Aim1 to further refine a model of biased agonists for these HASM TAS2Rs. Based on our preliminary data that support all three Aims, we will learn about the structural requirements for biasing for these receptors. And, we anticipate that multiple highly effective agonists with unexpected structures will be identified and that their bronchodilating properties in asthma will represent a new class of powerful non-desensitizing agents for treating and preventing bronchospasm.

哮喘仍然是世界范围内的一个主要公共卫生问题，影响所有年龄和种族，50%的患者