TARGET IN ASTHMA THERAPY-BETA ADRENERGIC RECEPTOR KINASE

哮喘治疗的靶点 - β 肾上腺素能受体激酶

• 批准号: 3489228
• 负责人: COLIN GODDARD
• 金额: $ 5万
• 依托单位: OSI PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-01 至 1991-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3489228
• 关键词: adenylate cyclase; asthma; beta adrenergic receptor; drug design /synthesis /production; enzyme inhibitors; high performance liquid chromatography; peptide chemical synthesis; protein kinase; protein purification; respiratory disorder chemotherapy; sports medicine; stimulant /agonist; tissue /cell culture

Beta-adrenergic agonists are used in the treatment of chronic and exercise- induced asthma. These agents work through the beta adrenergic receptor/adenylate cyclase coupled effector system producing relaxation of the smooth muscle of the trachea and bronchial tree thereby relieving asthmatic symptoms. Agonist binding by the receptor leads to a desensitization and reduced agonist response. A novel protein kinase, beta adrenergic receptor kinase, is intimately involved in this process. The aim of this proposal is to establish the means of identifying specific inhibitors of this kinase which could be used to extend the effectiveness of beta agonists. Specifically, a range of available human cells and tissues will be screened as potential sources of the kinase and then it will be purified from the best source. Candidate peptides will be prepared and examined as model substrates for the kinase. The components will then be configured to a high throughput assay designed to identify potential drugs. In phase II we will clone and express the kinase, if this is required, and initiate screening. We will also establish secondary screens designed to evaluate the specificity and in vivo effectiveness of lead compounds from the primary high throughput screen.

β-肾上腺素能激动剂用于治疗慢性和运动- 诱发哮喘 这些药物通过β-肾上腺素能受体 受体/腺苷酸环化酶偶联效应系统产生的松弛 气管和支气管树的平滑肌从而缓解 哮喘症状 受体与激动剂的结合导致 脱敏和减少激动剂反应。 一种新的蛋白激酶β 肾上腺素能受体激酶密切参与这一过程。 的 该提案的目的是确定识别具体 这种激酶的抑制剂可用于延长 β受体激动剂 具体来说，一系列可用的人类细胞和 组织将被筛选为激酶的潜在来源， 将从最好的源头得到净化。 将制备候选肽 并作为激酶的模型底物进行检查。 然后，组件将 被配置为高通量测定，其被设计为鉴定潜在的 毒品 在第二阶段，我们将克隆和表达激酶，如果这是 要求，并启动筛选。 我们还将建立二级屏幕 旨在评价电极导线的特异性和体内有效性 化合物从初级高通量筛选。