A High Capacity Screen for Membrane-Active Compound(RMI)

膜活性化合物（RMI）的高容量筛选

• 批准号: 7021230
• 负责人: DONALD M. ENGELMAN
• 金额: $ 20.44万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7021230
• 关键词: biotechnology; drug discovery /isolation; drug screening /evaluation; fluorescence resonance energy transfer; fluorescent dye /probe; glycophorin; growth factor receptors; high throughput technology; lipid bilayer membrane; major histocompatibility complex; membrane proteins; membrane reconstitution /synthesis; platelet derived growth factor; protein protein interaction; recombinant proteins; small molecule; synthetic peptide; technology /technique development; virus protein

DESCRIPTION (provided by applicant): Membrane proteins are the targets of a majority of all drugs. Many of these drugs bind deeply within the non-polar region of the membrane, where transmembrane helix (TM) interactions are a dominant factor in the stability and activity of target proteins. We have developed assays that might be useful in finding molecules that specifically influence TM-TM interactions, either strengthening or weakening the association of these key elements of structure. If such molecules can be found in screens, they will provide leads for the discovery of new pharmacological agents. To investigate this possibility, we will set up screens using important proteins that we have worked with and already know to interact through their TM domains: the PDGF receptor TM, the TM of the E5 protein from Papilloma virus, the interaction of PDGFR TM with E5, and the li TM from the MHC. We will test specificity by cross comparison among different targets, by positive and negative controls with Glycophorin A TM, and by TM mutational analysis of the most specific and effective hits, where it is expected that modification of a specific binding site will alter affinity and efficacy.

描述（由申请人提供）：膜蛋白是大多数药物的靶点。这些药物中的许多深深地结合在膜的非极性区域内，其中跨膜螺旋（TM）相互作用是靶蛋白的稳定性和活性的主导因素。我们开发了一些检测方法，这些检测方法可能有助于寻找专门影响TM-TM相互作用的分子，从而加强或削弱这些关键结构元素的结合。如果这些分子可以在筛选中找到，它们将为发现新的药理学试剂提供线索。为了研究这种可能性，我们将使用我们已经研究过并且已经知道通过其TM结构域相互作用的重要蛋白质进行筛选：PDGF受体TM，来自乳头瘤病毒的E5蛋白的TM，PDGFR TM与E5的相互作用，以及来自MHC的li TM。我们将通过不同靶标之间的交叉比较、血型糖蛋白A TM的阳性和阴性对照以及最特异性和有效命中的TM突变分析来测试特异性，其中预期特异性结合位点的修饰将改变亲和力和功效。