HIGH THROUGHPUT SCREENING ASSAY DEVELOPMENT FOR PHARMACOPERONES

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 具体目标是生产和验证从分子库中鉴定 pharmaperone 药物的筛选，这些药物通过新近认可的治疗方法发挥作用，即控制翻译后蛋白质折叠，从而实现细胞运输和突变蛋白质的拯救。 G 蛋白偶联受体 (GPCR) 经常成为文库筛选的目标，但这种方法通常依赖于识别激动剂或拮抗剂的筛选，并且会错过许多将在提议的筛选中识别的药物。我们的方法依赖于目前分子库检测管道中尚未体现的细胞机制，识别出在治疗方法中具有显着新颖性的药物；这为使用 HTS 方法提供了一个尚未开发的机会。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The specific aim is to produce and validate screens for identification of pharmacoperone drugs from molecular libraries which exert their actions by a newly appreciated therapeutic approachnamely, control of post-translational protein folding and, as a consequence, cellular trafficking and rescue of mutated proteins. G protein coupled receptors (GPCRs) are frequently targeted in library screening, yet this approach generally relies on screens that identify agonists or antagonists and would have missed many of the drugs that will be identified in the proposed screens. Our approach identifies drugs with a significant degree of novelty in therapeutic approach, relying on cellular mechanisms that are not currently represented in the Molecular Libraries assay pipeline; this offers an untapped opportunity for use of the HTS approach.