POST-TRANSCRIPTIONALLY ACTING ALZHEIMER'S DRUGS

随着人口老龄化，阿尔茨海默病（AD）是一个主要问题，目前还没有真正有效的治疗方法。该疾病的特征之一是由淀粉样前体蛋白（APP）衍生的肽组成的不溶性斑块沉积。Message已经建立了一个药物发现项目，专注于通过改变RNA结合蛋白与其靶RNA的相互作用来调节蛋白质表达。该项目的总体目标是利用该技术开发降低APP水平的药物。目前的提案旨在(1)确定这些相互作用中涉及的所有必要成分；(2)筛选改变相互作用的化合物；(3)分析化合物在细胞培养中的作用；(4)测定其在AD动物模型中的体内疗效。这项工作的成功完成将产生临床前候选药物，并最终产生针对阿尔茨海默病进展的新治疗方法。到目前为止，我们已经证明Message在转录后水平受到调控，并且phenserine可以以特定的方式阻断APP mRNA的翻译。类似物目前正在测试更有效的分子，一旦更好地了解调控区域，将开发高通量筛选。拟议的商业应用：该项目的成功完成将为阿尔茨海默病治疗药物的临床前开发提供化合物。目前所有的阿尔茨海默病治疗方法都是治疗症状（认知），而这种策略将针对一个被认为在导致疾病中起作用的关键因素。此外，对转录后药物靶向的验证将对其他疾病的治疗产生广泛的影响。

Alzheimer's disease (AD) is a major concern as the population ages, with no truly effective treatments available. One of the hallmarks of the disease is the deposition of insoluble plaques composed of a peptide derived from Amyloid Precursor Protein (APP). Message has established a drug discovery program focused on regulating protein expression by altering the interaction of an RNA binding protein with its target RNA. The overall goal of this project is to use this technology to develop drugs that decrease levels of APP. The current proposal seeks to (1) identify all the necessary components involved in these interactions; (2) screen for compounds that alter the interactions; (3) analyze effects of the compounds in cell culture; and (4) determine the in vivo efficacy in animal models of AD. Successful completion of this work will result in preclinical drug candidates and ultimately in a novel treatment targeting AD progression. To date, we have demonstrated that Message is regulated at the post-transcriptional level and that phenserine can block translation of the APP mRNA in a specific fashion. Analogs are currently being tested for more potent molecules and a high throughput screen will be developed once the regulatory regions are better understood. PROPOSED COMMERCIAL APPLICATION: Successful completion of this project will provide compounds for preclinical development as AD therapeutics. All current treatments for AD treat the symptoms (cognition) whereas this strategy would target a key factor believed to play a role in causing the disease. In addition, validation of post-transcriptional drug targeting would have broad implications for the treatment of other diseases.