Alzheimer's Therapeutic Derived from a Natural Product

描述（由申请人提供）：本提案旨在为阿尔茨海默病（AD）治疗药物的开发提供资金，该药物采用创新方法开发可用作治疗和预防的药物。AD是一种破坏性的常见疾病，主要影响老年人，65岁以上人群的频率为5%，80岁以上增加到20%，85岁以上增加到50%。据估计，世界上有1400万人患有这种疾病，美国每年的费用为1000亿美元。随着人口平均年龄的增加，患病率和费用继续上升。目前，没有治愈AD的方法，治疗是姑息性的，而不是治疗疾病的根本原因。β-淀粉样蛋白（Abeta）是一种由β-淀粉样蛋白前体蛋白（APP）加工而成的天然肽，其过度产生是AD发展的关键因素。影响Abeta过度产生的因素增加了阿尔茨海默氏症的患病率和早发性。目前大多数药物开发计划都集中在改变加工酶的活性，以减少Abeta。然而，这些加工酶也参与其他重要的生物过程。处理活动的变化可能导致不期望的副作用。在一种新的方法中，我们提出从一种独特的天然产物来源中鉴定一种小分子化合物，该化合物改变APP构象和加工以减少Abeta的丰度。APP中的某些基因突变改变了构象和加工，导致阿尔茨海默病的早期发作，而没有任何其他明显的健康问题，这一证据预示着改变APP构象和加工的治疗剂副作用的风险较低。这种类型的药物不仅在治疗AD方面具有很高的实用性，而且还可以作为那些有患该疾病风险的人的预防药物。

DESCRIPTION (PROVIDED BY APPLICANT): This proposal seeks funding for the development of an Alzheimer's disease (AD) therapeutic using an innovative approach to develop a pharmaceutical that can be used as both a treatment and as a preventative. AD is a devastating common disorder affecting primarily elderly people with a frequency of 5% of the population over 65, increasing to 20% over 80 and 50 % over 85 years of age. An estimated 14 million people in the world have the disease, at a cost of $100 billion per year in the United States. The prevalence and the cost continue to escalate with the increase in the mean age of the population. Currently, there is no cure for AD, and treatments are palliative rather than treating the underlying causes of the disease. An over production of beta-amyloid (Abeta), a natural occurring peptide processed from beta-amyloid precursor protein (APP), is the key element in the development of AD. Factors influencing over-production of Abeta increase the prevalence and early onset of Alzheimer's. Most current drug development programs are focused on altering the activities of the processing enzymes to cause a reduction in Abeta. These processing enzymes, however, are also involved in other important biological processes. A change in processing activity is likely to lead to undesired side effects. In a novel approach, we propose to identify a small molecule compound from a unique natural product source that alters APP conformation and processing to reduce the abundance of Abeta. The evidence that certain genetic mutations in APP alter conformation and processing leading to early onset of Alzheimer's disease without any other apparent health problems predicts that a therapeutic that alters APP conformation and processing would have a low risk of side effects. This type of pharmaceutical would have high utility not only for treatment of AD but also as a prophylactic for those at risk of developing the disease.