Drug discovery of anti-ADDL therapeutics for Alzheimer's

描述(由申请人提供)：最近的证据表明，阿尔茨海默病的主要原因是Abeta1-42蛋白的神经毒性寡聚体的逐渐积累。这些神经毒性低聚物被称为ADDLS(抗体衍生的可扩散配体)。在转基因阿尔茨海默病动物模型Tg2576 AD小鼠中，随着Add1水平的增加，记忆能力下降。人类阿尔茨海默病患者的ADDR水平比未受影响的年龄匹配的对照组高出70倍。ADDLS通过直接干扰突触功能来影响记忆，最终导致突触随着时间的推移而丧失。这一证据表明，小分子、ADTL指导的疗法可能会预防ADDL诱导的认知障碍，并减缓或逆转人类的疾病进展。这与目前FDA批准的药物形成了鲜明对比，后者治疗阿尔茨海默病的症状而不是根本原因。ADTL导向疗法最有希望的方法是通过阻断Abeta1-42蛋白的组装来防止ADTL的形成。这项建议的主题是建立和验证初级和次级化学筛选的级联，并筛选具有代表性的CNS靶向化学库，以识别阻止ADD1组装的小分子。在第一阶段，我们建议开发和验证均相ADTL组装阻滞剂筛选实验，进行分子动力学模拟以建立ADDL结构模型，并对选定的小分子文库进行中试筛选。

DESCRIPTION (provided by applicant): Recent evidence suggests that the primary cause of Alzheimer's disease is the progressive accumulation of neurotpxic oligomeric assemblies of the Abeta 1-42 protein. These neurotoxic oligomeric species are known as ADDLs (Ab-derived diffusible ligands). In Tg2576 AD mice, a transgenic Alzheimer's disease animal model, memory performance declines as ADDL levels increase. Human patients with Alzheimer's disease show a 70-fold elevation in ADDL levels relative to unaffected age-matched controls. ADDLs affect memory by directly interfering with synaptic function, which eventually results in synaptic loss over time. This evidence suggests that small molecule, ADDL-directed therapeutics might prevent ADDL-induced cognitive deficits, and slow or reverse disease progression in humans. This stands in contrast to current FDA-approved drugs, which treat the symptoms and not the underlying cause of Alzheimer's disease. The most promising approach to ADDL-directed therapeutics is to prevent ADDL formation by blocking assembly of the Abeta 1-42 protein. The subject of this proposal is to establish and validate a cascade of primary and secondary chemical screens and screen a representative CNS targeted chemical library to identify small molecules that block ADDL assembly. In Phase I, we propose to develop and validate a homogeneous ADDL assembly blocker screening assay, conduct molecular dynamics simulations to build an ADDL structural model, and carry out pilot screening of a selected small molecule library.