Curcumin-based analogs as improved inhibitors of Abeta aggregation

描述（由申请人提供）：阿尔茨海默病（AD）的发展伴随着神经代谢活性的降低和突触完整性的丧失，这归因于淀粉样蛋白样斑块的形成，淀粉样蛋白样斑块开始于内嗅复合体和海马，随后进入新皮质。这些斑块由称为Abeta的40或42个氨基酸的疏水肽的细胞外聚集引起。尽管Abeta是由所有年龄段的个体持续产生的，但其聚集高度依赖于单体肽的浓度。一旦达到临界浓度，Abeta经历从α-螺旋/无规卷曲到β-折叠构型的转变，这是其聚集和沉积的主要原因。 目前阿尔茨海默病的治疗集中在临床病理学的症状方面，包括乙酰胆碱酯酶抑制剂和NMDA受体活性的调节。虽然这些疗法对减缓认知能力下降有一定的效果，但它们尚未证明对疾病进展有任何重大影响。迄今为止，最令人鼓舞的疗法集中在预防Abeta寡聚化或预先形成的Abeta原纤维的溶解，从而减少总体淀粉样蛋白负担。许多研究已经描述了有效防止Abeta聚集的抑制剂;然而，由于毒性或它们不能穿过血脑屏障，它们的有用性受到限制。姜黄素是一种多酚类天然产物，最近显示在体外抑制Abeta寡聚体的形成，并且据报道当注射到循环中时穿过血脑屏障并减少体内淀粉样斑块负担。然而，姜黄素在添加到饮食中时效果较差，因为其口服生物利用度有限。从这些令人兴奋的新发现中，我们假设姜黄素具有分子特征，使其成为开发更有效的Abeta聚集抑制剂的优秀先导化合物，这些抑制剂表现出改善的生物利用度。为了解决这一假设，我们将检查我们现有的姜黄素类似物的化学文库，以确定负责抑制Abeta肽寡聚化的姜黄素的分子特征（具体目标1），测量证明是有效抑制剂的每种类似物的生物利用度（具体目的2），并使用从目的1和2获得的实验数据，使用基于配体的药物设计（具体目的3）改善这些化学类似物的功效。

DESCRIPTION (provided by applicant): The development of Alzheimer Disease (AD) is accompanied by a decrease in neural metabolic activity and loss of synaptic integrity, which are attributed to the formation of amyloid-like plaques beginning in the entorhinal complex and hippocampus, later advancing into the neocortex. These plaques result from extracellular aggregation of a 40 or 42 amino acid hydrophobic peptide called Abeta. Although Abeta is continually produced by individuals of all ages, its aggregation is highly dependent on the concentration of monomeric peptide. Once a critical concentration is reached, Abeta undergoes a transition from alpha-helix/random coil to a beta-sheet configuration, which is primarily responsible for its aggregation and deposition. Current therapies for Alzheimer's disease focus on symptomatic aspects of the clinical pathology and include acetylcholine esterase inhibitors and modulation of NMDA receptor activity. Although these therapies have shown a modest effect on slowing cognitive decline, they have yet to demonstrate any major impact on the progression of the disease. The most encouraging therapies to date focus on preventing Abeta oligomerization or dissolution of pre-formed Abeta fibrils, thereby reducing overall amyloid burden. Numerous studies have described inhibitors that are effective in preventing Abeta aggregation; however, their usefulness has been limited due to toxicity or their inability to cross the blood-brain barrier. Curcumin, a polyphenolic natural product, was recently shown to inhibit the formation of Abeta oligomers in vitro and was reported to cross the blood-brain barrier when injected into the circulation and reduce amyloid plaque burden in vivo. However, curcumin was less effective when added to the diet, due to its limited oral bioavailability. From these exciting new findings, we hypothesize that curcumin presents molecular features making it an excellent lead compound for the development of more effective inhibitors of Abeta aggregation that demonstrate improved bioavailability. To address this hypothesis, we will examine our existing chemical library of curcumin-analogs to identify the molecular features of curcumin that are responsible for inhibition of Abeta peptide oligomerization (Specific Aim 1), measure bioavailability of each analog that proves to be an effective inhibitor (Specific Aim 2), and using the experimental data obtained from Aims 1 and 2, improve upon the efficacy of these chemical analogs using ligand-based drug design (Specific Aim 3).