Curcumin-based analogs as improved inhibitors of Abeta aggregation

描述(申请人提供)：阿尔茨海默病(AD)的发展伴随着神经代谢活性下降和突触完整性的丧失，这是由于淀粉样斑块的形成始于内嗅觉复合体和海马体，后来进入新皮质。这些斑块是一种称为Abeta的40或42个氨基酸的疏水肽在细胞外聚集的结果。尽管Abeta在各个年龄段的个体中持续产生，但它的聚集高度依赖于单体多肽的浓度。一旦达到临界浓度，Abeta将经历从α-螺旋/随机卷曲到β-折叠构型的转变，这是其聚集和沉积的主要原因。 目前治疗阿尔茨海默病的方法主要集中在临床病理的症状方面，包括乙酰胆碱酯酶抑制剂和调节NMDA受体活性。尽管这些疗法在减缓认知衰退方面显示出温和的效果，但它们尚未显示出对疾病进展的任何重大影响。到目前为止，最鼓舞人心的治疗方法集中在防止Abeta寡聚或预先形成的Abeta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，由于毒性或它们无法通过血脑屏障，它们的有效性一直受到限制。姜黄素是一种多酚类天然产物，最近被证明在体外可以抑制Aβ寡聚体的形成，并被报道在体内注射时可以穿过血脑屏障，减少淀粉样蛋白斑块的负担。然而，姜黄素添加到饮食中时效果较差，因为它的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聚集抑制剂的极佳先导化合物，证明了生物利用度的提高。为了解决这一假设，我们将检查我们现有的姜黄素类似物化学库，以确定负责抑制Abeta肽齐聚的姜黄素的分子特征(特定目标1)，测量每个被证明是有效抑制剂的类似物的生物利用度(特定目标2)，并使用从目标1和2获得的实验数据，通过基于配体的药物设计(特定目标3)来改善这些化学类似物的有效性。

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).