Curcumin-based analogs as improved inhibitors of Abeta aggregation

基于姜黄素的类似物作为改进的 Abeta 聚集抑制剂

• 批准号: 7196922
• 负责人: Robert Anthony Orlando
• 金额: $ 14.85万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7196922
• 关键词: Acetylcholine; Address; Age; Alzheimer' s Disease; Amino Acids; Amyloid; Amyloid beta-Protein; Amyloid deposition; Artificial Membranes; Biological Assay; Biological Availability; Biological Factors; Blood - brain barrier anatomy; Blood Circulation; Cell Line; Cells; Chemicals; Clinical Pathology; Clinical Trials; Complex; Curcumin; Data; Deposition; Development; Diet; Disease Progression; Drug Design; Effectiveness; Event; Goals; Hippocampus (Brain); Impaired cognition; In Vitro; Individual; Inhibitory Concentration 50; Intestinal Absorption; Lead; Libraries; Ligands; Literature; Measures; Metabolic; Modeling; Modification; Molecular; Molecular Structure; N-Methyl-D-Aspartate Receptors; Neocortex; Neuraxis; Neuroblastoma; Neurons; Numbers; Oral; Peptides; Permeability; Pharmaceutical Preparations; Prevention; Property; Quantitative Structure-Activity Relationship; Reporting; Research Personnel; Screening procedure; Senile Plaques; Spices; Standards of Weights and Measures; Structure; Structure-Activity Relationship; Synapses; Testing; Therapeutic; Toxic effect; Transgenic Organisms; Tumeric; abeta accumulation; abeta oligomer; alpha helix; amyloid formation; analog; base; beta pleated sheet; cytotoxicity; esterase inhibitor; extracellular; improved; in vivo; inhibitor/antagonist; mouse model; neurotoxic; novel; prevent; programs; relating to nervous system; small molecule libraries; virtual

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).

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，这是由于淀粉样斑块的形成，开始于内嗅复合体和海马，后来进入新皮层。这些斑块是由一种叫做Abeta的40或42个氨基酸的疏水肽的细胞外聚集造成的。尽管所有年龄的个体都能不断产生β，但它的聚集高度依赖于单体肽的浓度。一旦达到临界浓度，α - β就会从α -螺旋/随机线圈结构转变为β -薄片结构，这是其聚集和沉积的主要原因。