Identify Abeta Oligomer Inhibitors By Combinatorial Chemistry

通过组合化学鉴定 Abeta 寡聚物抑制剂

• 批准号: 7676057
• 负责人: LEE-WAY JIN
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676057
• 关键词: Affinity; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Animals; Binding; Biological; Biological Assay; Brain; Cells; Cerebrum; Chemicals; Computer Simulation; Data; Dementia; Deposition; Development; Diagnosis; Docking; Drug Delivery Systems; Emerging Technologies; Epitopes; Event; Future; Health; Human; Image; In Vitro; Inhibitory Concentration 50; Integrins; Kinetics; Laboratories; Lead; Libraries; Ligands; Masks; Memory impairment; Methods; Molecular; Mus; Names; Nerve Degeneration; Neurons; Pathogenesis; Peptides; Pharmaceutical Preparations; Phase; Property; Reporting; Screening procedure; Series; Site; Solutions; Study models; Synapses; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Toxic effect; abeta oligomer; amyloid imaging; analog; base; brain cell; combinatorial; combinatorial chemistry; design; drug development; extracellular; high throughput screening; improved; in vivo; inhibitor/antagonist; molecular dynamics; mouse model; neuroprotection; neurotoxic; novel; novel strategies; peptidomimetics; polymerization; prevent; prophylactic; protective effect; protein aggregate; protein aggregation; public health relevance; research study; scaffold; small molecule; small molecule libraries; success; uptake

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the major cause of dementia and one of the most disabling and burdensome health conditions worldwide. Currently there is an urgent need for new compound development for AD. Recent studies support that the accumulation of neurotoxic oligomeric aggregates made of the amyloid-beta protein (Ab) is a central event in the pathogenesis of AD. Recently, small molecule compounds that neutralize the neurotoxic effect of Ab oligomers (AbO) have shown promises in several studies. We have taken a new approach employing combinatorial chemistry and high throughput screening methods to discover cell-permeable, AbO-binding small molecule ligands that block AbO toxicity within both extracellular and intraneuronal sites. We hypothesize that these AbO ligands would interact with AbO to mask their epitopes that interact with cell targets, to prevent or reverse the aggregation of Ab peptides, and to reduce the level of AbO. These effects would provide neuroprotection from AD-like abnormalities in AD mouse models. Toward these ends, we have identified from screening several combinatorial libraries a promising compounds named LRL22. In this proposal, we plan to further optimize LRL22 using the "one-bead one-compound (OBOC)" combinatorial library method (Aim 1). Using this method, thousands to millions of compounds can be easily generated and screened concurrently. We will synthesize OBOC libraries based on the building blocks of LRL22 and select compounds that bind AbO by screening using the ultra high throughput on-bead binding assay. The selected AbO ligands will be further screened for their cell protective effect using our high throughput cell-based AbO toxicity assays. In Aim 2, we will determine the binding kinetics of selected AbO ligands, and will determine whether the binding results in interference with the AbO's interaction with synapses, or the reversal of Ab aggregation. Both are desirable neuroprotective properties. In Aim 3, we will test the in vivo efficacy of the most promising compound. We will determine whether the application of this compound reduces the levels of early intraneuronal Ab deposits in an AD mouse model called 3xTg-AD mice. Optimized compounds might be developed into therapeutic agents for AD. Since an important property of our selected compounds is binding to Ab aggregates, they might also be developed into amyloid imaging agents too. PUBLIC HEALTH RELEVANCE: The amyloid-beta protein is toxic to brain cells and is widely considered a drug target for Alzheimer's disease treatment. We will use emerging chemical and cell biological technologies to find small molecular compounds that block the toxic effect of the amyloid-beta protein. These compounds can be developed into therapeutic agents for Alzheimer's disease or into imaging agents for radiological diagnosis of Alzheimer's disease, a leading cause of dementia worldwide.

描述（由申请人提供）：阿尔茨海默病（AD）是痴呆症的主要原因，也是全球最具致残性和负担最重的健康状况之一。目前，迫切需要开发新的AD化合物。最近的研究支持由淀粉样β蛋白（Ab）组成的神经毒性寡聚体聚集体的积累是AD发病机制中的中心事件。最近，中和Ab寡聚物（AbO）的神经毒性作用的小分子化合物在几项研究中显示出希望。我们已经采取了一种新的方法，采用组合化学和高通量筛选方法，发现细胞渗透性，ABO结合小分子配体，阻止ABO毒性细胞外和神经元内的网站。我们假设这些AbO配体会与AbO相互作用，以掩盖其与细胞靶点相互作用的表位，从而防止或逆转Ab肽的聚集，并降低AbO的水平。这些作用将在AD小鼠模型中提供针对AD样异常的神经保护。为了这些目的，我们已经从筛选几个组合文库中鉴定出一种名为LRL 22的有前途的化合物。在该提案中，我们计划使用“一珠一化合物（OBOC）”组合文库方法（Aim 1）进一步优化LRL 22。使用这种方法，可以同时轻松生成和筛选数千至数百万种化合物。我们将基于LRL 22的结构单元合成OBOC文库，并通过使用超高通量珠上结合测定筛选来选择结合AbO的化合物。将使用我们的高通量基于细胞的AbO毒性测定进一步筛选所选择的AbO配体的细胞保护作用。在目的2中，我们将确定所选AbO配体的结合动力学，并将确定结合是否导致干扰AbO与突触的相互作用或Ab聚集的逆转。两者都是理想的神经保护特性。在目标3中，我们将测试最有希望的化合物的体内功效。我们将确定该化合物的应用是否降低了称为3xTg-AD小鼠的AD小鼠模型中早期神经元内Ab沉积的水平。优化后的化合物有可能成为AD的治疗药物。由于我们选择的化合物的一个重要特性是与Ab聚集体结合，因此它们也可能被开发成淀粉样蛋白成像剂。公共卫生相关性：淀粉样β蛋白对脑细胞有毒，被广泛认为是治疗阿尔茨海默病的药物靶点。我们将使用新兴的化学和细胞生物学技术来寻找小分子化合物，阻断淀粉样β蛋白的毒性作用。这些化合物可以开发成阿尔茨海默病的治疗剂或阿尔茨海默病的放射学诊断的成像剂，阿尔茨海默病是全球痴呆症的主要原因。