权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Towards Treatment of Alzheimer’s Disease by Targeting Pathogenic Tau and Beta-Amyloid Structures

通过靶向致病性 Tau 和 β-淀粉样蛋白结构来治疗阿尔茨海默病

基本信息

批准号：
10330046
负责人：
DAVID EISENBERG
金额：
$ 107.56万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10330046
关键词：
Acquired Immunodeficiency Syndrome Address Affinity Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease test American Amyloid Amyloid Fibrils Amyloid beta-Protein Amyloidosis Antibodies Autopsy Binding Binding Sites Brain Cells Clinic Collaborations Complex Cryoelectron Microscopy Dementia Development Disease Drug Design Effectiveness Electron Microscopy Etiology Exhibits HIV Human Knowledge Learning Malignant Neoplasms Masks Mass Spectrum Analysis Methods Modeling Mole the mammal Molecular Molecular Structure Mus Nature Nerve Degeneration Organoids Pathology Peptides Pharmaceutical Preparations Phosphorylation Post-Translational Protein Processing Proteins Role Science Specificity Structure Testing Translations United States National Institutes of Health Vacuum Weight Work X ray diffraction analysis abeta accumulation abeta oligomer amyloid structure base brain behavior cell type cofactor cytotoxic design drug candidate drug testing electrical property frontier improved inhibitor/antagonist interest neuron loss prophylactic protein aggregation small molecule tau Proteins tau aggregation tau mutation tau phosphorylation tau-1 tool

项目摘要

Project Summary Aim 1 addresses the dearth of drugs for dementia, by structure-based drug design. This approach, so fruitful for treating cancer and HIV-AIDS, is opening for Alzheimer’s Disease (AD) because of advances in diffraction and cryoEM. Aggregation of protein tau is strongly correlated with the onset of dementia. Based on atomic structures, 9 inhibitors of tau aggregation have been designed. Aim 1 proposes determination of the atomic structure of one of these inhibitors on the tip of tau fibrils extracted from the autopsied brain of an AD patient. By binding to fibril tips, our designed inhibitors halt “seeding” of new tau fibrils in connected cells. This atomic structure will reveal how to increase the affinity and specificity of the inhibitor. Aim 1 will also focus on the discovery of the identity and binding sites on tau of molecular factors that drive its aggregation. These structures will enable design of small molecules and peptides that mask the binding site, thereby interfering with factor binding, and hence producing prophylactic drugs for AD. The same approach will visualize binding sites of post-translational modifications of tau, including phosphorylation, offering a related strategy for drug design. Aim 2 proposes to fill the vacuum of knowledge of the structures of small aggregates of tau and beta- amyloid, known as oligomers. Numerous studies of others provide evidence that oligomers are more cytotoxic on a weight basis (but not a mole basis) than fibrils of the same protein. And, somewhat mysteriously, oligomers of different fibril-forming proteins share structural similarities in that a particular antibody (A11) recognizes them, but not their corresponding fibrils. The transient nature of oligomers has defeated previous attempts to learn their atomic structures, but fortunately our collaborators in the Kayed and Raskatov labs have found methods to stabilize oligomers of tau and beta-amyloid, respectively, long enough for us to make grids suitable for cryoEM structure determination. Preliminary micrographs are encouraging. Aim 3 proposes tests of AD drugs in “mini-brains” which are grown in the lab of our collaborator UCLA Prof. Novitch. These organoids are about the size of a BB yet display structure and electrical properties of actual human brains. They are made from human cells and display the cell types and electrical messaging of human brains. Preliminary work shows these mini-brains can be infected with tau pathology, and now the ability of our various drug candidates to interfere with the spreading and damage of aggregated tau will be tested in them. If successful, this approach can provide a new avenue for testing Alzheimer’s drugs prior to human trials.

项目概要目标 1 通过基于结构的药物设计解决痴呆症药物的缺乏问题。这种做法，所以由于进展，该疗法在治疗癌症和艾滋病毒/艾滋病方面卓有成效，正在为治疗阿尔茨海默氏病（AD）打开大门在衍射和冷冻电镜中。 tau 蛋白的聚集与痴呆症的发病密切相关。基于原子结构，设计了 9 种 tau 聚集抑制剂。目标 1 提出确定从提取的 tau 原纤维尖端上这些抑制剂之一的原子结构 AD 患者的尸检大脑。通过与原纤维尖端结合，我们设计的抑制剂可以阻止新的“播种” 连接细胞中的 tau 原纤维。这种原子结构将揭示如何增加亲和力和特异性的抑制剂。目标 1 还将重点发现 tau 的身份和结合位点驱动其聚集的分子因素。这些结构将使小分子的设计成为可能以及掩盖结合位点的肽，从而干扰因子结合，从而产生 AD 的预防药物。同样的方法将可视化翻译后的结合位点 tau 的修饰，包括磷酸化，为药物设计提供了相关策略。目标 2 旨在填补 tau 和 beta-小聚集体结构的知识真空。淀粉样蛋白，称为寡聚物。其他人的大量研究提供的证据表明低聚物更有效以重量为基础（但不是以摩尔为基础）的细胞毒性高于相同蛋白质的原纤维。并且，某种程度上神秘的是，不同原纤维形成蛋白的寡聚物具有结构相似性，因为特定的抗体（A11）识别它们，但不识别它们相应的原纤维。低聚物的瞬态性质已经挫败了之前学习其原子结构的尝试，但幸运的是我们的合作者 Kayed 和 Raskatov 实验室找到了稳定 tau 和 β-淀粉样蛋白寡聚体的方法，分别足够长，足以让我们制作适合冷冻电镜结构测定的网格。初步的显微照片令人鼓舞。目标 3 提议在我们的合作者 UCLA 实验室培养的“迷你大脑”中测试 AD 药物诺维奇教授。这些类器官的大小与 BB 相当，但具有结构和电特性真实的人类大脑。它们由人体细胞制成，显示细胞类型和电信号人类大脑的信息传递。初步研究表明这些迷你大脑可能被 tau 蛋白感染病理学，以及现在我们各种候选药物干扰传播和传播的能力将在其中测试聚集的 tau 蛋白的损伤。如果成功的话，这种方法可以提供一条新途径用于在人体试验之前测试阿尔茨海默氏症药物。