Structure and Inhibition of Amyloid in Alzheimer's Disease

阿尔茨海默病中淀粉样蛋白的结构和抑制

基本信息

批准号：
9194224
负责人：
DAVID EISENBERG
金额：
$ 377.99万
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：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9194224
关键词：
Acquired Immunodeficiency Syndrome Agreement Alzheimer&apos s Disease Amyloid Amyloid Fibrils Amyloid beta-Protein Animal Model Antibodies Binding Biological Assay Blood - brain barrier anatomy Cancerous Cell Surface Receptors Cell model Cells Chronic Communities Crystallization Dementia Development Drug Targeting Effectiveness Environment Evolution Failure Goals HIV Hand Hemoglobin In Vitro Lipids Membrane Metabolic Diseases Methods Nature Pharmaceutical Preparations Prealbumin Proteins Ribosomes Seeds Structure Temperature Testing Therapeutic Therapeutic Agents Time Toxic effect Vertebral column Work abeta accumulation abeta oligomer abeta toxicity alpha synuclein amyloid formation amyloid structure base combat design electron diffraction frontier improved inhibitor/antagonist insight leukemia neurotoxicity new technology stem tau Proteins tau aggregation tau-1 tool

项目摘要

Our hypothesis is that the lack of drugs to halt Alzheimer’s disease stems in large part from ignorance of the structures of the most pertinent drug targets: the aggregated forms of the proteins tau and beta-amyloid. Here we propose to extend our studies of the structures of amyloid fibrils and oligomers to enable structure-based design of inhibiting compounds. For each of our proposed projects, structure determination will be followed by structure-based design of one or more inhibitors. Then each inhibitor will be assayed for effectiveness in inhibiting aggregate formation in vitro and inhibiting toxicity in cell models. The most effective inhibitors will then be assessed in animal models of our collaborators. Among our projects are the following: (1) Structure determination of oligomers of tau that can seed spreading of tau from cell to cell, and subsequent design of an inhibitor of oligomerization; (2) Inhibitor design of tau aggregation based on our newly determined structure of the amyloid-forming segment of tau with sequence VQIINK; (3) Evolution by ribosome display of inhibiting single-domain antibodies against tau aggregates, with the possibility that these may penetrate the blood-brain- barrier; (4) Optimization of existing crystals of the 20 residue segment of beta-amyloid with sequence GKLVFFGENVGSNKGAIIGL, which seems to form an oligomer. Improved crystals will be followed by structure determination and inhibitor design; (5) Crystallization of beta-amyloid or its segments in a lipid environment to gain possible insight into its toxic function; (6) Structure determination of a segment of beta-amyloid bound to its putative cell-surface receptor, followed by inhibitor design; (7) Exploration of the action of our newly discovered segment of the protein transthyretin which breaks up oligomers of beta-amyloid and inhibits toxicity. Each of these projects, if successful, opens a path to a possible therapeutic agent against Alzheimer’s disease. These paths have not been previously available because the pertinent structures have been unknown. We find the principal barrier to determination of amyloid structures is the miniscule size of the crystals. We propose to surmount this barrier by further exploitation of advanced methods of electron diffraction.

我们的假设是，缺乏阻止阿尔茨海默氏病的药物很大程度上远离无知最相关的药物靶标的结构：蛋白质tau和 β-淀粉样蛋白。在这里，我们建议扩展我们对淀粉样纤维原纤维结构的研究和低聚物可以实现基于结构的抑制化合物设计。对于我们的每个建议项目，结构确定将是一个或多个抑制剂的基于结构的设计。然后，将分配每个抑制剂在体外抑制骨料形成方面的有效性抑制细胞模型中的毒性。然后将在动物模型中评估最有效的抑制剂我们的合作者。我们的项目中有以下内容：（1）tau的低聚物的结构测定，可以从细胞到细胞播种tau的种子，以及随后的寡聚化抑制剂的设计；（2）基于我们新确定的淀粉样蛋白形成结构的抑制剂设计用序列vqiink的tau段；（3）核糖体显示抑制单域的进化针对tau聚集体的抗体，这些抗体可能会穿透血脑障碍; （4）用序列优化β-淀粉样蛋白的20个居住段的现有晶体 Gklvffgenvgsnkgaiigl，似乎形成了一种低聚物。将遵循改进的晶体按结构确定和抑制剂设计；（5）在A中结晶的β-淀粉样蛋白或其片段脂质环境可以洞悉其毒性功能；（6）结构确定与其推定的细胞表面受体结合的β-淀粉样蛋白段，然后是抑制剂设计；（7）探索我们新发现的蛋白质经硫蛋白的作用向上β-淀粉样蛋白的低聚物并抑制毒性。如果成功的话，这些项目中的每一个都为针对阿尔茨海默氏病的可能的治疗剂开辟了道路。这些路径以前尚未获得，因为永久性结构尚不清楚。我们发现确定淀粉样结构的主要障碍是晶体的微小尺寸。我们建议通过进一步利用高级电子衍射方法来克服这一障碍。