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PERK inhibition as a therapeutic approach for Alzheimer's disease

PERK 抑制作为阿尔茨海默病的治疗方法

基本信息

批准号：
9763416
负责人：
BINGDONG SHA
金额：
$ 18.56万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763416
关键词：
Affect Affinity Alzheimer&apos s Disease Amyloid deposition Animal Disease Models Apoptosis Attenuated Binding Biochemical Biological Assay Brain Diseases Cell Line Cells Chemicals Chronic Collaborations Complex Crystallization Data Deposition Drug Design Endoplasmic Reticulum Exhibits Fluorescence Polarization Human Hydrophobicity Lead Libraries Measures Modeling Neurodegenerative Disorders Pathogenesis Peptides Proteins Resolution Senile Plaques Signal Pathway Signal Transduction Solid Specificity Stretching Structural Protein Structure Testing Therapeutic Toxic effect Universities analog base beta-site APP cleaving enzyme 1 design endoplasmic reticulum stress high throughput screening improved in vivo inhibitor/antagonist misfolded protein mouse model neuron loss neuroprotection novel overexpression protein complex protein structure screening sensor small molecular inhibitor stable cell line tau Proteins tau phosphorylation virtual

项目摘要

Disturbance in the folding capacity of endoplasmic reticulum (ER) prompts a cellular condition known as ER stress. ER stress is induced in neurodegenerative diseases including Alzheimer’s disease (AD). PERK is one of the major ER stress sensor proteins which can be activated by misfolded protein in ER luminal domain to initiate the ER stress. Accumulating evidences have demonstrated that the PERK activation is closely associated with the pathogenesis of AD. PERK activation can lead to overexpression of BACE1, the deposition of amyloid β (Aβ) plaques and the phosphorylation of tau protein. Prolonged PERK activation may also cause the neuronal loss by apoptosis. Solid data from AD animal models have shown that depletion or inhibition of PERK may exhibit substantial neuroprotection and reduce the amount of AD-related plaques in the AD brains. However, the existing PERK inhibitors are ATP-analogues and represent high toxicity and low specificity in vivo. Our data support the hypothesis that misfolded proteins can directly interact with PERK to activate the PERK signaling pathway. We propose to identify novel inhibitors of PERK that can block the interactions between PERK luminal domain and the misfolded protein by high throughput screening. These small molecular inhibitors may represent novel treatments for AD by attenuating the ER stress signals. We have determined the complex crystal structure of PERK luminal domain and its peptide substrate, which allows us to optimize the identified inhibitors by use of structure-based drug design.

内质网（ER）折叠能力的紊乱提示了这就是所谓的内质网应激。神经退行性疾病中诱导ER应激包括阿尔茨海默病（AD）。PERK是一种主要的内质网应激感受蛋白其可被内质网腔结构域中的错误折叠蛋白激活而启动内质网应激。越来越多的证据表明，PERK激活与 AD的发病机制。PERK激活可导致BACE1过表达，淀粉样β（Aβ）斑块的沉积和tau蛋白的磷酸化。延长 PERK的激活也可能导致神经元的凋亡损失。AD动物的可靠数据模型显示，PERK的消耗或抑制可表现出显著的神经保护和减少AD大脑中AD相关斑块的数量。然而，在这方面，现有的PERK抑制剂是ATP类似物体内特异性。我们的数据支持错误折叠的蛋白质可以直接与PERK相互作用以激活PERK信号通路。我们建议识别新的可以阻断PERK管腔结构域与PERK管腔结构域之间的相互作用的PERK抑制剂，通过高通量筛选错误折叠的蛋白。这些小分子抑制剂可以代表了通过减弱ER应激信号治疗AD的新方法。我们有确定了PERK管腔结构域与其肽底物的复合物晶体结构，这使我们能够通过使用基于结构的药物设计来优化所鉴定的抑制剂。