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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称为 ER 应激的细胞状况。神经退行性疾病中诱导内质网应激包括阿尔茨海默病（AD）。 PERK 是主要的 ER 应激传感器蛋白之一它可以被 ER 腔域中的错误折叠蛋白激活以引发 ER 应激。越来越多的证据表明PERK的激活与与AD的发病机制有关。 PERK 激活可导致 BACE1 过度表达， β 淀粉样蛋白 (Aβ) 斑块的沉积和 tau 蛋白的磷酸化。延长 PERK 激活还可能导致神经元因细胞凋亡而丢失。来自 AD 动物的可靠数据模型表明，PERK 的消耗或抑制可能会表现出显着的神经保护并减少 AD 大脑中 AD 相关斑块的数量。然而，现有的 PERK 抑制剂是 ATP 类似物，具有高毒性和低体内特异性。我们的数据支持这样的假设：错误折叠的蛋白质可以直接与 PERK 相互作用，激活 PERK 信号通路。我们建议识别新颖的 PERK 抑制剂，可以阻断 PERK 管腔结构域和通过高通量筛选错误折叠的蛋白质。这些小分子抑制剂可能代表了通过减弱内质网应激信号来治疗 AD 的新疗法。我们有确定了 PERK 管腔结构域及其肽底物的复杂晶体结构，这使我们能够通过使用基于结构的药物设计来优化已识别的抑制剂。