Mitophagy inhibitors for treatment of Alzheimer's Disease

用于治疗阿尔茨海默病的线粒体自噬抑制剂

• 批准号: 9046308
• 负责人: Feng Wang
• 金额: $ 20.52万
• 依托单位: PROGENRA, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9046308
• 关键词: Acetylcholine; Address; Adverse effects; Affect; Age-Years; Alzheimer' s Disease; Animal Model; Area; Autophagocytosis; Axon; Biological Assay; Brain; Caring; Cause of Death; Cell model; Cessation of life; Cognition; Collection; Deglutition; Dementia; Deubiquitinating Enzyme; Disease; Disease Progression; Effectiveness; Emotional; Enzymes; Excision; Goals; Hippocampus (Brain); Incidence; Knock-out; Lead; Learning; Life Expectancy; Link; Mediating; Memory; Memory Disorders; Mitochondria; Morbidity - disease rate; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotransmitters; PINK1 gene; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Phagosomes; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phosphorylation; Phosphotransferases; Plant Roots; Population; Production; Quality Control; Reactive Oxygen Species; Series; Staging; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Time; Ubiquitin; United States; United States National Institutes of Health; Walking; age related; analog; base; cost; drug discovery; entorhinal cortex; high throughput screening; improved; in vivo; in vivo Model; inhibitor/antagonist; interest; mitochondrial dysfunction; mortality; mouse model; neuron loss; novel; novel therapeutics; overexpression; parkin gene/protein; prevent; programs; public health relevance; screening; small molecule; tool; ubiquitin ligase; ubiquitin-specific protease

 DESCRIPTION (provided by applicant): Millions currently suffer from Alzheimer's disease (AD); as life expectancy increases, it will become increasingly widespread. AD results from the degeneration and death of neurons of the hippocampus and entorhinal cortex. End stage patients require continuous care, and AD is currently the sixth leading cause of death in the U.S. There is currently no cure; approved treatments, aimed at improving cognition and slowing progression, focus primarily on increasing the level of acetylcholine in the brain. Such treatments, which have serious side effects and relieve AD symptoms only for a limited time, cannot prevent neuronal death. Thus, an urgent need exists to identify novel agents that prevent AD progression by acting on targets that mediate neuronal death. The mitochondrion is such a target; excess dysfunctional mitochondria in AD-linked neurons lower energy efficiency and release reactive oxygen species contributing to neuronal death. The dysfunctional mitochondria are cleared by phosphorylation and ubiquitin-mediated autophagy (mitophagy), or degradation in auto phagosomes. The ubiquitin pathway component consists of the conjugating enzyme parkin, which tags defective mitochondria with ubiquitin for removal, and the deubiquitinating enzyme USP30, which deconjugates ubiquitin, preventing the removal of defective mitochondria. Normally, in AD patients the ability to clear defective mitochondria is overwhelmed, and replacement of parkin function by overexpression can rescue AD symptoms in vivo. Moreover, USP30 knockout has been shown to enhance parkin activity and increase mitochondrial integrity in neurons. These findings lead to the hypothesis that USP30 is a novel target for developing small molecule inhibitors for treatment of AD; USP30 inhibitors are expected to prevent mitophagy deficiency-induced neuronal death, thereby hindering progression of AD. It is proposed to identify novel modulators of USP30 by screening a diverse collection of small molecules. An enzymatic-based USP30 assay for high throughput screening (HTS) will be configured and Progenra's 220,000 compound collection will be screened. Confirmed hits will be reordered, along with a subset of related analogs, and profiled against a series of DUBs and other proteases before initiating a hit to lead optimization program. The most promising compounds from this program will be examined in cellular models of mitophagy rescue. In phase II, the most interesting compounds will be progressed to hit-to-lead medicinal chemistry optimization with associated DMPK and additional cellular and animal model studies. The commercial goal is a novel drug to treat AD.

 描述（由申请人提供）：数百万人目前患有阿尔茨海默病（AD）;随着预期寿命的增加，它将变得越来越普遍。AD是海马和内嗅皮质神经元变性和死亡的结果。终末期患者需要持续的护理，AD目前是美国第六大死亡原因，目前还没有治愈方法;批准的治疗方法旨在改善认知和减缓进展，主要集中在增加大脑中乙酰胆碱的水平。这种治疗具有严重的副作用，并且只能在有限的时间内缓解AD症状，不能防止神经元死亡。因此，迫切需要鉴定通过作用于介导神经元死亡的靶点来预防AD进展的新型药剂。线粒体就是这样一个靶点; AD相关神经元中过多的功能失调的线粒体降低了能量效率，释放出活性氧，导致神经元死亡。功能障碍的线粒体通过磷酸化和泛素介导的自噬（线粒体自噬）或在自噬体中降解而被清除。泛素途径组分由缀合酶parkin和去泛素化酶USP 30组成，所述缀合酶parkin用泛素标记缺陷线粒体以用于去除，所述去泛素化酶USP 30使泛素去缀合，从而防止缺陷线粒体的去除。通常，在AD患者中，清除缺陷线粒体的能力被压倒，并且通过过表达替代parkin功能可以在体内挽救AD症状。此外，USP 30敲除已显示增强parkin活性并增加神经元中的线粒体完整性。这些发现导致假设USP 30是开发用于治疗AD的小分子抑制剂的新靶标; USP 30抑制剂预计可预防线粒体自噬缺陷诱导的神经元死亡，从而阻碍AD的进展。建议通过筛选不同的小分子集合来鉴定USP 30的新型调节剂。将配置用于高通量筛选（HTS）的基于酶的USP 30测定，并将筛选Progenra的220，000种化合物。确认的命中将被重新排序，沿着相关类似物的子集，并在启动命中以引导优化程序之前针对一系列DUB和其他蛋白酶进行分析。最有前途的化合物，从这个计划将在细胞模型的线粒体自噬救援。在第二阶段，最令人感兴趣的化合物将通过相关的DMPK和额外的细胞和动物模型研究进行药物化学优化。商业目标是一种治疗AD的新药。