Misfolded protein clearance enhancers for Alzheimers therapy

用于治疗阿尔茨海默病的错误折叠蛋白清除增强剂

基本信息

批准号：
9139393
负责人：
GAL BITAN
金额：
$ 31.57万
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：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9139393
关键词：
Address Affect Aging Alzheimer&apos s Disease American Amyloid Amyloid beta-Protein Autophagocytosis Benign Binding Biological Availability Blood - brain barrier anatomy Brain Caring Characteristics Clinical Development Disease Dose Drug Industry Drug Kinetics Electrostatics Enhancers Formulation Future Goals Grant Head Health Hydrogen Bonding Hydrophobic Interactions In Vitro Investigational Drugs Lead Learning Memory impairment Modification Molecular Molecular Mechanisms of Action Mus Neurofibrillary Tangles Oral Pathogenesis Patients Penetration Pharmaceutical Preparations Physiological Processes Play Population Post-Translational Protein Processing Prevention Process Prodrugs Production Proteins Public Health Role Safety Senile Plaques Side Structure System Testing Therapeutic Toxic effect Transgenic Mice Transgenic Organisms Variant Work amyloid formation base beta pleated sheet cost design disorder prevention improved in vivo mouse model multicatalytic endopeptidase complex neuron loss novel pharmacokinetic characteristic prevent protein misfolding research study self assembly synaptic failure tau Proteins tau aggregation tau mutation treatment duration

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a proteinopathy characterized by deficient proteostasis of amyloid ß-protein and tau. Therefore, enhancement of clearance of the misfolded proteins involved in AD is a promising therapeutic strategy for preventing and treating the disease. We have been developing "molecular tweezers" (MTs) which act as Misfolded-Proteins Clearance Enhancers (MPCEs) using a unique mechanism. MTs bind to amyloidogenic proteins and remodel their abnormal self-assembly into non-toxic and non-amyloidogenic structures that can be efficiently degraded by the natural cellular clearance mechanisms. Our current lead compound, CLR01, has been found to be effective in multiple in vitro and in vivo systems, including prevention of Aß self-assembly and toxicity, inhibition of tau aggregation, and reduction of both amyloid plaques and neurofibrillary tangles in transgenic mouse brain. In addition, CLR01 was shown to have a high safety margin. However, the pharmacological characteristics of CLR01 need to be optimized, its effect on tau needs to be explored further, and certain questions about its mechanism of action and therapeutic potential are yet to be answered. In this project we will use a multi-prong approach to optimizing CLR01's pharmacokinetics, expand the characterization of its effect on tau, study CLR01's binding to amyloid plaques and neurofibrillary tangles in the brain, and characterize the capability of different doses and treatment durations of CLR01 treatment to remove toxic Aß and tau oligomers, reduce synaptotoxicity, and improve learning and memory deficits in a mouse model of AD. The study is expected to address currently unanswered questions and provide strong support for future formal development of MTs towards prevention and disease-modifying treatment of AD.

描述（由适用提供）：阿尔茨海默氏病（AD）是一种蛋白质病，其特征是淀粉样蛋白β-蛋白质和tau的确切蛋白质抑制作用。因此，加强对AD涉及的折叠蛋白的清除是预防和治疗疾病的有前途的治疗策略。我们一直在开发“分子镊子”（MTS），它们使用独特的机制充当错误折叠的蛋白质清除剂（MPCE）。 MTS与淀粉样蛋白结合，并将其异常的自组装重塑为无毒和非淀粉样生成结构，这些结构可以通过自然细胞清除机制有效降解。我们目前的铅化合物CLR01已被发现在多个体外和体内系统中有效，包括预防Aß自组装和毒性，抑制tau聚集以及还原淀粉样蛋白斑块和淀粉样蛋白斑块和神经原纤维缠结中的缠结转基因小鼠大脑。此外，CLR01被证明具有很高的安全边缘。但是，需要对CLR01的药理特征进行优化，需要进一步探索其对TAU的影响，并且有关其作用机理和治疗潜力机理的某些问题尚未得到回答。 In this project we will use a multi-prong approach to optimizing CLR01's pharmacokinetics, expand the characterization of its effect on tau, Study CLR01's binding to amyloid plaques and neurofibrillary tangles in the brain, and characterize the capability of different doses and treatment durations of CLR01 treatment to remove toxic Aß and tau oligomers, reduce synaptotoxicity, and improve learning and memory defines in AD的鼠标模型。预计该研究将解决当前未解决的问题，并为MTS未来的预防和疾病改良AD治疗提供大力支持。