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

• 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
• 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' 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

 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（由申请人提供）：阿尔茨海默氏病（AD）是一种以淀粉样β-蛋白和tau蛋白稳态缺陷为特征的蛋白质病，因此，增强AD中涉及的错误折叠蛋白的清除是预防和治疗该疾病的有前途的治疗策略。我们一直在开发“分子镊子”（MT），它使用独特的机制充当错误折叠蛋白质清除增强剂（MPCE）。 MT 与淀粉样蛋白结合，并将其异常自组装重塑为无毒和非淀粉样蛋白结构，可通过自然细胞清除机制有效降解，我们目前的先导化合物 CLR01 已被发现在多种体外试验中有效。和体内系统，包括预防 Aß 自组装和毒性、抑制 tau 聚集以及减少淀粉样斑块和神经原纤维缠结 此外，CLR01被证明具有较高的安全性，但CLR01的药理学特性需要优化，其对tau的作用需要进一步探索，其作用机制和治疗潜力也存在一些问题。在这个项目中，我们将采用多管齐下的方法来优化 CLR01 的药代动力学，扩大其对 tau 的作用的表征，研究 CLR01 与淀粉样蛋白的结合。该研究预计将在 AD 小鼠模型中观察大脑中的斑块和神经原纤维缠结，并表征不同剂量和治疗持续时间的 CLR01 治疗去除有毒 Aß 和 tau 寡聚体、减少突触毒性并改善学习和记忆缺陷的能力。解决目前悬而未决的问题，并为今后正式开发 MT 来预防和缓解 AD 疾病提供强有力的支持。