权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
9267131
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/9267131
关键词：
Abeta clearance Abeta synthesis Address Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease model American Amyloid beta-Protein Autophagocytosis Benign Binding Biological Availability Blood - brain barrier anatomy Brain Caring Characteristics Development Disease Dose Drug Industry Drug Kinetics Electrostatics Enhancers Formulation Future Goals Grant Head Hydrogen Bonding Hydrophobic Interactions Hydrophobicity In Vitro Investigational Drugs Lead Learning Memory impairment Modification Molecular Molecular Mechanisms of Action Mus Neurofibrillary Tangles Oral Pathogenesis Patients Penetration Pharmaceutical Preparations Pharmacology Physiological Processes Play Population Post-Translational Protein Processing Prevention Process Prodrugs Proteins Public Health Role Safety Senile Plaques Side Structure System Testing Therapeutic Toxic effect Transgenic Mice Transgenic Organisms Variant Work abeta accumulation amyloid formation amyloid structure base beta pleated sheet clinical candidate cost design experimental study improved in vivo misfolded protein mouse model multicatalytic endopeptidase complex neuron loss novel pharmacokinetic characteristic prevent protein B proteostasis public health relevance 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.