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Preventing Tau uptake by novel inhibitors of tau binding to LRP1

通过与 LRP1 结合的新型 tau 抑制剂阻止 Tau 摄取

基本信息

批准号：
10343473
负责人：
Michael Jackson
金额：
$ 88.57万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10343473
关键词：
Affect Affinity Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology American Animal Model Antibodies Antisense Oligonucleotides Automation Binding Biochemical Biological Assay Biology Biophysics Brain Brain region Cells Cellular biology Chemicals Critical Pathways DNA Dementia Disease Disease Progression Dose Event Fluorescence Resonance Energy Transfer Future Goals Healthcare Systems Human Impaired cognition In Vitro Intervention LDL-Receptor Related Protein 1 Lead Learning Libraries Ligand Binding Domain Measures Mediating Mediator of activation protein Medical Morphologic artifacts Mus Neurodegenerative Disorders Neurofibrillary Tangles Neurons Pathogenesis Pathologic Pathology Pathway interactions Patients Pattern Penetration Performance Pharmaceutical Preparations Phenotype Powder dose form Probability Procedures Production Property Publishing Reagent Recombinant Proteins Series Site Societies Surface System Tauopathies Testing Validation Work analog base cheminformatics effective therapy high throughput screening in vivo Model in vivo evaluation induced pluripotent stem cell inhibitor insight knock-down member neurofibrillary tangle formation neurotoxicity new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics prevent protein aggregation prototype receptor response scaffold scale up screening small molecule small molecule libraries tau Proteins tau aggregation tau interaction tau mutation treatment strategy uptake

项目摘要

PROJECT SUMMARY Several neurodegenerative diseases, such as Alzheimer's disease (AD), are characterized by the spread and aggregation of the protein tau. Tau aggregates or neurofibrillary tangles (NFTs) accumulate throughout the brain of patients and lead to dementia. No effective treatments currently exist for tauopathies. Those approaches that have been considered, such as tau antibodies and antisense oligonucleotides, directly target tau. The complexity of tau cell biology, however, makes this approach challenging. A completely novel approach is to take advantage of the tau spreading pathway. The spread of NFTs correlate with disease progression and is a likely mediator for the observed neurotoxicity. Recently, we identified a cellular receptor, LRP1 (Low-density lipoprotein Receptor-related Protein 1), that regulates the tau spread pathway. Knockdown of LRP1 prevents tau spread in human iPS neurons and the mouse brain, suggesting that the tau-LRP1 interaction could be an important entry point for disease intervention. Therefore, the main objective of this project is to identify small-molecule chemical probes that prevent the binding of tau to LRP1, with the hypothesis that these molecules would serve as key starting points for novel therapeutics. In preliminary work, we have identified the primary interaction surface for tau on LRP1 and have developed a TR-FRET high-throughput screening (HTS) assay to identify compounds that can disrupt this interaction. We have optimized the assay to 1536-well format and conducted a pilot screen of 5,000 compounds with excellent performance, Z'~0.7 and a hit rate of ~0.4%. Analysis of the 20 hits from this screen in primary, artifact, and orthogonal assays identified several compounds with modest potency in dose response. To fully develop this work, we propose three aims. In Aim 1, we will use the TR-FRET assay to screen a 420,000 chemical library and, in parallel, conduct an affinity screen of a 4.4-billion- member DNA encoded library leveraging the DELopen platform (WuXi AppTec). In Aim 2, we will narrow our hit selection using orthogonal and novel biochemical profiling assays to determine mechanism of action. Finally, in Aim 3 we will validate hits with advanced biophysical and cell-based assays. We expect our multi-pronged approach will identify multiple chemical series with different mechanisms of action. Subsequent hit expansion efforts will produce chemical probes with properties suitable to test our hypothesis that small molecule LRP1-tau inhibitors can prevent tau uptake and spread. In future studies we intend to develop these probes into drugs that prevent tau spreading in tauopathies such as AD. As the critical path testing funnel is in place, we anticipate we can rapidly obtain and evaluate selective in vitro hits, explore their activity, and ultimately their suitability as starting points for hit-to-lead studies and for future in vivo evaluation in animal models and eventually patients.

项目总结