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Developing a cell-based high throughput screening for USP15 deubiquitinase inhibitor discovery

开发基于细胞的高通量筛选以发现 USP15 去泛素酶抑制剂

基本信息

批准号：
10287750
负责人：
Zhihao Zhuang
金额：
$ 43.47万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10287750
关键词：
Academia Active Sites Biological Biological Assay Biotin Carbidopa Cell Line Cell membrane Cell physiology Cells Chemicals Collaborations Cysteine DNA Repair Deubiquitination Disease Drug Compounding Drug Targeting Economic Burden Ensure Enzymes Event Excision FDA approved Goals Human Impairment Individual Industry Intervention Investigational Drugs Label Lead Levodopa Libraries Malignant Neoplasms Mitochondria Natural Immunity Neurodegenerative Disorders Neurologic Parkinson Disease Pathway interactions Peptides Performance Periodicity Permeability Pharmaceutical Preparations Pharmacology Physiological Play Process Proteins Recombinant Proteins Recombinants Research Personnel Retroviridae Role Running Signal Transduction Societies Speed System Technology Tertiary Protein Structure Testing Therapeutic Translational Research UBD protein Ubiquitin Ubiquitination United States Validation Variant Virus Diseases Work aging population base drug discovery high throughput screening human disease inhibitor/antagonist miniaturize multicatalytic endopeptidase complex nervous system disorder novel polyarginine propargylamine protein complex protein function reduce symptoms robotic system screening small molecule small molecule inhibitor stable cell line success therapy development

项目摘要

Developing a cell-based high throughput screening for USP15 deubiquitinase inhibitor discovery The goal of this project is to develop a ubiquitin probe-based AlphaLISA deubiquitinase HTS assay that enables cell-based and high throughput screening for human deubiquitinase USP15. It is now clear that the human ubiquitin system is fundamentally important to the normal cellular and organismal functions. Deubiquitinases or DUBs as an important class of enzyme have been associated with neurological disorders, particularly Parkinson’s disease (PD). Many disease-relevant and potentially druggable deubiquitinases are currently inaccessible to HTS-based inhibitor discovery due to the difficulty in their purification as homogeneous and active recombinant proteins in quantity large enough for HTS campaign. In this proposal, we aim at developing a cell-based AlphaLISA deubiquitinase assay for high throughput screening against USP15 and other DUBs, and setting the ground work for identifying and developing USP15 inhibitors with a mitophagy-promoting effect and the potential being developed into PD therapeutics.

开发基于细胞的高通量筛选以发现USP 15去遍在蛋白酶抑制剂本项目的目标是开发一种基于泛素探针的AlphaLISA去泛素化酶HTS检测方法，使得能够基于细胞和高通量筛选人去泛素化酶USP 15。现在很清楚，人泛素系统对正常细胞和生物体功能至关重要。去泛素化酶或DUB作为一类重要的酶，与神经系统疾病有关，尤其是帕金森病（PD）。许多疾病相关的和潜在的可药物化的去泛素化酶是目前无法发现基于HTS的抑制剂，这是由于它们难以纯化为均相的和足够用于HTS活动的量的活性重组蛋白。在本建议中，我们的目标是开发基于细胞的AlphaLISA去泛素化酶测定，用于针对USP 15和其他 DUBs，并为鉴定和开发具有促进线粒体自噬作用的USP15抑制剂奠定基础。效果和潜力正在开发成PD疗法。