Development of Inhibitors of UCH-L1 for treatment of neurodegenerative disorders

开发用于治疗神经退行性疾病的 UCH-L1 抑制剂

• 批准号: 7486456
• 负责人: Melissa Rae Landon
• 金额: $ 4.48万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-04 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7486456
• 关键词: Adverse effects; Alzheimer' s Disease; Binding; Binding Sites; Characteristics; Chemicals; Computer Simulation; Crystallography; Data; Development; Directories; Down-Regulation; Drug Industry; Elevation; Enzymes; Family suidae; Frequencies; Goals; Homology Modeling; Huntington Disease; Hydrolase; Induced Mutation; Institutes; Lead; Learning; Ligand Binding; MDL-1 receptor; Maps; Melissa; Membrane Proteins; Memory; Methods; Molecular Chaperones; Molecular Conformation; Mutation; Neurodegenerative Disorders; Normal Cell; Pancreatic Elastase; Parkinson Disease; Pharmaceutical Preparations; Point Mutation; Predisposition; Prevention; Protein Region; Proteins; Published Directory; Purpose; Roentgen Rays; Screening procedure; Serine; Silicon Dioxide; Solvents; Structure; Synaptic plasticity; Techniques; Testing; Therapeutic; Thermolysin; Tyrosine; Ubiquitin; base; brain tissue; cost; enzyme replacement therapy; inhibitor/antagonist; molecular dynamics; mouse model; mutant; protein structure; research study; small molecule; small molecule libraries; virtual

DESCRIPTION (provided by applicant): Uch-L1, an ubiquitin hydrolase, is implicated in numerous neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Specifically, down regulation of Uch-L1 is both characteristic of neurodegenerative disorders and has been shown to decrease synaptic plasticity in normal cells, while an increase in Uch-L1 activity has proven to increase synaptic plasticity and contextual memory learning in mouse models of AD. Taken together these data suggest that elevation of the catalytic activity of Uch-L1 may be an effective approach in the treatment and prevention of neurodegenerative disorders. The overall goal of this proposal is to characterize Uch-L1 via X-ray crystallographic techniques to determine binding regions that may accommodate binding of a pharmacological chaperone that will increase levels of the activity of Uch-L1 in brain tissue by stabilization of the catalytically active conformation of Uch-L1, where a pharmacological chaperone is small molecule that binds and stabilizes a protein and, consequently, increase cellular abundance and activity. During the course of the two specific aims I will (1) identify non-catalytic binding sites on Uch-l_1 that are capable of binding small, drug-like molecules using an x-ray crystallography technique, specifically the multiple solvent crystal structure (MSCS) method; (2) characterize the structural effects of a single point mutation that is known to increase the catalytic hydrolase activity of Uch-L1 in order to develop a chaperone that would mimic the effects of the mutant. The multiple solvent crystal structures (MSCS) method developed in the Petsko-Ringe lab involves the x-ray crystallographic analysis of enzymes soaked in various solvents. Ligand binding sites are determined by examination of regions of the protein surface where multiple types of solvent molecules bind with high frequency. In the first specific aim the MSCS approach will be employed to identify non-catalytic binding sites of Uch-L1 that, based on their interactions with solvent molecules, will likely be able to bind drug-like molecules.

描述（由申请人提供）：Uch-L1是一种泛素水解酶，与许多神经退行性疾病有关，如阿尔茨海默病（AD）、帕金森病（PD）和亨廷顿病（HD）。具体来说，Uch-L1的下调是神经退行性疾病的特征，并且已被证明会降低正常细胞的突触可塑性，而Uch-L1活性的增加已被证明会增加AD小鼠模型中的突触可塑性和上下文记忆学习。综上所述，这些数据表明，提高Uch-L1的催化活性可能是治疗和预防神经退行性疾病的有效方法。本提案的总体目标是通过x射线晶体学技术表征Uch-L1，以确定可能容纳药物伴侣结合的结合区域，通过稳定Uch-L1的催化活性构象来增加Uch-L1在脑组织中的活性水平，其中药物伴侣是小分子的