IDENTIFICATION OF SMALL MOLECULE INHIBITORS FOR CASPASE-2 AND CASPASE-6

CASPASE-2 和 CASPASE-6 小分子抑制剂的鉴定

• 批准号: 8170278
• 负责人: YI TANG
• 金额: $ 0.03万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170278
• 关键词: Attenuated; Biological Assay; Caspase; Cells; Cleaved cell; Computer Retrieval of Information on Scientific Projects Database; Crystallography; Cysteine Protease; Dementia; Disease; Drug Delivery Systems; Enzymes; Funding; Genes; Goals; Grant; Huntington Disease; Individual; Institution; Mutation; Neurodegenerative Disorders; Pathology; Personality; Proteins; Research; Research Personnel; Resources; Source; United States National Institutes of Health; Work; base; caspase-2; caspase-6; high throughput screening; human Huntingtin protein; inhibitor/antagonist; motor control; mutant; small molecule; therapeutic target

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Huntington?s Disease (HD) is a fatal neurodegenerative disease, which results from a mutation in the gene encoding the Huntingtin protein. The mutant protein is cleaved into toxic fragments by a class of cysteine proteases called caspases. Individuals afflicted with the disease develop loss of motor control, personality changes, and dementia. The goal of this work aims to inhibit the cleavage of the mutant Huntingtin protein by caspase-2 and caspase-6 in order to validate these two enzymes as therapeutic targets and to identify compounds that attenuate the accumulation of toxic Htt fragments involved in the pathology of the disease. Compounds identified through high-throughput screenings will be characterized and validated by x-ray crystallography prior to the application in cell-based assays. The long-term goals of the project are to validate caspase-2 and caspase-6 as drug targets and develop cures for Huntington?s Disease.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 亨廷顿病 (HD) 是一种致命的神经退行性疾病，由编码亨廷顿蛋白的基因突变引起。这种突变蛋白被一类称为半胱天冬酶的半胱氨酸蛋白酶裂解成有毒片段。患有这种疾病的人会失去运动控制、性格改变和痴呆。这项工作的目标是抑制 caspase-2 和 caspase-6 对突变型亨廷顿蛋白的裂解，以验证这两种酶作为治疗靶点的作用，并鉴定能够减弱与疾病病理有关的有毒 Htt 片段积累的化合物。通过高通量筛选鉴定出的化合物将在应用于基于细胞的测定之前通过 X 射线晶体学进行表征和验证。该项目的长期目标是验证 caspase-2 和 caspase-6 作为药物靶标并开发亨廷顿病的治疗方法。