High-throughput compound screening for modulators of insulin-degrading enzyme.

胰岛素降解酶调节剂的高通量化合物筛选。

基本信息

批准号：
7619035
负责人：
MALCOLM A LEISSRING
金额：
$ 18.82万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-15 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7619035
关键词：
AD 20 Affect Alzheimer&apos s Disease Amyloid Amyloid Proteins Amyloid beta-Protein Precursor Animal Model Attention Behavioral Biological Assay Biological Process Catabolism Cells Collection Cultured Cells Defect Detection Development Disease Enzyme Activators Equilibrium Experimental Genetics Extracellular Space Florida Fluorescence Polarization Funding Future Genetic Goals Hela Cells Housing Human In Vitro Insulinase Laboratories Lead Libraries Mediating Miniaturization Mutation Nature Neurons Pathology Peptide Hydrolases Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Plasmin Plasminogen Activator Inhibitor 1 Post-Translational Protein Processing Preparation Process Production Property Proteins Public Health Recombinants Resources Robotics Screening procedure Structure Substrate Specificity System Testing Therapeutic Transgenic Organisms Work amyloidogenesis assay development base bone chemical genetics cost counterscreen cytotoxicity design drug discovery enzyme activity experience high throughput screening in vivo inhibitor/antagonist man novel overexpression pharmacophore prevent secretase small molecule therapeutic target trafficking

项目摘要

DESCRIPTION (provided by applicant): Proteases that degrade the amyloid ¿-protein (A¿), which accumulates abnormally in Alzheimer's disease (AD), have emerged as critical regulators of amyloidogenesis in vivo, yet have only begun to be explored for their therapeutic potential. Accumulating experimental, genetic and animal modeling studies implicate insulin-degrading enzyme (IDE), as a particularly important A¿-degrading protease. Importantly, recent evidence shows how IDE activity might be increased by any of several mechanisms, including the displacement of endogenous inhibitors and modulation of its secretion into the extracellular space. Moreover, new crystal structures of IDE show that this protease possesses unorthodox enzymological properties that can be exploited to directly activate the protease as much as 40-fold. Here we propose to conduct ultra high- throughput screening (uHTS) on a chemically diverse library of ~550,000 compounds using a cell-based assay optimized for the detection of IDE activators. The development and implementation of the primary assay will largely be performed by Scripps Florida's highly experienced uHTS Core for a modest cost, permitting greater attention to be focused on critical secondary assays essential for identifying bone fide IDE activators and characterizing their mechanism(s) of action. Our long-term goal is to identify pharmacophores suitable for use in cultured cells and in vivo, which may lead to the development of novel therapies to treat this devastating disease. PUBLIC HEALTH RELELVANCE: The goal of this proposal is to test a large collection of molecules for their potential to affect fundamental biological processes known to regulate Alzheimer's disease, specifically relating to insulin-degrading enzyme. Discovered molecules will be evaluated for their possible therapeutic potential, and potentially developed into novel drugs through future funding proposals.

描述（由申请人提供）：降解淀粉样蛋白的蛋白酶 ¿ -在阿尔茨海默病 (AD) 中异常积累的蛋白质 (A¿) 已成为体内淀粉样蛋白生成的关键调节因子，但其治疗潜力的探索才刚刚开始，越来越多的实验、遗传和动物模型研究表明胰岛素的作用。降解酶（IDE），作为一个特别重要的A¿重要的是，最近的证据表明 IDE 活性可以通过多种机制中的任何一种来增加，包括内源性抑制剂的置换和其分泌到细胞外空间的调节。此外，IDE 的新晶体结构表明这种蛋白酶具有非正统的特性。酶学特性可用于直接激活蛋白酶高达 40 倍。在此，我们建议对化学多样化的文库进行超高通量筛选 (uHTS)。使用针对 IDE 激活剂检测而优化的基于细胞的测定法检测约 550,000 种化合物主要测定法的开发和实施将主要由 Scripps Florida 经验丰富的 uHTS Core 进行，成本适中，从而可以将更多注意力集中在关键的二级测定上。对于鉴定真正的 IDE 激活剂并表征其作用机制至关重要的测定方法我们的长期目标是鉴定适合在培养细胞和体内使用的药效团，这可能会导致开发。治疗这种破坏性疾病的新疗法的研究目的是测试大量分子对已知调节阿尔茨海默病的基本生物过程的影响，特别是与胰岛素降解酶相关的分子。将评估其可能的治疗潜力，并有可能通过未来的资助提案开发成新药。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Deletion of insulin-degrading enzyme elicits antipodal, age-dependent effects on glucose and insulin tolerance.

胰岛素降解酶的缺失会对葡萄糖和胰岛素耐量产生反足的、年龄依赖性的影响。

DOI：
发表时间：
2011
期刊：
影响因子：
3.7
作者：
Abdul;Kang, Dongcheul;McBride, Melinda;Li, Lilin;Zhao, Ji;Leissring, Malcolm A
通讯作者：
Leissring, Malcolm A

Aβ-Degrading Proteases: Therapeutic Potential in Alzheimer Disease.

Aβ 降解蛋白酶：阿尔茨海默病的治疗潜力。

DOI：
发表时间：
2016-08
期刊：
影响因子：
6
作者：
Leissring; Malcolm A
通讯作者：
Malcolm A

Selective Targeting of Extracellular Insulin-Degrading Enzyme by Quasi-Irreversible Thiol-Modifying Inhibitors.

准不可逆硫醇修饰抑制剂选择性靶向细胞外胰岛素降解酶。

DOI：
发表时间：
2015-12-18
期刊：
影响因子：
4
作者：
Abdul;Bannister, Thomas D;Wang, Hui;Cameron, Michael D;Caulfield, Thomas R;Masson, Amandine;Bertrand, Juliette;Howard, Erin A;McGuire, Michael P;Crisafulli, Umberto;Rosenberry, Terrone R;Topper, Caitlyn L;Thompson, Caroline R;Sch
通讯作者：
Sch