A Poly(ADP-Ribose) Detection Assay Enabling Drug Discovery and Development

聚 (ADP-核糖) 检测分析促进药物发现和开发

• 批准号: 8123053
• 负责人: REENA ZUTSHI
• 金额: $ 28.74万
• 依托单位: LUCEOME BIOTECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8123053
• 关键词: ADP ribosylation; Academia; Animals; Antibodies; Apoptosis; Benchmarking; Binding; Binding Proteins; Biological Assay; Cancerous; Cell Cycle Arrest; Cell Death; Cells; Cellular Assay; Clinical Trials; Collection; DNA Damage; DNA Repair; Data; Detection; Development; Diagnostic; Engineering; Enzymes; Evaluation; Exposure to; Goals; In Situ; Industry; Inflammation; Inhibitory Concentration 50; Label; Lead; Libraries; Light; Luciferases; Malignant Neoplasms; Measurement; Measures; Mediating; Metabolic; Metabolic stress; Metastatic Melanoma; Methods; Methylnitronitrosoguanidine; Mission; Nuclear; Organism; Pharmacodynamics; Phase; Play; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerases; Polymerase; Post-Translational Protein Processing; Product Labeling; Proteins; Publishing; Regulation; Reporter; Reporting; Ribose; Role; Sampling; Signal Transduction; Single Strand Break Repair; Surrogate Markers; Technology; Time; Tissues; Toxin; Treatment Protocols; Validation; base; combat; cost; design; drug development; drug discovery; high throughput screening; inhibitor/antagonist; luminescence; malignant breast neoplasm; poly ADP-ribose glycohydrolase; poly ADPR glycohydrolase inhib; success; therapeutic target; tumor xenograft

DESCRIPTION (provided by applicant): Poly(ADP-ribosyl)ation is a post-translational modification that plays a central role in the regulation of cell death and DNA repair. PAR serves as a surrogate marker for poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG), which are being actively pursued as therapeutic targets with several PARP inhibitors already in clinical trials. Central to understanding PAR regulation and PARP/PARG drug discovery would be the availability of sensitive, simple and low-cost assays, which are currently unavailable. Thus this Phase 1 application seeks to develop homogeneous assays for PAR utilizing engineered split-protein reporters. The new pharmacodynamic and cellular assays that are proposed will help advance treatment regimens as well as accelerate the development of PARP and PARG inhibitors in both academia and industry. PUBLIC HEALTH RELEVANCE: Poly (ADP-ribosylation), a post-translational modification of proteins, plays a central role in the repair of single strand breaks caused by environmental and metabolic stress. Poly(ADP-ribose) levels in cells are maintained by the dual action of PARP, which synthesizes PAR; and PARG, which degrades PAR in cells. Hence PAR can be used to report on the activity of both these enzymes. The purpose of our application is to develop low-cost, sensitive, luminescence based poly(ADP-ribose) detection assays for drug discovery.

描述（由申请人提供）：聚（ADP-核糖基）ation是一种翻译后修饰，在调节细胞死亡和DNA修复中起着核心作用。 PAR是Poly（ADP-核糖）聚合酶（PARP）和Poly（ADP-核糖）Glydrololase（PARG）的替代标记物，它们正在积极地作为具有多种PARP抑制剂的治疗靶标的，该靶标在临床试验中已有多种PARP抑制剂。了解PAR法规和PARP/PARG药物发现的核心是敏感，简单和低成本测定的可用性，这些测定目前不可用。因此，该第1阶段的应用程序旨在开发使用工程分裂蛋白记者的同质测定法。拟议的新药效和细胞分析将有助于进步治疗方案，并加速学术界和工业中PARP和PARG抑制剂的发展。 公共卫生相关性：蛋白质后翻译后的Poly（ADP-核糖基化）在修复由环境和代谢压力引起的单链断裂中起着核心作用。细胞中的聚（ADP-核糖）水平通过PARP的双重作用来维持，该动作合成PAR；和PARG，它在细胞中降解。因此，可以使用PAR报告这两种酶的活性。我们应用的目的是开发低成本，敏感，发光的聚（ADP-核糖）检测测定法以发现药物发现。