Activity-based Proteomics for Toxicological Analysis

用于毒理学分析的基于活性的蛋白质组学

• 批准号: 6744762
• 负责人: JONATHAN S ROSENBLUM
• 金额: $ 28.15万
• 依托单位: ACTIVX BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-08 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6744762
• 关键词: biotechnology; chemical synthesis; drug adverse effect; drug interactions; endopeptidases; fluorescent dye /probe; laboratory mouse; nucleic acid probes; peptide chemical synthesis; peptidyl dipeptidase; protein engineering; protein protein interaction; protein structure function; proteomics; serine proteinases; toxicology

DESCRIPTION (provided by applicant): ActivX Biosciences (ActivX) will develop and validate a novel toxicoproteomics platform to correlate changes in protein activity with compound toxicology. This platform uses fluorescent chemical probes to interrogate catalytically active proteins related by super-family derived from any biological sample. Alterations in protein activity are expected to be more interpretable and relevant to toxicant molecular mechanism than the more commonly used transcript-profiling approaches. This Phase II study will demonstrate the utility of this protein activity platform. This study has several stages. 1) The platform will be established as a predictive platform for compound toxicity by investigating protein activities of a) cell lines and b) tissues from animals exposed to compounds that have been well-studied using pharmacology, genomics, and other techniques. 2) The resulting protein activity profiles will be integrated into a database that also includes publicly available transcription data, and will allow for seamless correlation of treatments with changes in protein activity levels of the serine hydrolase, cysteine protease, kinase, epoxide hydrolase, and glutathione-S-transferase families. The activity-based probes (ABPs) for some of these enzyme families are cell-permeable, which is a useful feature that allows for in vivo, rather than in vitro measurements of protein activity in cell lines. 3) Cell-permeable derivatives of ABPs that are currently not cell permeable will be synthesized. 4) To expand the breadth of our profiling abilities, ActivX will also design, synthesize and validate ABPs for the phosphatase and cytochrome P450 families. This platform will be useful for detecting toxicity of chemicals, including therapeutics, and will be important for classifying and exploring the molecular basis of toxicities. Therefore, this technology has a great potential for reducing the time and cost in early compound development, and for revealing underlying toxicity mechanisms of different compounds. ActivX plans to commercialize its technology by establishing a toxicoproteomic database, and by providing a service to the pharmaceutical industry that will detect toxicities of compounds early in the drug screening process.

描述（由申请人提供）： ActivX Biosciences（ActivX）将开发和验证一种新的毒理蛋白质组学平台，将蛋白质活性变化与化合物毒理学联系起来。该平台使用荧光化学探针来询问来自任何生物样品的超家族相关的催化活性蛋白。蛋白质活性的改变，预计将更可解释和相关的毒性分子机制比更常用的转录谱的方法。该II期研究将证明该蛋白活性平台的实用性。这项研究有几个阶段。1)通过研究暴露于化合物的动物的a）细胞系和B）组织的蛋白质活性，将该平台建立为化合物毒性的预测平台，这些化合物已使用药理学、基因组学和其他技术进行了充分研究。2)所得蛋白质活性谱将整合到数据库中，该数据库还包括公开可用的转录数据，并且将允许治疗与丝氨酸水解酶、半胱氨酸蛋白酶、激酶、环氧化物水解酶和谷胱甘肽-S-转移酶家族的蛋白质活性水平变化的无缝关联。 这些酶家族中的一些的基于活性的探针（ABP）是细胞可渗透的，这是允许在体内而不是在体外测量细胞系中的蛋白质活性的有用特征。第三章 将合成目前不具有细胞渗透性的ABP的细胞渗透性衍生物。4)为了扩大我们分析能力的广度，ActivX还将设计，合成和验证磷酸酶和细胞色素P450家族的ABP。该平台将有助于检测化学品的毒性，包括治疗药物，并将对分类和探索毒性的分子基础非常重要。因此，该技术在减少早期化合物开发的时间和成本以及揭示不同化合物的潜在毒性机制方面具有巨大的潜力。ActivX计划通过建立一个毒性蛋白质组学数据库来商业化其技术，并为制药行业提供一项服务，在药物筛选过程的早期检测化合物的毒性。