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: 6546032
• 负责人: JONATHAN S ROSENBLUM
• 金额: $ 15.6万
• 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 2003-02-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6546032
• 关键词: biotechnology; chemical synthesis; drug adverse effect; drug interactions; fluorescent dye /probe; peptidyl dipeptidase; protein engineering; protein protein interaction; protein structure function; proteomics; serine proteinases; toxicology

DESCRIPTION (provided by applicant): Chemical probes will be developed to profile toxicities resulting from drug interactions. We have developed fluorescent probes that exclusively identify active members of the serine hydrolase super-family of enzymes. Using our technique, we can elucidate activity profiles of diseases, and broadly investigate interactions between the proteome and potential therapeutics. This technology could be used to determine molecular toxicological profiles, rapidly and inexpensively, early in the drug development process. To expand the range of detectable toxicologies, we will design, synthesize, and characterize probes for the following pharmacologically interesting families: kinases, phosphatases, and cytochromes P450. Phase I will demonstrate the use of our current probes in investigating the protein interactions of various inhibitors of enzymes implicated in the etiology of diabetes, obesity, and Alzheimers disease. In phase II we will design and synthesize probes for kinases, phosphatases, cytochromes P450, and cysteine proteases. Phase II will include profiling various compounds and tissue sources, identifying toxicological markers, and creating a database of tissue-specific protein-compound interactions. PROPOSED COMMERCIAL APPLICATIONS: A service for accurately screening potential drugs for toxicity before animal trials will be commercialized. The database component will also be marketed for interrogation with proteomas, targets, or compounds.

描述(由申请人提供)：将开发化学探针来分析药物相互作用造成的毒性。我们已经开发了专门识别丝氨酸水解酶超家族酶活性成员的荧光探针。使用我们的技术，我们可以阐明疾病的活动概况，并广泛地研究蛋白质组和潜在疗法之间的相互作用。这项技术可用于在药物开发过程的早期快速、廉价地确定分子毒理学特征。为了扩大可检测到的毒物的范围，我们将设计、合成和表征以下药理上感兴趣的家族的探针：激酶、磷酸酶和细胞色素P450。第一阶段将演示使用我们目前的探针来研究与糖尿病、肥胖症和阿尔茨海默氏病的病因有关的各种酶抑制剂的蛋白质相互作用。在第二阶段，我们将设计和合成针对激酶、磷酸酶、细胞色素P450和半胱氨酸蛋白酶的探针。第二阶段将包括分析各种化合物和组织来源，识别毒理学标记，并创建组织特定蛋白质-化合物相互作用的数据库。 建议的商业应用： 一项在动物试验前准确筛选潜在药物毒性的服务将商业化。数据库组件还将用于对蛋白质瘤、靶标或化合物进行讯问。