Activity-based Proteomics for Toxicological Analysis

描述（由申请人提供）：化学探针将用于分析药物相互作用引起的毒性。我们已经开发出荧光探针，专门识别丝氨酸水解酶超家族的活性成员。利用我们的技术，我们可以阐明疾病的活动概况，并广泛研究蛋白质组与潜在治疗方法之间的相互作用。该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。为了扩大可检测毒理学的范围，我们将为以下药理学上有趣的家族设计，合成和表征探针：激酶，磷酸酶和细胞色素P450。第一阶段将展示我们目前的探针在研究与糖尿病、肥胖和阿尔茨海默病病因有关的各种酶抑制剂的蛋白质相互作用中的应用。在II期，我们将设计和合成用于激酶、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，确定毒理学标记，并创建组织特异性蛋白质-化合物相互作用的数据库。

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.