Activity-based Proteomics for Toxicological Analysis

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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.