The overall goals of the proposed research is to identify small molecule regulators of critical cellular processes in high-throughput screens of synthetic chemical libraries and to develop new methods to rapidly identify the cellular targets of active compounds from phenotypic screens. Chemical genomic approaches to identify the cellular functions of proteins have recently be shown to have great promise as a new tool for functional genomics and for the identification of new lead compounds and cellular targets for drug development. The proposed research aims to address two current deficiencies in the Chemical Genomic approach: modulating protein-protein interactions as targets of small molecules; identifying the cellular targets of bioactive small molecules identified in phenotype-directed screens.
The specific aims of the proposed research are (1) Develop synthetic chemistry to achieve a versatile high-yield, convergent solid-phase synthesis of the streptogramin B analogs. (2) Devise novel linkers for attachment of library members to solid phase synthesis resins such that linker cleavage generates an electrophilic reactive site (Michael acceptor) on each member of the library. (3) Synthesis and evaluation of a 'target identification probe' (TIP) reagent to enable the rapid identification of the cellular targets of bioactive compounds from combinatorial libraries. (4) Identification of biologically active library members and determine the cellular targets of bioactive library members using target identification probe reagents. Our integrated approach to chemical genomics includes new methods for the synthesis of electrophilic libraries, novel biological assays and a novel method for target identification as a platform for biological discovery.
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