A Chemical Genetics Approach to the Discovery and Synthesis of Bioactive Marine Natural Products

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The main objective of the proposal will be to use a chemical genetics approach to discover new bioactive marine natural products (MNPs) that can be used as tools in fundamental studies of autophagy, MRSA hub proteins, histone methylation, and F508del-CFTR correction. A secondary objective will be the function-oriented synthesis of the new MNPs in order to define the SAR for their pharmacophores, generate probes for protein target identification, and provide material for in vivo experiments. Chemical genetics uses small molecules to alter the function of a single gene product within a cellular context in order to link a specific gene to a phenotype. Forward chemical genetics screens for molecules that elicit a phenotype of interest in a cell-based assay and then identifies the protein target. Reverse chemical genetics screens for inhibitors of pure proteins and then exposes cells to the inhibitors to reveal the phenotype. We will focus on biological processes that are important in human biology and disease, but are not well characterized at the protein or genetic level. Our library of crude extracts of marine invertebrates and cultured microorganisms will be the source of novel small molecule protein ligands. Each project will involve an established collaboration with an expert on the biological process. The significance of the research will be multifold. Discovery of new MNPs adds unique diversity to the pool of known chemical entities and reveals unknown biosynthetic pathways and pharmacophores. Complex bioactive MNPs are attractive targets for synthetic organic chemists, driving the development of new synthetic strategies and methodology. Discovery of MNPs that modulate proteins involved in autophagy, MRSA biology, histone methylation, and F508del-CFTR correction will provide tools to study these important biological processes at the genetic and protein level in single cells and animals, and help identify new drug targets. The new bioactive MNPs will have the potential to provide the inspiraton for development of drugs for TB, MRSA, cancer, and cystic fibrosis. Our interdisciplinary research provides training that will enable HQP to obtain high-level industrial, government, and academic jobs.