Bioactivity Guided Marine Natural Product Discovery Using Phenotypic Assays

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The main objective of the proposed research will be to use Forward Chemical Genetics cell-based phenotypic assay screening platforms to facilitate the discovery of structurally novel bioactive marine natural products (MNPs) that can be used as tools in basic biological studies of i) MHC-1 antigen expression, ii) vascular integrity, and iii) expression of the gene MYC. A secondary objective will be the chemical synthesis of selected MNPs and analogs to define the Structure Activity Relationship (SAR) for their pharmacophores, generate probes for protein target identification, and provide material and analogs for biological studies. The proposed research is interdisciplinary and collaborative. Phenotypic assays to be used in the MNP discovery program have been developed by our collaborators to find the chemical tools they require to study fundamental processes that are important in healthy human biology. Natural products discovery and synthesis are core activities of basic organic chemistry NSE research. Funds requested in this proposal will only support the natural products chemistry activities in Andersen's group. The discovery bioassays, protein target identification, and other biological studies will take place in our collaborator's labs funded by their independent research grants. The discovery of novel MNPs is neither routine or trivial. Experience has taught us that a Forward Chemical Genetics approach using cell-based biological screens looking for novel non-cytotoxic phenotypic responses is one of the most effective ways to discover truly unique MNPs that are of significant interest to the organic chemistry community and have practical value as cell biology tools. 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 and gene product to a phenotype. Forward chemical genetics screens for molecules that elicit a phenotype of interest in a cell-based or whole organism assay and then identifies the protein target. Our library of crude extracts of marine invertebrates and cultured microorganisms will be the source of novel small molecule protein ligands. 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 MHC-1 expression, vascular integrity, and expression of MYC will provide tools to study these important biological processes in single cells and animals and generate deeper understanding of their normal regulatory networks. Our interdisciplinary research will provide training that will enable HQP to obtain high-level industrial and academic jobs.