The long-term objective is finding medically useful compounds among the secondary metabolites produced by various organisms. The emphasis will be on accurately describing the complete three-dimensional structures of biologically active natural products. Specific projects in the proposal are: 1. Kederacidin and other chromoproteins. Chromoproteins such as neocarzinostatin, macromomycin, and the recently discovered kederacidin comprise the most potent class of antitumor antibiotics yet discovered. The three-dimensional structures of functional chromoproteins have not been described with precision, and a high resolution X-ray structure of the kederacidin complex will be undertaken as part of this proposal. Such information would be useful to learn how to package and deliver potent compounds to specific targets. 2. Farnesylation inhibitors. A new bioassay to find inhibitors of ras protein processing will be used to find natural products with potential utility as anticancer agents. The ras protein, which must be farnesylated to become active, has been implicated in many forms of cancer. Two farnesylation inhibitors have been discovered from fungal sources, and proposed work towards their structure elucidation is described. 3. Complexes of marine natural products with their protein receptors. Several marine natural products have potent activity as inhibitors of protein phosphatases or thrombin. Protein phosphatases are important cell signalling proteins, and learning how to design inhibitors for them could lead to useful agents. Thrombin inhibitors would be useful as anticoagulants or as general models for protease inhibitors. 4. Structural characterization of various natural products. A variety of compounds from many sources will be examined for potentially useful materials. The molecular structure information obtained from this research will be of direct benefit to chemistry, biochemistry and pharmacology. Several of the research targets could become useful drugs for the treatment of human diseases.
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