Career: Total Synthesis and Study of the Molecular Recognition Determinants of Amanita Phalloides Toxins

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The focus of this research is the development of synthetic methods for the preparation of amanitin and phalloidin. The synthetic strategy involves late introduction of problematic functionality and early introduction of the thioether bridges common to the two targets. The majority of the peptide backbone will be assembled using solid phase peptide synthesis. Analog studies will be used to allow understanding of the specific binding properties of amanitin to RNA polymerase II and phalloidin to polymerized actin. The educational focus of the project will be the development of a new graduate training program in Chemical Biology.With this CAREER award, the Organic and Macromolecular Chemistry Program is supporting the research and educational activities of Dr. Rodney K. Guy of the Department of Pharmaceutical Chemistry at the University of California-San Francisco. Dr. Guy will focus his research on the total synthesis and study of the molecular modes of action of two related natural products:amanitin and phalloidin. The natural products and synthetic analogs will be studied to understand the molecular determinants that drive the selectivity of binding for these compounds. The educational portion of the project involves curriculum development at the graduate level.