Zinc Fingers as Templates for Metal and Metal-DNA Interactions

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This research award in the Chemistry of Life Processes (CLP) program supports work by Professor Nicholas Farrell at Virginia Commonwealth University to explore the fundamental chemistry and biology of platinum-metal complexes with zinc finger proteins and model zinc chelates. The proposed work centers on a series of studies pertaining to the coordination chemistry of the so-called zinc fingers, small protein assemblies of zinc ions and a combination of cysteine or histidine residues that play a key role in the structural stability of proteins and other biomolecules such as RNA and DNA. New patterns of zinc-finger chemistry are explored by recognizing the conceptual analogy between alkylation and metallation. These patterns include molecular recognition and electrophilic attack by platinum-metal compounds on zinc-thiolate bonds. Zinc finger proteins are involved in a host of biological processes such as transcription and DNA repair and they are important targets for therapeutic intervention in viral diseases and cancer. The study on the "coordination chemistry" of zinc expands the known properties of this important class of proteins in hitherto unrecognized directions. The research will suggest new mechanisms of action and new targets for biologically active inorganic compounds with long-term possibilities for new medicinal applications. Broader impacts of the project also include the training of undergraduate and graduate students, including joint activities with institutions in Brazil, China, and the Czech Republic.