Development of Thioester Exchange for Generation and Screening of Cyclic Peptides for Nucleic Acid Recognition

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This award in the Chemistry of Life Processes (CLP) program within the Division of Chemistry supports work by Professor Marcey Waters at UNC Chapel Hill to carry out fundamental studies on development of a high-throughput method for the synthesis and identification of cyclic peptides with biological function. Cyclic peptides are a "privileged" class of molecules for binding to proteins and nucleic acids due to their protease-resistance and excellent ability to mimic protein domains. However, there are few good methods for the synthesis and screening of libraries of cyclic peptides. The methodology described in this proposal provides a solution to current limitations through development of an equilibrium screening approach called dynamic combinatorial chemistry. A key aspect of the methodology proposed here is that it offers rapid approach to perform iterative re-design of cyclic peptides, not only to optimize binding, but to perform structure-function studies and to learn about the critical features for binding. This basic research provides a significant advancement for the application of this class of compounds, which fall in class between typical small molecule drugs (molecular weight 500) and biopharmaceuticals.The broader impacts of the proposal range from potential applications in the pharmaceutical industry (i.e., drug discovery) to the training of high school, undergraduate, and graduate students in a variety of research fields, including peptide synthesis and molecular biology.