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.
Cyclic peptides (small protein fragments) are a "privileged" class of molecules for binding to proteins and nucleic acids due to their protease-resistance and excellent ability to function as mimics of whole proteins for inhibiting protein-protein and protein-nucleic acid interactions. However, there are few good methods for the synthesis and screening of libraries of cyclic peptides. In this project, we developed a high-throughput method for both synthesis and screening of cyclic thiodepsipeptides (peptides with one or more thioester linkage) for binding to biomolecules of interest. This provided access to large libraries of cyclic peptides that could function as potential ligands (or inhibitors) of biomolecules of interest. A second method was developed to cyclize structured beta-hairpin peptides, which are common motifs in proteins that mediate protein-protein and protein-nucleic acid interactions. This method was shown to maintain the correct structure and function of the peptide, while maintaining function (binding of ATP) and increasing protease resistance. This project provided a significant advancement for the application of this class of compounds, which fall in class between typical small molecule drugs (MW < 500) and biopharmaceuticals such as recombinant proteins. The work has been disseminated in chemistry journals and conference presentations. This grant has also supported the training of a number of graduate students and undergraduates, including underrepresented groups such as women and minorities, who have pursued careers in both scientific research and education.
