Development of Macrocyclic Organo-Peptide Hybrids for Selective Targeting of Protein-Protein Interfaces

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With this award, the Chemistry of Life Processes program is supporting Professor Rudi Fasan at the University of Rochester to investigate the design, synthesis, and functional selection of macrocyclic organo-peptide hybrids (MOrPHs) as chemical agents for selectively targeting protein interfaces. This research will investigate and implement this new methodology for generating organo-peptide macrocycles via a chemoselective reaction between synthetic precursors and genetically encoded polypeptides. Library diversity will benefit from the inclusion of both synthetic organic and encoded peptidyl elements of structural variation. This versatile strategy for ligand assembly and diversification will be coupled to a display system in E. coli and a high throughput screening system for the macrocycle libraries. As a platform to test this approach to chemical biology, the hydrid cyclic peptide libraries will be screened for the selective modulation of protein complex formation between the tumor suppressor protein, p53, and its repressors HdmX and Hdm2. This approach to modular organo-peptide library generation and screening, if successful, could find broad application in the field of Chemical Biology. Moreover, if selective Hdm2/HdmX-targeting molecules are identified these would likely serve as useful chemical biological tools for the study of regulation/signal transduction in the p53 pathway in cell physiology and cancer biology. This cross-disciplinary research project will expose graduate and undergraduate students to techniques in organic chemistry, biology, and biophysics. The project will also engage members of traditionally underrepresented groups in scientific research at the chemistry-biology interface.