A Systematic Approach to Targeting Protein Interfaces with Nonpeptidic Helix Mimetics

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With support from the Chemistry of Life Processes Program in the Chemistry Division of the National Science Foundation, Professors Paramjit Arora and Richard Bonneau, of the Departments of Chemistry and Biology at New York University, will study synthetic mimics of protein subdomains that can modulate the function of chosen proteins. Targets include nonpeptidic oligomers that mimic the alpha-helical conformation and display protein-like functionality. The oxopiperazine helix mimetic oligomers will be synthesized using standard procedures from natural and nonnatural amino acids. The researchers will develop experimental and computational approaches for screening libraries of nonpeptidic helix mimetics against model protein targets to identify high affinity, selective ligands. They will implement computational tools that can accurately predict local conformations of nonpeptidic oligomers and estimate optimum constructs for chosen protein receptors. Furthermore, they will explore the potential of oligooxopiperazines to target the DNA major groove. With this award, these researchers will demonstrate computational and synthetic design principles, and synthetic organic methods to develop new classes of biologically active compounds. This approach will result in biomimetic oligomers that are anticipated to become valuable reagents for the biomedical community. This work represents a new direction in bioorganic chemistry: providing access to nonpeptidic oligomers that assemble from amino acids while preserving the chiral backbone and side chain functionality. Students engaged in this work will gain broad experience in molecular design, conformational analysis, synthesis, and biochemistry. Members of the research team will include graduate and undergraduate students, drawing also from underrepresented groups. Students trained on the project may go on to careers in the pharmaceutical or biotechnology industry, or academia, and will thus contribute to the US scientific endeavor and the economy. Professors Arora and Bonneau will continue to engage educators that teach at predominantly minority institutions by organizing workshops that discuss research and teaching advances at the interface of chemistry and biology.