With support from the Organic and Macromolecular Chemistry Program for this new award, Professor Paramjit Arora, of the Department of Chemistry at New York University, will provide synthetic mimics of protein subdomains that can modulate the function of chosen proteins. Targets include nonpeptidic oligomers that mimic alpha-helical and beta-strand conformations, contain chiral backbones, and display protein-like functionality. The beta-strand mimics are synthesized by replacing amide bonds in a peptide by triazole rings. The potential of these resulting triazolamers as inhibitors of specific proteases and protein-protein interactions will be evaluated. The principal investigator's group will also prepare nonpeptidic helix mimetics composed of oxopiperazine units. The oxopiperazine oligomers will be synthesized using standard procedures from natural and nonnatural amino acids. They will determine the solution and solid-state conformations of oligooxopiperizines and test their potential to inhibit protein-protein interactions. NMR spectroscopy in conjunction with molecular modeling will be used to elucidate structural features of these nonpeptidic oligomers that display protein-like functionality.
With this award, Professor Arora will demonstrate chemical design principles and synthetic organic methods to prepare new classes of biologically active compounds. This approach will afford 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 principal investigator's research team include graduate and undergraduate students, including members of the underrepresented groups. The PI's research group is comprised of greater than 50% women and underrepresented minority students, including minority high school students from New York City high schools. The results of the proposed research will be disseminated through traditional and web-based methods. Students trained on the project will go on to careers in the pharmaceutical or biotechnology industry, or academia, and will thus contribute to the US scientific endeavor and the economy. Professor Arora 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 through New York University's Faculty Resource Network (FRN). The FRN is a faculty development initiative whose mission is to improve the quality of teaching and learning at its member and affiliate institutions, a consortium of 13 historically black colleges and universities in the South and 15 regional liberal arts colleges. Professor Arora's workshop introduces educators at these institutions to contemporary approaches in drug design, and highlights the fundamental role organic chemistry plays in understanding the complexity of biological systems.
Proteins often utilize small folded domains for recognition of other biomolecules. The basic hypothesis guiding our research is that by mimicking these folded domains one can modulate the function of a particular protein with metabolically stable synthetic molecules. This proposal described two efforts to generate nonpeptidic oligomers synthesized from amino acids that mimic helical and strand conformations. The resulting products have proven to be important for targeting biomolecular interactions that have traditionally proven to be "undruggable" by standard means. The technology developed from this project has been patented and licensed by a biotechnology company with the aim of developing new classes of cancer therapeutics. The project provided training for 2 postdoctoral fellow, 3 graduate students and 6 undergraduates. During the period of the award, all members of the group were engaged in teaching activities. This project was the focal point of research activities in the group, bringing together a talented team of scientists, who then helped to fulfill the training mission of the Chemistry Department at NYU. A recently departed postdoctoral fellow, Dr. Danielle Guarracino, is now an Assistant Professor of Chemistry at the College of New Jersey. Members of the principal investigator's research team included graduate and undergraduate students, including members of the underrepresented groups. The PI engaged educators that teach at predominantly minority institutions by organizing workshops that discuss research and teaching advances at the interface of chemistry and biology. The workshop introduced educators at predominantly minority institutions to contemporary approaches in drug design, and highlights the fundamental role organic chemistry plays in understanding the complexity of biological systems. The PI has presented the research findings from this project as part of 40 seminars at universities and conferences. Prof. Leyte L. Winfield of Spelman College has worked cloasely with the PI to develop teaching modules on drug design for her students at Spelman.