With the support of this CAREER award from the Organic and Macromolecular Chemistry Program, Professor Kent Kirshenbaum of New York University will pursue fundamental research in biomimetic chemistry by establishing new approaches for the study of folding in synthetic polymers. The ability to control precisely the architecture of complex chemical structures in three dimensions will provide molecules with sophisticated properties, such as specific molecular recognition and catalysis. The project will explore the design, synthesis, characterization and applications of a versatile family of protein mimics: sequence-specific N-substituted glycine polymers, also termed 'peptoids'. Some peptoid sequences have been shown to adopt stable helical conformations. The research program will focus upon this class of compounds since peptoids can effectively mimic more complex secondary and tertiary structures. The efforts will include the introduction of macrocyclic constraints to enforce peptoid conformational stability, design of novel folding motifs, enzymatic ligation of peptoid fragments, synthesis of peptoid macromolecules, and the structural characterization of folded peptoids. An enhanced understanding of macromolecular folding and its application in the design of functional chemical structures will be developed.
With this CAREER award from the Organic and Macromolecular Chemistry Program, Professor Kirshenbaum will utilize experimental approaches in his research that will span the disciplines of bioorganic chemistry, physical chemistry and macromolecular engineering. This project will yield broader impacts by enhancing the discovery of chemical structures suitable for diverse materials and biomedical applications. The research program will provide an excellent training environment for undergraduate and graduate students to obtain skills in fields ranging from bionanotechnology to organic synthesis and drug design. Professor Kirshenbaum will establish an innovative approach to introduce topics in Macromolecular Chemistry to students from diverse backgrounds in the New York City Public School system. Working in partnership with New York University's Steinhardt School of Education, educational modules in 'Molecular Gastronomy' will be developed. Demonstrations utilizing unusual and delicious preparations of food polymers will allow students to learn that we perform chemical reactions in our kitchens on a daily basis; that the organization of molecules can be subjected to our control; and that Chemistry has an influence in every aspect of what we breathe, drink and eat.
With the support of the NSF CAREER award, we have contibuted significant advances to the field of biomimetic chemistry, we have participated in training a group of very talented students at New York University, and we have conducted innovative science outreach programs. In the area of Intellectual Merit: Extensive efforts were devoted to the mimicry of the structures and functions of complex biopolymers such as proteins and nucleic acids. We pursued the study of synthetic sequence-specific heteropolymers in the search for new chemical systems that exhibit the capability of self-encoded folding to precise three-dimensional structures. The ability to precisely orient diverse chemical groups in three-dimensional space is yielding critical advances in molecular recognition, catalysis, and discovery of human therapeutics. The class of molecules that we studied are oligomers of N-substituted glycine 'peptoids'. Because of their ability to self-assemble into stable conformations, they are a promising example of "foldamer" molecules. Our techniques are greatly enhancing the opportunities for controlling the structures of peptoid molecules, and are beginning to generate molecules with valuable biological and materials properties, such as the ability to treat pathogenic bacterial infections and exhibit selective catalysis. In the area of molecular pharmacology, we identified peptoids that have valuable bioactivities, and may lead to the discovery of therapeutics for infectious disease and cancer. We discovered a family of peptoid oligomers bearing a combination of cationic and hydrophobic side chain groups that exhibit potent antimicrobial activity. The peptoids were found to be effective against both gram negative and gram positive pathogenic bacteria, including clinical isolates of methicillin-resistant staph aureus (MRSA). We explored the use of peptoid oligomers for the multivalent display of bioactive ligands in a site-directed manner. Peptoid oligomers were generated and used as scaffolds for the conjugation of ligands capable of binding to steroid hormone receptors. These findings indicated the potential of the conjugates to alter signalling pathways that drive the growth of cancers, such as breast and prostate cancer. We believe that peptoids will provide a general scaffold for constructing multivalent displays, and that this will create a modular route to molecules with enhanced biological activities compared to traditional small molecule therapeutic agents. We advanced our capabilities to design well-ordered peptoid structures. We demonstrated that cyclization is highly effective for enhancing peptoid conformational ordering. X-ray crystal structures were obtained for a number of these constrained products, consistently yielding hairpin-type structures. We assembled peptoid macrocyclic hairpins as modular secondary structure components. We initiated efforts to develop peptoids as mimics of protein tertiary structures. We synthesized a covalently crosslinked dimer of peptoid octamer macrocycles and determined the crystal structure by X-ray diffraction. The product (1,995 Daltons) is the largest peptoid for which a structure has been obtained at high resolution. We have established that computational techniques, including Quantum Mechanics calculations, can be used accurately to evaluate and predict the conformational preferences of peptoid oligomers. Using this approach, we have calculated an energy landscape for the folding of peptoids. Comparisons with experimentally determined structures revealed that these calculations provide a realistic description of peptoid conformational tendencies. These advances will be used to establish methods for the computer-assisted design of complex peptoid structures. In the area of Broader Impacts: Results from our project have contributed to the training of students at all levels. We have hosted high school students who are participating in this project under the 'Project Seed' program of the American Chemical Society. Undergraduate students participated extensively in our projects and were the primary authors on several of our peer-reviewed articles.Our undergraduates have gone on to prestigious graduate programs. We have participated in NYU's REU program as part of ongoing efforts to foster involvement of students from under-represented groups. Two of the graduate students supported by the NSF award have now taken on their own University faculty positions. Our science outreach program in 'Experimental Cuisine' garnered extensive media attention, allowing us to broadly disseminate educational materials at the interface of chemistry and cooking. Our monthly lecture series hosted at NYU generated enthusiasm among the general public to embrace science and engineering as interesting career paths. We worked with the NBC-Learn program to create educational materials for the NSF that will encourage students to pursue training in STEM-related topics and as a route to improving human nutrition and well-being. We submitted several patent applications describing potential commerical uses of technology related to peptoid oligomers. We pursued opportunities to conduct technology transfer to industry regarding potential therapeutic applications for peptoids. We were awarded a patent for the construction of peptoid-based multivalent displays, and we submitted an applicaiton related to the use of structured amphiphilic peptoids as novel antimicrobials. This technology was licensed for personal care applications.
