Expanding the Chemistry of Nucleic Acids for the Discovery of Molecular Function

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The encompassing theme within my research program is the development and application of technologies that harness the power of DNA toward the evolution and discovery of novel molecules capable of molecular recognition and catalysis. Our research centres on developing robust screening technologies that address critical needs such as new artificial antibodies for biomedical research and new catalysts for organic synthesis. To this end, my research group has established new methods that enable the generation and high-throughput screening of large DNA-encoded combinatorial libraries ranging from synthetic biopolymers capable of binding proteins to small-molecules capable of catalyzing chemical transformations. Building from these findings, this proposal will study the potential of DNA as a tool for the discovery of molecular function.The first thrust of this program is the study of nucleic acid polymers with increased chemical diversity and their evolution for novel function. My lab has pioneered enzymatic methods to generate DNA with diverse chemical functionality. We will develop scalable synthetic methods for their generation, study the functional group influence on molecular recognition and catalysis, improve binding and catalytic properties of DNA, and demonstrate their evolution as receptors and catalysts for biomedical research. In a second thrust we will develop DNA-encoded small-molecule catalyst libraries for high-throughput catalyst screening of bond-forming chemistries. Central to achieving this is an amphiphilic DNA developed in our lab, which enables the encoding and screening of >10 million unique molecules in as little as 20 uL of solvent. In advancing this research, we will focus on studying the limitations of our recently developed screening platform, including reaction scope and catalyst type. Furthermore, we will develop new synthetic methods for the generation of DNA-encoded small-molecule libraries, which will enable the rapid discovery of catalysts for synthesis of fine chemicals including pharmaceutically-relevant small molecules.This interdisciplinary program on nucleic acids research relies on expertise in synthetic chemistry, polymer chemistry, biological chemistry, combinatorial science, catalysis, and molecular biology. If successful, access to improved nucleic acid-based artificial antibodies for biomedical research and therapeutics will be made possible. Furthermore, greener' high-throughput technologies for catalyst development will be available. Lastly, this research seeks to expand our fundamental understanding of the evolutionary fitness of synthetic polymers for various molecular function, including the chemical diversity and structure-activity relationships required to achieve such molecular function. This program will train 19 multidisciplinary scientists.