Chemical Synthesis and Applications of Nucleic Acids and their Analogues

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Nucleic acids are the fundamental molecules of life, carrying the genetic blueprints for all living things on Earth. Refined through billions of years of evolution, they achieve an ideal balance between complexity and elegance, a perfect marriage of form and function. As such, synthetic DNA and RNA oligonucleotides and their analogues are incredibly useful tools for molecular biology, functional genomics, and the development of oligonucleotide therapeutics. We will pursue three specific aims within this proposed NSERC Discovery Grant program, all directed to nucleic acid chemistry and biology. The short-term objective of our research is to develop methods for oligonucleotide synthesis and to design a suite of DNA/RNA analogues as tools to characterize nucleic acid structure and function. This will enable our medium-term aim of elucidating sequence-structure- function relationships for telomeric and promoter DNA quadruplexes (undoubtedly the most important classes of non-canonical DNA) and gaining a better understanding of enzymes implicated in gene regulation (CRISPR-Cas12, telomerase, etc.). This information is prerequisite to achieving our long-term goals of large-scale synthesis of improved DNA/RNA-based therapeutics capable of silencing and editing genes of interests. Hence, our research program will deliver new knowledge and new technologies to significantly advance nucleic acid chemistry and therapeutics Our scientific approach combines solution and solid-phase synthetic methods, drug discovery, spectroscopic analysis, and molecular biology techniques. These studies expose students to a wide range of topics in nucleic acid chemistry and biology research, and to strategies used for identifying candidate molecules and developing them into useful probes and/or therapeutic drugs.