Grant: Discovery Grants Program - Individual

The nucleic acids, DNA and RNA, are molecules central to life. Our understanding of the double helix structure formed by complementary DNA strands has led to discoveries in biology and medicine. This structure continues to inspire scientists across disciplines who harness its recognition properties and formation of predictable structures for a myriad of applications including diagnostics and therapeutics. The responsiveness of nucleic acids to environmental conditions and their structural polymorphism has been explored for the development of stimuli responsive nanodevices. By employing organic chemistry, the nucleic acid scaffold can be specifically modified enhancing their properties, expanding their functionality and applications. Engineered DNA nanostructures such as tetrahedra have been developed as cages for guest molecules, which can release their payload in response to stimuli. We will explore the synthesis of modified DNA nanostructures that can be acted upon by endogenous DNA repair proteins that carry out specific reactions to trigger the functionality of these nanodevices. We will develop efficient synthetic methodologies to prepare nucleic acid conjugates designed to enhance their properties such as cellular uptake. Specifically, peptide and small molecule conjugates of DNA and RNA will be constructed from diselenide cross-linked nucleic acid precursors using various approaches including diselenide selenoester ligation-deselenization/alkylation and diselenide metathesis. Diselenide cross-linked oligonucleotides will be used for the preparation of DNA and RNA micelles and oxidative conditions explored for triggering release of the nucleic acids from these structures. We will examine sugar modified nucleic acids, also known as xenonucleic acids (XNA), as probes for DNA repair proteins and bypass DNA polymerases. Correlations between the structural properties of these XNA candidates with the activity of repair proteins and polymerases will provide important insights into the processing of DNA alkylation damage and guide the rational design of inhibitors of these proteins. Chemically modified oligonucleotides are useful tools for gene silencing by the antisense strategy, targeting RNA which can be degraded by the enzyme RNase H. Arabinonucleic acids, promising gene silencing agents, face challenges including moderate thermal stability of duplexes formed with RNA and RNase H mediated cleavage. To improve these properties, nucleobase modifications will be explored to improve their effectiveness. Canada has a dynamic nucleic acid research community and our discoveries in the synthesis and characterization of nucleic acid structures that are acted upon by DNA repair proteins and methodologies to modify the oligonucleotide scaffold will impact the fields of nanomaterials and biotechnology to benefit society. Our research program will provide trainees with a versatile and marketable skill-set that is in demand for the pharmaceutical industry.