Research Projects

Guanine- and cytosine-rich sequences, known as G-quadruplexes (GQs) and i-motifs (iMs), are found in human oncogenes and pathogens, including viruses. However, understanding their structural polymorphism in cell-free and cellular environments remains a significant challenge. The questions in this field include the topology of a given G-rich and C-rich sequence, which topology is responsible for its function, and how to target a specific topology using small molecules. Current tools are not compatible with both cell-free and cellular assays, and most studies use single-stranded G-rich and C-rich oligonucleotides (ONs), which coexist in the genome and constantly compete with the duplex form. To fully understand their biological role, a probe should provide unique spectral signatures for different conformations, enabling resolution and quantification of population equilibrium. An innovative probe design platform is proposed to study these structures by developing conformation-sensitive multifunctional nucleoside analogs composed of a fluorophore, ¹⁹F NMR label, and Se atom. The probes will be assembled by conjugating heterocycles containing ¹⁹F and or Se atoms at the C5 position of pyrimidines, and phosphoamidite substrates will be site-specifically incorporated into G-rich and C-rich ON motifs of human oncogenes and viral genes. The structure and ligand binding properties of labeled ONs will be investigated concurrently by fluorescence, NMR, and X-ray crystallography techniques. Key results and findings from these studies will advance the basic understanding of non-canonical nucleic acid structures and accelerate GQ and iM-based therapeutic strategies.