Sequence Effects and Ligand Selectivity in Targeting Non-Canonical DNA Structures
G-Quadruplex (G4) DNA is a secondary DNA structure that can occur in G-rich DNA sequences. These structures, which are compact and diverse, have been implicated in a wide range of processes including telomere maintenance, transcriptional control, and DNA replication and repair. In order to target specific G4 structures, and thus selectively affect these functions, improved small-molecule ligands are required. We have embarked on the synthesis of one such novel bis(quinolin-3-ylmethylene)-based ligand, which is predicted to be more selective for hybrid-stranded G4 structures. In addition, this ligand is predicted to be more readily taken up by cells compared to the parent bis(quinolin-3-ylmethylene)-based ligands. The human telomeric sequence TEL22 dTGGGTTAGGGTTAGGGTTAGGG has been shown to form different G4 topologies in the presence of Na+ ions versus in the presence of K+ ions. The ligand TMPyP4 has four cationic substituents and has been shown to bind with high affinity to various G4 structures. Interestingly, while TMPyP4 stabilizes and increases the Tm of the TEL22 G4 in the presence of K+, TMPyP4 decreases the Tm of TEL22 G4 in the presence of Na+. We have embarked on a study utilizing ultraviolet-visible spectroscopy to determine how various Na+ cation concentrations affect thermal stability of TEL22 with and without the TMPyP4 ligand.
G-Quadruplex, small molecule ligand, hTEL22, TMPyP4
Rodriguez, M. (2022). Sequence effects and ligand selectivity in targeting non-canonical DNA structures (Unpublished thesis). Texas State University, San Marcos, Texas.