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About 15% of deaths worldwide come as a result of cancer. Existing chemotherapeutics have extreme and debilitating side effects, making the discovery and improvement of chemotherapeutics of the utmost importance. RAPTA molecules have demonstrated success in cell studies targeting tumor progression. Examining how ruthenium-based potential chemotherapeutics inhibit CRISPR activity, destabilize, and bind to a DNA:RNA hybrid serves to characterize the nature of these promising compounds in terms of their mechanism of action. Prevalent chemotherapeutic cisplatin completely inhibits CRISPR activity at 50 μM. In this study, four ruthenium-based compounds -a RAPTA compound (RAPTA-C), a RAED compound (RAED-B), and three-ringed compounds (LM5400 and Compound B)- are bound to guide RNA in a CRISPR/Cas9 model system to target and cleave a specific locus on a strand of DNA. Melting studies and fluorescence spectroscopy are also performed to characterize the nature of how they interact with the hybrid sequence. Results indicate inhibition of CRISPR activity at varying concentrations, with the two three-ringed compounds inhibiting CRISPR at the lowest concentrations (2.5 μM and 5 μM). All compounds destabilized the DNA:RNA hybrid and three out of four lowered fluorescence, indicating possible mechanisms that suggest groove binding. These results display promise for ruthenium-based potential chemotherapeutics as this area of research grows and their mechanism can be more deeply understood.
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Jenks, Macy Renae, "Chemotherapeutic Potential of Ruthenium-Based Compounds’ via DNA:RNA Hybrid Studies" (2023). Senior Projects Spring 2023. 19.
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