Antonia Bruce: Defense- "Interrogating the Small Molecule Modulation of Viral RNA Secondary Structures"

"Interrogating the Small Molecule Modulation of Viral RNA Secondary Structures" RNA viruses have been the cause of viral outbreaks, epidemics and pandemics worldwide. However, many viruses do not have specific antiviral treatments. As such, there is an imperative need for the development of viral therapeutics. The recent advances in our understanding of RNA have shown that RNA plays a critical role in various disease states and has properties that make it an attractive potential therapeutic target. One property of interest is the structure-function relationship of RNA, where the structure and dynamics of viral RNA has been found to significantly impact biological function. Small molecules can potentially be used to modulate the biological function of viral RNA by exploiting its structure-function relationship. However, the impact small molecules have on functional, viral RNA secondary structures has been underexplored. RNA viruses contain a variety of different RNA secondary structures that have been found to have biological function. Therefore, we used the functional RNA secondary structures found in different RNA viruses and two different methods, Förster energy transfer resonance (FRET) and fluorescence indicator displacement (FID), to investigate small molecule binding to viral RNA secondary structures and the impact small molecules have on their dynamics. High-throughput screening was used to identify small molecules that bind to or induced conformational change in viral RNA targets containing the bulge and three-way junction structural motif. Additionally, computational analysis was used to determine the cheminformatic properties that were important for the interaction. The computational analysis revealed that cheminformatic properties such as surface area and the number of hydrogen bond donors were important for binding to viral RNA targets with different RNA secondary structures, and for prompting conformational changes in viral RNA switches. The findings from this work furthered our understanding of viral RNA secondary structures and has the potential to aid in the development of novel antiviral treatments.