The Bevilacqua lab has contributed to the field of RNA biology through two disparate approaches. One is rigorous ribozyme mechanism and the other is discovery-based RNA structural genomics. A major goal of the parent award is to bridge these two areas to discover new RNA biology and to characterize it at the molecular level. This proposal advances ways to investigate RNA structure and its contribution to the COVID-19 outbreak. We have already computationally identified structural domains in the RNA genome of SARS-CoV-2, which causes COVID-19, and confirmed these with recent reports on BioRxiv. Uniquely, we identified potential pseudoknots, which are regions of RNA folding complexity that are typically essential for function. The plan for the summer is for our undergraduate student Peter Forstmeier to work through the thousands of available SARS-CoV-2 genomes that contain single nucleotide polymorphisms (SNPs) to identify changes in pseudoknot strength and RNA folding. SNPs in pseudoknots may lead to changes in the stability of the structure, as so- called riboSNitches. The effect of these SNPs on pseudoknots may have implications on the spread and potential virulence of COVID-19. Our hypothesis is that such information will provide targets for therapeutics, both antisense oligonucleotides and small molecules, which can halt spread of the virus. This administrative supplement would provide a unique opportunity for Peter to advance his training to pursue his eventual goal of being a physician-scientist. Because it is computational, it is amenable to working from home during the pandemic, and we can mentor Peter using videoconferencing. Peter is a rising junior and has already spent a year in the Bevilacqua lab developing his coding skills and preparing a pipeline to search for novel RNA structures making him a good fit for this project.
This MIRA administrative supplement will elucidate novel structures in the SARS-CoV-2 RNA genome, which causes COVID-19. By identifying accessible and critical RNA elements, this work may lead to the ability to design antisense oligonucleotide (ASO) and small molecule therapeutics. It also will inform the relationship between RNA structure and spread of the virus.
