Comparative analysis of coronavirus genomic RNA structure reveals conservation in SARS-like coronaviruses

Sanders, Wes; Fritch, Ethan J.; Madden, Emily A.; Graham, Rachel L.; Vincent, Heather A.; Heise, Mark T.; Baric, Ralph S.; Moorman, Nathaniel J.

Coronaviruses, including SARS-CoV-2 the etiological agent of COVID-19 disease, have caused multiple epidemic and pandemic outbreaks in the past 20 years(1–3). With no vaccines, and only recently developed antiviral therapeutics, we are ill equipped to handle coronavirus outbreaks(4). A better understanding of the molecular mechanisms that regulate coronavirus replication and pathogenesis is needed to guide the development of new antiviral therapeutics and vaccines. RNA secondary structures play critical roles in multiple aspects of coronavirus replication, but the extent and conservation of RNA secondary structure across coronavirus genomes is unknown(5). Here, we define highly structured RNA regions throughout the MERS-CoV, SARS-CoV, and SARS-CoV-2 genomes. We find that highly stable RNA structures are pervasive throughout coronavirus genomes, and are conserved between the SARS-like CoV. Our data suggests that selective pressure helps preserve RNA secondary structure in coronavirus genomes, suggesting that these structures may play important roles in virus replication and pathogenesis. Thus, disruption of conserved RNA secondary structures could be a novel strategy for the generation of attenuated SARS-CoV-2 vaccines for use against the current COVID-19 pandemic.