Targeting SARS-CoV-2 RNA Structure Could Help Combat COVID-19

Targeting SARS-CoV-2 RNA Structure Could Help Combat COVID-19
3d illustration of a part of RNA chain from which the deoxyribonucleic acid or DNA is composed

A collaboration between the Justus-Liebig University in Germany and the University of Cambridge has revealed the complex RNA structure of the SARS-CoV-2 virus and investigated how it binds with the host cells to drive infection.

Most efforts to produce therapeutics and vaccines are targeting viral proteins of SARS-CoV-2, such as the spike protein. The researchers believe that targeting the RNA directly, for example, using drugs to disrupt its structure, could be an alternate way to combat the virus.

Coronaviruses have unusually large, single stranded RNA genomes and SARS-CoV-2 is no exception. Although, it is single stranded, its genome binds to itself in many places to form a complex structure, according to the researchers who published their findings in the journal Molecular Cell. These bindings are essential for the virus to survive and propagate itself.

“The RNA genome of coronaviruses is about three times bigger than an average viral RNA genome—it’s huge,” said lead author Omer Ziv, Ph.D., a research fellow at the Gurdon Institute at the University of Cambridge and lead author on the paper. Ziv previously worked to develop methods of studying viral genome structure in previous research on the Zika vrus.

“Researchers previously proposed that long-distance interactions along coronavirus genomes are critical for their replication and for producing the viral proteins, but until recently we didn’t have the right tools to map these interactions in full. Now that we understand this network of connectivity, we can start designing ways to target it effectively with therapeutics.”

The team observed many long distance RNA:RNA interactions in the SARS-CoV-2 genome, both with itself and also some host RNAs. One of the connections was linked to a spot in the viral genome involved with a process called ribosomal frameshifting, where there is a kind of molecular switch that allows the virus to make different proteins depending on its environment and circumstances. These kinds of proteins are often those involved in infecting human or animal cells and so breaking up this link could help target the virus and prevent it from replicating correctly.

“We show that interactions occur between sections of the SARS-CoV-2 RNA that are very long distances apart, and we can monitor these interactions as they occur during early SARS-CoV-2 replication,” said Lyudmila Shalamova, Ph.D., a co-lead investigator at Justus-Liebig University, Germany.

“Our findings illuminate RNA structure-based mechanisms governing replication, discontinuous transcription, and translation of coronaviruses, and will aid future efforts to develop antiviral strategies,” write the authors.

However, they acknowledge that more knowledge is needed about the function of the various RNA structures they discovered.

To help stimulate more research in this area, one of the authors of this study, Jon Price, Ph.D., a researcher based at the Gurdon Institute, has developed a website to share the data with other researchers. This will allow them to access the RNA structure and ‘interactome’ of SARS-CoV-2 for free and use this information to inform and develop their own research.