SARS-CoV-2 genome comprises all the genetic code the virus needs to produce proteins, evade the immune system, and replicate inside the human body. The 3D structure adopted by this RNA holds most of the information while infecting cells.
Most current work dedicated to discovering drugs and vaccines for COVID-19 is focused on targeting the virus’s proteins. Since the RNA molecule’s shape is critical to its function, targeting the RNA directly with drugs to destroy its structure would obstruct the lifecycle and stop the virus replication.
In a new study, scientists from the University of Cambridge in collaboration with Justus-Liebig University, Germany, uncovered the entire structure of the SARS-CoV-2 genome inside the host cell. Their work demonstrates that a network of RNA-RNA interactions spanning very long sections of the genome. Different functional parts work together with the genome to enable the coronavirus life cycle and cause disease.
Lead author Dr. Omer Ziv at the University of Cambridge’s Wellcome Trust/Cancer Research UK Gurdon Institute said, “The RNA genome of coronaviruses is about three times bigger than an average viral RNA genome – it’s huge.”
“Scientists 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.”
There is a special spot in coronavirus where the ribosome stops half of the times before the stop sign. In the other half of cases, a unique RNA structure makes the ribosome jump over the stop sign and produce additional viral proteins. By planning this RNA structure and the long-range interactions included, the new examination reveals the methodologies by which coronavirus produce their proteins to control our cells.
Dr. Lyudmila Shalamova, a co-lead investigator at Justus-Liebig University, Germany, said, “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.”
Dr. Jon Price, a postdoctoral associate at the Gurdon Institute and co-lead of this study, has developed a free, open-access interactive website hosting the entire RNA structure of SARS-CoV-2. This will enable researchers worldwide to use the new data to develop drugs to target specific virus’s RNA genome regions.
The genome of most human viruses is made of RNA rather than DNA. Ziv developed methods to investigate such long-range interactions across viral RNA genomes inside the host cells to understand the Zika virus genome. This has proved a valuable methodological basis for understanding SARS-CoV-2. Ziv is now planning to set up an independent research group to study the genomes of emerging pathogens at the University of Cambridge’s Department of Biochemistry.
This research is a collaborative study between the group of Professor Eric Miska at the University of Cambridge’s Gurdon Institute and Department of Genetics, and the group of Professor Friedemann Weber from the Institute for Virology, Justus-Liebig University, Gießen, Germany. It was funded by Cancer Research UK, Wellcome, and Deutsche Forschungsgemeinschaft (DFG).
- Ziv, O. et al.: ‘The short- and long-range RNA-RNA Interactome of SARS-CoV-2.’ Mol Cell, November 2020. DOI: 10.1016/j.molcel.2020.11.004