Genome origami of Covid-19 virus unravelled by University of Cambridge researchers
The ‘genome origami’ performed by the SARS-CoV-2 virus to infect us with Covid-19 has been unravelled by scientists at the University of Cambridge.
The study, carried out in collaboration with Justus-Liebig University in Germany, could prove vital in the development of effective drugs to target parts of the virus genome.
SARS-CoV-2 is one of many coronaviruses, all of which are made from RNA, rather than DNA. In fact, they share the trait of having the largest single-stranded RNA genome in nature.
In it lies the genetic code needed for the virus to produce proteins, evade the human systems and replicate inside the body.
Much of this information is held in the 3D structure adopted by the RNA genome when it infects cells.
Most work designed to combat Covid-19 with drugs or vaccines is focused on targeting its proteins – particularly the now-infamous spike protein.
But as the shape of the RNA molecule is critical to its function, targeting the RNA directly with drugs to disrupt its structure could block its lifecycle – and, critically, stop it replicating.
The entire structure of the SARS-CoV-2 genome inside the host cell is laid bare in the team’s open-access study, published last Thursday in the journal Molecular Cell.
It reveals a network of RNA-RNA interactions, spanning very long sections of the genome, and shows how functional parts along the genome need to work together,
in spite of the great distance between them.
The new structural data published reveals how this is accomplished to enable the coronavirus life cycle, and cause disease – findings that could help us identify ways to disrupt it.
Lead author Dr Omer Ziv, at the University of Cambridge’s Wellcome Trust/Cancer Research UK Gurdon Institute, has earned a nomination for Researcher of the Year in the 2020 Cambridge Independent Science and Technology Awards for the work.
He said: “The RNA genome of coronaviruses is about three times bigger than an average viral RNA genome – it’s huge.
“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 genome inside all cells holds the instructions for producing specific proteins.
These are made when the ribosome, a molecular machines, along the RNA reading the code until it meets a stop sign, known as a stop codon, telling it to terminate.
Coronaviruses feature a section where the ribosome only stops half the time at this point. The rest of the time, a unique RNA shape makes the ribosome effectively leap over the stop sign and produce extra viral proteins. This “hairpin-type pseudoknot RNA structure” is known as the frameshifting element (FSE).
While efforts have been made before to understand this RNA structure, until now, it was not possible to fully map the long-range interactions, or base-pairing, involved.
But the study used an advanced technique developed by Dr Ziv and colleagues called COMRADES (Crosslinking Of Matched RNAs And Deep Sequencing), developed in 2018 initially to understand the Zika virus. Designed to help understand interactions across viral RNA genomes inside the host cells, it is able to measure the structural diversity and capture both short and long-range base-pairing.
The technique allowed the researchers to uncover the strategies by which coronaviruses produce their proteins to manipulate our cells.
Dr Lyudmila Shalamova, a co-lead investigator at Justus-Liebig University, 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.
It will enable researchers around the world to use the new data in the development of drugs to target specific regions of the virus’s RNA genome.
The work was a collaboration between Professor Eric Miska’s group at the Gurdon Institute and Prof Friedemann Weber’s group at the Institute for Virology, Justus-Liebig University and was supported by the Department of Biochemistry at the University of Cambridge, which provided specialist laboratory facilities. The study was funded by Cancer Research UK, Wellcome, and Deutsche Forschungsgemeinschaft (DFG).
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