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UrduThe researchers say most current work to find drugs and vaccines for COVID-19 is focused on targeting the proteins of the virus. Because the shape of the RNA molecule is critical to its function, targeting the RNA directly with drugs to disrupt its structure would block the lifecycle and stop the virus replicating.
In a study published today in the journal Molecular Cell, the team uncovered the entire structure of the SARS-CoV-2 genome inside the host cell, revealing a network of RNA-RNA interactions spanning very long sections of the genome. Different functional parts along the genome need to work together despite the great distance between them, and the new structural data shows how this is accomplished to enable the coronavirus life cycle and cause disease.
“The RNA genome of coronaviruses is about three times bigger than an average viral RNA genome – it’s huge,” said lead author Dr Omer Ziv at the University of Cambridge’s Wellcome Trust/Cancer Research UK Gurdon Institute.
He added: “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.”
In all cells the genome holds the code for the production of specific proteins, which are made when a molecular machine called a ribosome runs along the RNA reading the code until a ‘stop sign’ tells it to terminate. In coronaviruses, there is a special spot where the ribosome only stops 50% of the times in front of the stop sign. In the other 50% of cases, a unique RNA shape makes the ribosome jump over the stop sign and produce additional viral proteins. By mapping this RNA structure and the long-range interactions involved, the new research uncovers the strategies by which coronaviruses produce their proteins to manipulate our cells.
“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 Dr Lyudmila Shalamova, a co-lead investigator at Justus-Liebig University, Germany.
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 world-wide to use the new data in the development of drugs to target specific regions of the virus’s RNA genome.
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, in work to understand the Zika virus genome. This has proved a valuable methodological basis for understanding SARS-CoV-2.
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. The authors are grateful for the support of the Biochemistry Department at the University of Cambridge, who provided specialist laboratory facilities for performing part of this research.
The study was funded by Cancer Research UK, Wellcome, and Deutsche Forschungsgemeinschaft (DFG).
About the University of Cambridge
The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. To date, 109 affiliates of the University have won the Nobel Prize.
Founded in 1209, the University comprises 31 autonomous Colleges, which admit undergraduates and provide small-group tuition, and 150 departments, faculties and institutions. Cambridge is a global university. Its 19,000 student body includes 3,700 international students from 120 countries. Cambridge researchers collaborate with colleagues worldwide, and the University has established larger-scale partnerships in Asia, Africa and America.
The University sits at the heart of the ‘Cambridge cluster’, which employs 60,000 people and has in excess of £12 billion in turnover generated annually by the 4,700 knowledge-intensive firms in and around the city. The city publishes 341 patents per 100,000 residents.
About the Wellcome Trust/ Cancer Research UK Gurdon Institute
Named after its co-founder, Nobel Laureate Sir John Gurdon, the Gurdon Institute (part of the University of Cambridge) is a world-leading centre for research at the interface between developmental biology and cancer biology.
More than 200 scientists work in the Gurdon Institute’s purpose-built laboratories on projects ranging from breast cancer and brain development to lung regeneration and mitochondrial disease. Many have made pioneering contributions to the fields of basic cell biology, cellular reprogramming, epigenetics and DNA repair.
Institute scientists use a range of model systems such as yeast, nematode worms, fruit flies, frogs, mammalian cells and organoids to study development and disease at the level of molecules, cells and tissues.
Research conducted at the Institute has so far led to a dozen spin-out companies (including KuDOS Pharmaceuticals, Abcam, Chroma Therapeutics, CellCentric, Mission Therapeutics and STORM Therapeutics) and five candidate drugs. One of these, the PARP inhibitor olaparib (Lynparza), has been approved for use against certain types of ovarian, breast and prostate cancers.
