SARS-CoV-2 RNA structures reveal potential drug targets


The structure of the SARS-CoV-2 RNA genome has been studied by researchers who have identified several potential drug targets.


The structure of the SARS-CoV-2 RNA genome has been studied in detail by the researchers, revealing potential targets for drug development against the virus. Scientists say this is the first time the structure of the entire novel coronavirus RNA (one of the longest viral RNAs with around 30,000 nucleotides) has been determined.

The study was conducted at the University of Groningen and the University of Leiden, both Netherlands, and the International Institute of Molecular and Cell Biology, Poland.

According to the researchers, SARS-CoV-2 is a beta coronavirus with a single-stranded, positive-sense linear RNA genome. Similar to those of other RNA viruses, SARS-CoV-2 RNA structures are expected to play a crucial role in how coronavirus replicates in human cells. Despite this importance, only a handful of functionally relevant structural RNA elements of the coronavirus have been studied to date. This prompted the researchers to perform an extensive characterization of the SARS-CoV-2 RNA genome structure.

The team probed the RNA structure to obtain basic single-resolution secondary structure maps of the complete genome of the SARS-CoV-2 coronavirus and in vitro and in living infected cells. Next, they identified at least 87 regions in the SARS-CoV-2 RNA sequence that appear to form well-defined compact structures. Of these, at least 10% are under severe evolutionary selection pressure among coronaviruses, suggesting functional relevance.

“We first identified the structures in vitro and subsequently confirmed their presence in the RNA of the viruses within the cells, “explained the study coordinator, Dr. Danny Incarnato.” This means that our results are very solid … Furthermore, a number of structures are conserved among the different coronaviruses, which means that a successful drug that targets SARS-CoV-2 could also be effective against future new strains of the virus. “


Schematic representation of the experimental approach adopted by the researchers. After “probing” the structure of the SARS-CoV-2 RNA genome using specific chemical compounds, the secondary structure of stable RNA elements throughout the viral genome was determined. Using this information, the three-dimensional (3D) model of these elements of the RNA structure was computationally determined, enabling the identification of potential pockets that could provide targets for the development of antiviral therapeutic strategies. [credit: Danny Incarnato, University of Groningen].

Additionally, pockets have been identified in some RNA structures that could be targeted by small molecules to hinder viral RNA function. Scientists have also identified parts of SARS-CoV-2 RNA that are inherently unstructured.

“These could be targeted by antisense oligonucleotide therapies,” Incarnato commented. Adding short strands of nucleic acid that can bind to these viral RNA sections would create double-stranded regions, which are naturally targeted by enzymes within human cells.

The researchers say this collaborative study lays a solid foundation for future work to develop potential small molecule drugs to treat SARS-CoV-2 infections and possibly other coronavirus infections as well.

The results were published in Research on nucleic acids.

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