RNA Structures of SARS-CoV-2 Reveal Potential Drug Targets

Researchers who studied the SARS-CoV-2 coronavirus RNA genome structure in detail have identified potential targets for the development of drugs against the virus.

COVID-19 is caused by SARS-CoV-2, a betacoronavirus with a linear single-stranded, positive-sense RNA genome. Similar to those in other RNA viruses, the SARS-CoV-2 RNA structures are expected to play a crucial role in how the coronavirus replicates in human cells. Despite this importance, only a handful of functionally relevant coronavirus structural RNA elements have been studied to date. Therefore, researchers from the University of Groningen (Groningen, Netherlands), together with scientists from the the International Institute of Molecular and Cell Biology (Warsaw, Poland) and Leiden University (Leiden, Netherlands), performed an extensive characterization of the SARS-CoV-2 RNA genome structure using various advanced techniques.

The study involved RNA structure probing to obtain single-base resolution secondary structure maps of the full SARS-CoV-2 coronavirus genome both in vitro and in living infected cells. Subsequently, the team identified at least 87 regions in the SARS-CoV-2 RNA sequence that appears to form well-defined compact structures. Of these, at least 10% are under strong evolutionary selection pressure among coronaviruses, suggesting functional relevance. Importantly, this is the first time that the structure of the entire coronavirus RNA (one of the longest viral RNAs with approximately 30,000 nucleotides) was determined.

Also, pockets were identified in some RNA structures that could be targeted by small molecules to hamper the function of the viral RNA. The scientists also identified parts of the SARS-CoV-2 RNA that are intrinsically unstructured. Adding short nucleic acid strands that can bind to these viral RNA sections would create double-stranded regions, which are naturally targeted by enzymes inside human cells. Thus, the collaborative research has established a firm foundation for future work aimed at developing potential small-molecule drugs for the treatment of SARS-CoV-2 infections and possibly also infections by other coronaviruses.

“We first identified the structures in vitro, and subsequently confirmed their presence in the RNA of viruses inside cells,” said Dr. Danny Incarnato from the University of Groningen who coordinated the study. “This means that our results are very robust. Furthermore, a number of the structures are conserved between different coronaviruses, meaning that a successful drug targeting SARS-CoV-2 could also be effective against future new virus strains.”

Related Links:
University of Groningen
International Institute of Molecular and Cell Biology
Leiden University