RNA structures of coronavirus reveal potential drug targets

The SARS-CoV-2 coronavirus RNA genome structure was studied in detail by researchers from the University of Groningen, the International Institute of Molecular and Cell Biology in Warsaw, and Leiden University. The RNA structures are potential targets for the development of drugs against the virus. The results were published on 10 November as 'Breakthrough paper' in the journal Nucleic Acid Research.

Infectious diseases caused by bacteria and viruses have been around throughout the history of mankind. Over the past 18 years, many deaths worldwide have occurred because of severe acute respiratory syndromes caused by coronaviruses, including SARS and MERS. This, together with the ongoing COVID-19 pandemic that has already taken more than a million lives, demonstrates the urgent need for new ways of combating coronavirus infections.

Genome structure

COVID-19 is caused by SARS-CoV-2, a beta coronavirus 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 IIMCB (Poland), together with scientists from the University of Groningen and Leiden University (both in the Netherlands), performed an extensive characterization of the SARS-CoV-2 RNA genome structure using various advanced techniques.

The study, coordinated by Dr Danny Incarnato from the University of Groningen, 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 appear 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.

Drug

'We first identified the structures in vitro, and subsequently confirmed their presence in the RNA of viruses inside cells,' explains Incarnato. 'This means that our results are very robust.' Also, pockets were identified in some RNA structures that could be targeted by small molecules to hamper the function of the viral RNA. '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 .'

The scientists also identified parts of the SARS-CoV-2 RNA that are intrinsically unstructured. 'These could be targeted by antisense oligonucleotide therapeutics,' explains Incarnato. 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.

Weak spots

In conclusion, this collaborative research establishes 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. 'This work would not have been possible without the collaboration between the Netherlands and Poland,' says Janusz Bujnicki, head of the Laboratory of Bioinformatics and Protein Engineering at the IIMCB in Warsaw. 'Together, we invented a new way of searching for potential weak spots in large viral RNAs. Collectively, our work lays the foundation for the development of innovative RNA-targeted therapeutic strategies to fight SARS-CoV-2 infections.'

The article describing the results of these analyses has been published in Nucleic Acids Research and reviewers who evaluated the manuscript nominated it for featured status as a 'breakthrough paper'.

Ilaria Manfredonia, Chandran Nithin, Almudena Ponce-Salvatierra, Pritha Ghosh, Tomasz K. Wirecki, Tycho Marinus, Natacha S. Ogando, Eric J. Snider, Martijn J. van Hemert, Janusz M. Bujnicki, Danny Incarnato.
Genome-wide mapping of therapeutically-relevant SARS-CoV-2 RNA structures.
Nucleic Acids Research, 2020. doi: 10.1093/nar/gkaa1053

Most Popular Now

Scientists identify synthetic mini-antibody to com…

The ability of SARS-CoV-2 to infect cells depends on interactions between the viral spike protein and the human cell surface protein ACE2. To enable the virus to hook ont...

New drug candidate for the treatment of COVID-19

Researchers from the University of Kent, the Goethe-University in Frankfurt am Main (Germany), and the Hannover Medical School (Germany) have identified a drug with the p...

Cancer treatment could be replicated for COVID-19

Beta-blockers could potentially be used to treat COVID-19, according to a new international study by Italian and Australian scientists. University of South Australia c...

European Commission approves contract with BioNTec…

Today, the European Commission approved a fourth contract with pharmaceutical companies BioNTech and Pfizer, which provides for the initial purchase of 200 million doses ...

Lilly's neutralizing antibody bamlanivimab (LY-CoV…

The U.S. Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) for Eli Lilly and Company's (NYSE: LLY) investigational neutralizing antibody bamlan...

Medicago and GSK announce start of Phase 2/3 clini…

Medicago, a biopharmaceutical company headquartered in Quebec City, and GSK have announced the start of Phase 2/3 clinical trials of its plant-derived vaccine candidate f...

Pre-existing coronavirus antibodies could help pro…

Researchers at the Francis Crick Institute and University College London have found that some antibodies, created by the immune system during infection with common cold c...

Swissmedic begins rolling review of Moderna's mRNA…

Moderna, Inc., (Nasdaq: MRNA) a biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines to create a new generation of transformative medicines for...

Fluvoxamine may prevent serious illness in COVID-1…

In a preliminary study of COVID-19 patients with mild-to-moderate disease who were attempting to recover in their homes, researchers at Washington University School of Me...

Remdesivir for COVID-19: FDA approved but still un…

The United States has become the epicenter of the world in the ever increasing pandemic of COVID-19. While public health prevention strategies of social distancing, crowd...

The Sputnik V COVID-19 vaccine efficacy amounted t…

The National Research Center for Epidemiology and Microbiology named after N.F. Gamaleya of the Ministry of Health of the Russian Federation (Gamaleya Center) and the Rus...

Novartis provides update on CAN-COVID trial in hos…

Novartis today announced new data from an interim analysis for the randomized, double-blind, placebo-controlled CAN-COVID trial evaluating the efficacy and safety of cana...