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For the first time, an international research alliance has observed the RNA folding structures of the SARS-CoV2 genome with which the virus controls the infection process. Because these structures are very similar between the various beta corona viruses, scientists have not only laid the groundwork for the targeted development of new drugs to treat COVID-19, but also for future cases of infection with new corona viruses that could develop. in the future.
The genetic code of the SARS-CoV2 virus is exactly 29,902 characters long, tucked into a long RNA molecule. Contains information for the production of 27 proteins. This isn’t much compared to the possible 40,000 types of proteins a human cell can produce. Viruses, however, use the metabolic processes of their host cells to multiply. Crucial to this strategy is that viruses can precisely control the synthesis of their own proteins.
SARS-CoV2 uses spatial folding of its inherited RNA molecule as a control element for protein production: predominantly in areas that do not code for viral proteins, single-stranded RNA adopt structures with double-stranded sections and rings of RNA. However, until now the only models of these folds have been based on computer analysis and indirect experimental evidence.
Now, an international team of scientists led by chemists and biochemists from Goethe University and TU Darmstadt have experimentally tested the models for the first time. Researchers from the Israeli Institute of Sciences Weizmann, the Swedish Karolinska Institute and the Catholic University of Valencia were also involved.
The researchers were able to characterize the structure of a total of 15 of these regulatory elements. To do this, they used nuclear magnetic resonance (NMR) spectroscopy in which the RNA atoms are exposed to a strong magnetic field and thus reveal something about their spatial arrangement. They compared the results of this method with the results of a chemical process (dimethyl sulfate imprint) that makes it possible to distinguish single-stranded regions of RNA from double-stranded regions of RNA.
Consortium coordinator Professor Harald Schwalbe of the Center for Biomolecular Magnetic Resonance at Goethe University in Frankfurt explains: “Our findings have laid a broad foundation for future understanding of exactly how SARS-CoV2 controls the infection process. Scientifically. , this was a huge and very laborious effort that we were only able to realize thanks to the extraordinary commitment of the teams here in Frankfurt and Darmstadt together with our partners in the COVID-19-NMR consortium. But the work continues: together with our partners, we are currently investigating which viral proteins and which human host cell proteins interact with the folded regulatory regions of RNA and whether this could lead to therapeutic approaches. “
Worldwide, more than 40 working groups with 200 scientists are conducting research within the COVID-19-NMR consortium, including 45 doctoral and postdoctoral students in Frankfurt working two shifts a day, seven days at the week from the end of March 2020.
Schwalbe is convinced that the potential for discovery extends beyond new therapeutic options for SARS-CoV2 infections: “The viral RNA control regions whose structure we have examined are, for example, nearly identical for SARS-CoV and also very similar for other beta-coronaviruses. For this reason, we hope to be able to contribute to being better prepared for future “SARS-CoV3” viruses. “
The Center for Biomolecular Magnetic Resonance was founded in 2002 as a research infrastructure at Goethe University in Frankfurt and has since received substantial funding from the Hessian state.
Reference: Wacker A, Weigand JE, Akabayov SR, et al. Determination of the secondary structure of conserved SARS-CoV-2 RNA elements by NMR spectroscopy. Research on nucleic acids. 2020.doi: 10.1093 / nar / gkaa1013
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