An international team of researchers showed that a domain of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein (Nsp3) interacts with unusual deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) structures called G-quadruplexes or G4s.
The study, published in the journal Nucleic Acids Research, demonstrated that G4 ligands, the chemical that binds with G4s, prevent this interaction. The results could pave the way for developing inhibitors of these interactions as potential antiviral compounds.
The SARS-CoV-2, the virus behind the coronavirus disease (COVID-19) pandemic, continues to spread across the globe, infecting over 194 million people. The pandemic has claimed more than 4.16 million lives.
The SARS-CoV-2 genome contains 14 open reading frames, with ORF1a and ORF1b occupying two-thirds of the genome and encoding 16 non-structural proteins (Nsp1-16). Among these, the Nsp3 proteins play a pivotal role in the formation and activity of the viral replication complex.
The protein was exhibited to contain a non-conserved domain known as SARS-Unique Domain (SUD), which is not present in less pathogenic coronaviruses that infect humans, or incomplete in the Middle East respiratory syndrome coronavirus (MERS-CoV-2) Nsp3 protein.
SARS-CoV-2 replication relies on a series of interactions between viral proteins and various cellular partners like nucleic acids. Therefore, investigating these interactions is essential to showcase the process of viral replication.
In the current study, the researchers from Institut Pasteur, the Ecole Polytechnique, the Institut Curie, Inserm, the CNRS, and the universities of Paris, Paris-Saclay, Bordeaux, and Toulouse decided to investigate whether a SUD domain is equally present in SARS-CoV-2 Nsp3. If this domain was present, the team aimed to analyze its ability to bind G4s and to see whether these interactions can be modulated by G4-ligands.
The study showed that the SARS-CoV-2 Nsp3 protein contains a SUD domain that interacts with specific DNA and RNA G4s but not with the putative G4s predicted in the SARS-CoV-2 genome. The team also found that these interactions can be disrupted by mutations preventing oligonucleotides from folding into G4 structures and by G4 ligands.
Potential therapeutic applications
Host-virus interactions represent promising targets for antiviral strategies. The study focused on the interaction between SARS-CoV-2’s SUD domain Nsp3 protein and the DNA or RNA G-quadruplexes. The interactions reflect a high therapeutic potential.
Also, the study results pave the way for further studies on the role of the SUD/G4 interactions during SARS-CoV-2 replication. It shows promise in the development of preventive therapeutics that can hinder SARS-CoV-2 reproduction.
Experiments are ongoing to determine the preferential partners of the SARS-CoV-2 SUD domain, more likely messenger RNAs (mRNAs) coding for proteins involved in the immune response, stress response, or inflammation.
“Our results, showing the capacity of some G4-ligands to inhibit the SARS-CoV-2 SUD/G4 interaction paves the way for a global screening of molecules able to inhibit this interaction and to test their antiviral properties,” the team concluded in the study.
Alongside the study, the researchers also developed G4 ligands. They demonstrated that these ligands, which hinder interactions between the SARS-CoV-2 protein and the G4 structure, elicit an antiviral activity. Hence, these structures could be used in therapeutics to combat the current pandemic.
As of July 26, 2021, the virus has affected 192 countries and territories. Among these, the United States reports the highest number of cases, topping 34.5 million cases, followed by India and Brazil, with over 31.41 million and 19.7 million cases, respectively.
Though over 3.87 billion vaccine doses have been administered, many countries still report surging cases brought about by emerging SARS-CoV-2 variants. Therefore, apart from vaccines, it is crucial to develop therapeutics to prevent and treat COVID-19.