Targeting a Critical Molecular Switch in COVID-19

07/31/2020

Solution X-ray scattering (SAXS) helps reveal a potential molecular target that may impair SARS-CoV-2 replication. The image represents a particular mRNA molecule from SARS-CoV, the virus that causes MERS, that controls the expression of viral proteins through a process called programmed −1 ribosomal frameshift (−1 PRF). The conformation and sequence are remarkably similar to that of SARS-CoV-2, in which a cytosine nucleotide is replaced by adenine (red). This suggests that compounds that inhibit -1 PRF in SARS-CoV may likewise inhibit SARS-CoV-2 replication. [Courtesy Brookhaven National Laboratory.]

The Science

Scientists studied the 3-D structure of parts of the COVID-19 virus and found a potential inhibitor for virus replication. They compared the three-stemmed RNA pseudoknots of SARS-CoV and SARS-CoV-2 that function as critical switches in the replication pathways of these viruses and found a small molecule that could inhibit their function.

The Impact

This work shows that such inhibitors may possibly be used to fight the COVID-19 pandemic.

Summary

The COVID-19 pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and researchers continue to work on treatments and vaccines, many of which can take years to develop. A good short-term strategy may lie in identifying virus-specific targets for small-molecule-based interventions.

In this work, a research team investigated how the virus replicates by studying a process called programmed −1 ribosomal frameshift (−1 PRF). In this process, a ribonucleic acid (RNA) pseudoknot acts as a critical switch in the replication programs of the virus and is therefore a promising drug target to inhibit virus replication.

The team used small-angle x-ray scattering (SAXS) analyses at the Life Science X-ray Scattering (LiX) beamline at the National Synchrotron Light Source II (NSLS-II) to compare the structure of the three-stemmed pseudoknots of SARS-CoV and SARS-CoV-2. SARS-CoV is a coronavirus strain that caused an epidemic 17 years ago and has been well studied since. NSLS-II is a U.S. Department of Energy Office of Science User facility located at DOE’s Brookhaven National Laboratory.

The team showed that the pseudoknots have a similar structure and function. This enabled testing whether a small molecule known to inhibit SARS-CoV frameshifting would be similarly effective against SARS-CoV-2. The results suggest that such frameshift inhibitors may be promising lead compounds to combat the COVID-19 pandemic.

Funding Acknowledgements

This research used resources including the LiX beamline of the National Synchrotron Light Source II, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Brookhaven National Laboratory under Contract No. DE-SC0012704. The Center for BioMolecular Structure (CBMS) is primarily supported by the National Institutes of Health, National Institute of General Medical Sciences (NIGMS) through a Center Core P30 Grant (P30GM133893), and by the DOE Office of Biological and Environmental Research (KP1605010).

References

J. A. Kelly, A. N. Olson, K. Neupane, S. Munshi, J. San Emeterio, L. Pollack, M. T. Woodside, J. D. Dinman. “Structural and functional conservation of the programmed −1 ribosomal frameshift signal of SARS coronavirus 2 (SARS-CoV-2).” J. Biol. Chem. 295(31):10741-10748 (2020). [DOI: 10.1074/jbc.AC120.013449]