Circumventing COVID-19’s Viral Replication Process

Recent data published in the journal PLOS Pathogens may have profound implications on the coronavirus disease 2019 (COVID-19) and putting a stop to its spread, as well as pandemics that occur in the future. The study was conducted by investigators at Vanderbilt University Medical Center (VUMC) and the University of Texas Medical Branch (UTMB) at Galveston.

COVID-19 is a ribonucleic acid (RNA) virus and has the exoribonuclease called nsp14-ExoN, which helps to correct errors in the RNA sequence that can occur during viral replication.

The investigators behind the study combined cutting-edge technology with a novel bioinformatics approach and discovered that ExoN regulates the rate of the virus’s recombination, which gives it the ability to shuffle some parts of its genome and acquire genetic material from other strains to gain an evolutionary advantage. The patterns of recombination are conserved across multiple coronaviruses that cause a similar illness.

"Finding that the viral ExoN plays a key role in recombination is exciting," Mark Denison, the director of the Division of Pediatric Infectious Diseases at VUMC said. "Knocking out this function leads to decreased recombination and a weaker virus. So, we think it may be possible to block this process with drugs as well and that it may make other drugs like remdesivir and molnupiravir work even better and last longer."

Previous research has demonstrated that the family of coronaviruses are resistant to a variety of nucleoside antiviral therapies. Antivirals work by introducing errors into the genetic code of the virus in an attempt to block replication, but nsp14-ExoN corrects them and continues the process.

However, some therapies like molnupiravir, which is being developed by Ridgeback Biotherapeutics, are able to circumvent nsp14-ExoN.

"If you can find a drug that prevents RNA recombination, you really shut down the virus," Andrew Routh, a co-corresponding author on the paper said. "It's really intriguing in terms of what we understand about virus adaptation and evolution."

Additional findings showed that the recombination process does not always work and can occasionally result in a defective genome, disabling the virus. This information may be of benefit to vaccine manufactures, as they may be able to exploit the defective genomes.

"We need to understand the capacity of all kinds of viruses to move between species and the mechanisms by which they cause disease," Denison said. "We need to make sure that there are fundamental things that we know about all identified viruses -- their genomic sequences, for example, and some basics about their biology."