Viral ExoN regulates remodeling rate in SARS-CoV-2

Researchers at the Vanderbilt University Medical Center (VUMC) and the University of Texas Medical Branch (UTMB) at Galveston have discovered what could be the Achilles heel of the coronavirus, a finding that may help control closing the door on COVID-19 and possibly shutting off pandemics in the future.

The coronavirus is an RNA virus that, in its enzymatic apparatus, has a “proofreading” exoribonuclease, called nsp14-ExoN, which can correct errors in RNA sequences that occur at the time of reproduction, when copies of the virus are created.

Using state-of-the-art technologies and bioinformatics techniques, the researchers found that this ExoN also regulates the reproducibility rate, the ability of the corona-virus to infect parts of its genome and even material genetically extracted from other viral strains during reproduction to gain an evolutionary advantage.

These repetitive patterns, the researchers reported last week in the journal Pathogens PLOS, retained over several coronaviruses, including SARS-CoV-2, which causes COVID-19, and MERS-CoV, which causes a similar illness, Middle East respiratory syndrome.

“The coronavirus exoribonuclease is therefore a conservative, important target for prevention and mitigation in the persistent pandemic of SARS-CoV-2, and in preventing future outbreaks of novel coronaviruses,” co- the paper’s first author, Jennifer Gribble, a VUMC graduate student in Mark Denison, MD’s lab.

“If you can find a drug that inhibits RNA replication, you are actually shutting down the virus,” said Andrew Routh, PhD, associate professor of biochemistry and molecular biology at UTMB and, with Denison, the paper’s corresponding author. “It’s very interesting in terms of what we understand about virus change and evolution.”

Previous studies have shown that coronaviruses are resistant to many nucleoside antiviral drugs, which work by introducing errors in the viral genetic code to prevent reproduction. The coronavirus tester corrects the errors until further reproduction.

Only a few drugs are able to get around the tester. They include the approved drug, remdesivir, and EIDD-2801 (molnupiravir), a study drug now in clinical trials. Both were developed with the help of VUMC scientists.

“Discovering that the viral ExoN plays a key role in retinal detachment,” said Denison, director of VUMC’s Department of Pediatric Infectious Diseases that has studied coronaviruses for more than 30 years.

“Deleting this function (in laboratory studies) leads to a decrease in reactivation and a weaker virus,” Denison said. “So we think it may be possible to stop this process with drugs as well (and) it could make other drugs like remdesivir and molnupiravir work even better and last longer.”

In 2007 Denison and his colleagues discovered the coronavirus diagnostic reader. They also found that inhibition of the enzyme accelerated the rate of uncorrected errors – mutations – and reduced its ability to cause disease in animals.

Several years later they discovered that remdesivir, a research antiviral drug, had strong activity against a wide range of coronaviruses, both in laboratory and animal trials. In October 2020 remdesivir was approved for emergency use in hospitalized patients with COVID-19.

For the past two years, Gribble and Routh have collaborated in an effort to understand the role of reproducibility in the reproduction of RNA viruses, which include influenza, polio, influenza. measles, hepatitis C, HIV and Ebola, as well as the coronaviruses.

Using computer software Routh had developed, which can classify data for evidence of “replication events,” Gribble was studying replication in model experimental viruses, such as coronaviruses that infect affecting mice.

As soon as the pandemic struck, Routh, Gribble and their colleagues were able to apply this approach to SARS-CoV-2 and other disease-causing coronaviruses in humans. . Other VUMC co-authors were Laura Stevens, MS, Maria Agostini, PhD, Jordan Anderson-Daniels, PhD, James Chappell, MD, PhD, Xiaotao Lu, MS, and Andrea Pruijssers, PhD.

Renaming does not always lead to a “fitter” virus, which may be stronger, Routh noted. If, during reproduction, for example, some of the genomes are erased, the result is a “defective” viral genome that can mix with, and eliminate, the more brutal snoring.

Coronaviruses often produce defective genomes, the researchers found. “That could be useful,” said Routh. “You may be able to exploit defective genomes as a way to make new vaccines … or to reproduce perturb (of a more violent series) … in the patient.”

Much remains to be learned about repercussions and their role in the continuing release of variable variants of SARS-CoV-2 worldwide and the potential of stopping antiviral drugs and vaccines.

That’s why basic science is so important, said Denison, who holds the Edward Claiborne Stahlman Chair in Pediatric Psychology and Cell Metabolism at Vanderbilt University School of Medicine.

We need to understand the ability of each type of virus to transmit between species and the ways in which they cause infection. We need to make sure there are basic things we know about each identified virus – their genomic sequences, for example, and some basic things about their biology. “

Mark Denison, MD, Author and Associate Director of Research, Department of Pediatric Infectious Diseases, Vanderbilt University Medical Center

That takes a lot of creativity, determination – and money.