This Corona Virus Enzyme Fights Antiviral Drugs

JAKARTA – The coronavirus that causes COVID-19 is known to exhibit “resilient” abilities when it comes to resisting most nucleoside antiviral treatments, but a new study led by Iowa State University scientists is helping to open up the door to the virus’ defenses.

The study, published recently in the peer-reviewed journal Science, details the structure of an important enzyme present in SARS-CoV-2, the coronavirus that causes COVID-19. This enzyme, known as proofreading exoribonuclease (or ExoN), removes nucleoside antiviral drugs from viral RNA, rendering most nucleoside analog-based antiviral treatments ineffective.

This latest study presents the atomic structure of the ExoN enzyme, which could lead to the development of new methods to inactivate the enzyme and open the door to better treatments for patients suffering from COVID-19.

“If we can find a way to inhibit this enzyme, perhaps we can achieve better results in killing the virus with existing nucleoside antiviral treatments. Understanding this structure and the molecular details of how ExoN works can help guide further antiviral development,” Yang Yang said. , lead author of the study and assistant professor in the Roy J. Carver Department of Biochemistry, Biophysics, and Molecular Biology at Iowa State University.

SARS-CoV-2 is an RNA virus, which means its genetic material consists of ribonucleic acid. When a virus replicates, it must synthesize RNA. But the viral genome is very large when compared to other RNA viruses, which creates a relatively high probability that errors arise during RNA synthesis. These errors are mismatched nucleotides, and too many errors can prevent the virus from spreading.

But the ExoN enzyme acts as a corrector, recognizing mismatches in viral RNA and correcting errors that occur during RNA synthesis, Yang said. According to him, the enzyme is only present in the corona virus and several other closely related virus families, as quoted from Iowa State University, Thursday (5/8/2021).

The same process that eliminates replication errors also removes antiviral agents provided by treatments commonly used against other RNA viruses, such as the HIV, HCV and Ebola viruses, which partly explains why SARS-CoV-2 has proved so difficult to treat, Yang said.

But Yang and his colleagues used cryogenic electron microscopy, a technique in which samples are rapidly cooled to cryogenic temperatures in vitreous ice to preserve their original structure, to detail the structure of the enzymes. Understanding that structure could allow the development of molecules that bind to enzymes and inactivate them.

That said it is the next step for his laboratory and colleagues. Finding such a molecule could make the virus more vulnerable to newly developed antivirals, Yang said. Alternatively, it could enable optimization of current antiviruses, such as Remdesivir. (E-4)

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