New study details enzyme that allows coronavirus to resist antiviral medications

Date:
August 3, 2021
Source:
Iowa State University
Summary:
A new study details the structure of a critical enzyme present in
SARS- CoV-2, the coronavirus that causes COVID-19. This enzyme
removes nucleoside antiviral medications from the virus's RNA,
rendering many treatments ineffective. Scientists could use data
uncovered in the new study to find ways to inhibit the enzyme,
possibly leading to more effective treatments.



FULL STORY ==========================================================================
The coronavirus that causes COVID-19 has demonstrated a stubborn ability
to resist most nucleoside antiviral treatments, but a new study led by
an Iowa State University scientist could help to overcome the virus's
defenses.


==========================================================================
The study, published recently in the peer-reviewed journal Science,
details the structure of a critical enzyme present in SARS-CoV-2, the coronavirus that causes COVID-19. This enzyme, known as the proofreading exoribonuclease (or ExoN), removes nucleoside antiviral medications
from the virus's RNA, rendering most nucleoside analogs-based antiviral treatments ineffective. The new study presents the atomic structures of
the ExoN enzyme, which could lead to the development of new methods for deactivating the enzyme and opening the door to better treatments for
patients suffering from COVID-19.

"If we could find a way to inhibit this enzyme, maybe we can achieve
better results to kill the virus with existing nucleoside antiviral
treatments.

Understanding this structure and the molecular details of how ExoN
works can help guide further development of antivirals," said Yang Yang,
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 is composed
of ribonucleic acid. When the virus replicates, it must synthesize
RNA. But the virus's genome is unusually large when compared to other
RNA viruses, which creates a relatively high likelihood that errors
arise during RNA synthesis.

These errors take the form of mismatched nucleotides, and too many errors
can prevent the virus from propagating.

But the ExoN enzyme acts as a proofreader, recognizing mismatches in
the virus RNA and correcting errors that occur during RNA synthesis,
Yang said. The enzyme is present only in coronaviruses and a few other
closely related virus families, he said.

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

But Yang and his colleagues utilized cryogenic electron microscopy, a
technique in which samples are flash cooled to cryogenic temperatures in vitreous ice to preserve their native structures, to detail the structure
of the enzyme.

Understanding that structure could allow for the development of molecules
that bind to the enzyme and disable it. Yang said that's the next step
for his laboratory and his colleagues. Finding such a molecule could
make the virus more susceptible to newly developed antivirals, Yang
said. Or, it could allow for the optimization of current antivirals,
such as Remdesivir.

Scott Becker, an ISU graduate student in the Roy J. Carver Department
of Biochemistry, Biophysics and Molecular Biology, also contributed to
the study.

The study also included scientists from Yale University and the Hormel Institute at the University of Minnesota.

========================================================================== Story Source: Materials provided by Iowa_State_University. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Chang Liu, Wei Shi, Scott T. Becker, David G. Schatz, Bin Liu,
Yang Yang.

Structural basis of mismatch recognition by a SARS-CoV-2
proofreading enzyme. Science, 2021; eabi9310 DOI:
10.1126/science.abi9310 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210803121345.htm

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