Molecular mechanisms of coronavirus drug candidate Molnupiravir
unraveled

Date:
August 16, 2021
Source:
Max-Planck-Gesellschaft
Summary:
The antiviral agent incorporates RNA-like building blocks into
the genome of the virus.



FULL STORY ==========================================================================
The United States recently secured 1.7 million doses of a compound
that could help to treat Covid-19 patients. In preliminary
studies, Molnupiravir reduced the transmission of the Sars-CoV-2
coronavirus. Researchers at the Max Planck Institute for Biophysical
Chemistry in Go"ttingen and the Julius Maximilians University Wu"rzburg
have now elucidated the underlying molecular mechanism.

The antiviral agent incorporates RNA-like building blocks into the RNA
genome of the virus. If this genetic material is further replicated,
defective RNA copies are produced and the pathogen can no longer
spread. Molnupiravir is currently being tested in clinical trials.


========================================================================== Since the onset of the coronavirus pandemic, numerous scientific projects
set out to investigate measures against the new virus. At full stretch, researchers are developing various vaccines and drugs -- with different
degrees of success.

Last year, the antiviral drug Remdesivir gained attention when it became
the first drug against Covid-19 to be approved. Studies, including work by Patrick Cramer at the Max Planck Institute for Biophysical Chemistry in Go"ttingen and Claudia Ho"bartner at the Julius Maximilians University Wu"rzburg (Germany), showed why the drug has a rather weak effect on
the virus.

Molnupiravir, another antiviral drug candidate, was originally developed
to treat influenza. Based on preliminary clinical trials, the compound
promises to be highly effective against Sars-CoV-2. "Knowing that a new
drug is working is important and good. However, it is equally important
to understand how Molnupiravir works at the molecular level in order to
gain insights for further antiviral development," Max Planck Director
Cramer explains. "According to our results, Molnupiravir acts in two
phases." Mutations in the genome stop the virus Molnupiravir is an
orally available drug which becomes activated through metabolization
in the body. When it enters the cell, it is converted into RNA-
like building blocks. In the first phase, the viral copying machine,
called RNA polymerase, incorporates these building blocks into the RNA
genome of the virus. However, unlike Remdesivir, which slows down the
viral RNA polymerase, Molnupiravir does not directly interfere with
the function of the copying machine. Instead, in the second phase, the
RNA-like building blocks connect with the building blocks of the viral
genetic material. "When the viral RNA then gets replicated to produce new viruses, it contains numerous errors, so- called mutations. As a result,
the pathogen can no longer reproduce," says Florian Kabinger, a doctoral student in Cramer's department. Together with the other first authors,
Carina Stiller and Jana Schmitzova', he conducted the crucial experiments
for the study.

Molnupiravir also appears to trigger mutations in other RNA viruses,
preventing them from spreading further. "The compound could potentially
be used to treat a whole spectrum of viral diseases," tells Ho"bartner,
a professor of chemistry at the University of Wu"rzburg. "Molnupiravir
has a lot of potential." Currently, the promising drug candidate is
in phase III studies, where it is being tested on a large number of
patients. Whether Molnupiravir is safe to be approved as a drug will
probably be announced in the second half of the year.

The U.S. government is already optimistic and has recently secured about
1.7 million doses worth more than a billion dollars.

========================================================================== Story Source: Materials provided by Max-Planck-Gesellschaft. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Florian Kabinger, Carina Stiller, Jana Schmitzova', Christian
Dienemann,
Goran Kokic, Hauke S. Hillen, Claudia Ho"bartner, Patrick Cramer.

Mechanism of molnupiravir-induced SARS-CoV-2
mutagenesis. Nature Structural & Molecular Biology, 2021; DOI:
10.1038/s41594-021-00651-0 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210816125710.htm

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