New mechanism of action against SARS-CoV-2 by antiviral drug remdesivir
Understanding how the conditionally approved COVID-19 drug works is key
to improving treatments, says researcher

Date:
September 24, 2020
Source:
University of Alberta Faculty of Medicine & Dentistry
Summary:
Researchers have discovered a novel, second mechanism of action
by the antiviral drug remdesivir against SARS-CoV-2. The research
team previously demonstrated how remdesivir inhibits the COVID-19
virus's polymerase or replication machinery in a test tube.



FULL STORY ========================================================================== Researchers at the University of Alberta have discovered a novel,
second mechanism of action by the antiviral drug remdesivir against
SARS-CoV-2, according to findings published today in the Journal of
Biological Chemistry.


==========================================================================
The research team previously demonstrated how remdesivir inhibits the
COVID-19 virus's polymerase or replication machinery in a test tube.

Matthias Go"tte, chair of medical microbiology and immunology in the
Faculty of Medicine & Dentistry, likened the polymerase to the engine
of the virus. He said the first mechanism the team identified is like
putting diesel fuel into an engine that needs regular gasoline.

"You can imagine that if you give it more and more diesel, you will go
slower and slower and slower," he said.

The newly identified mechanism is more like a roadblock, "so if you
want to go from A to B with the wrong fuel and terrible road conditions,
you either never reach B or you arrive extremely late," Go"tte said.

"Remdesivir stops or heavily delays replication of the virus, which in
turn reduces propagation and spread." Benchmark drug against COVID-19


========================================================================== Go"tte said it is not common for antiviral drugs to have more than one mechanism of action. The first mechanism his team uncovered affects what
is known as the "primer strand" of RNA or the first copy the virus makes
of the viral genome as it infects a cell. The second mechanism affects the "template strand" which is repeated over and over as the virus spreads.

Clinical trials of remdesivir in COVID-19 patients are underway around
the world, including one run by the U.S. National Institutes of Health
which reported preliminary results showing the average recovery time for treated patients was shortened to 11 days compared with 15 days for the
placebo group.

Go"tte said it is important to know how remdesivir works because it is
the only direct-acting antiviral currently approved for conditional
and/or emergency use as a COVID-19 treatment in several countries,
including Canada and the U.S.

"That means remdesivir is a benchmark that we need to understand in great detail in order to build on it and to improve therapies in the future,"
Go"tte said.

Next steps for human trials and laboratory studies Go"tte said that while remdesivir looks promising in laboratory tests and in cell cultures, he
is anxious to see more results from human clinical trials, in particular
how remdesivir affects the "viral load" or amount of virus in patients.



==========================================================================
"Is there a difference as to whether somebody has a low viral load
from the beginning or a high viral load? We don't know that yet," he
pointed out.

He said laboratory results can differ from human trials because there
could be reservoirs of the virus in the human body that the drug does not reach. SARS- CoV-2 may also develop resistance to the drug, although he
thinks this will be difficult based on what is known about how remdesivir interacts with other coronaviruses.

"We need these data to help us to better understand which patients will
benefit from remdesivir," he said.

Go"tte's lab will continue trying to understand more about how remdesivir
and other polymerase inhibitors work against SARS-CoV-2 to aid drug
discovery and development.

The research was supported by the Canadian Institutes of Health Research, Gilead Sciences and the Alberta Ministry of Jobs, Economy and Innovation.


========================================================================== Story Source: Materials provided by University_of_Alberta_Faculty_of_Medicine_&_Dentistry.

Original written by Gillian Rutherford. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Egor P Tchesnokov, Calvin J Gordon, Emma Woolner, Dana Kocincova,
Jason K
Perry, Joy Y. Feng, Danielle P Porter, Matthias
Gotte. Template-dependent inhibition of coronavirus RNA-dependent
RNA polymerase by remdesivir reveals a second mechanism of
action. Journal of Biological Chemistry, 2020; jbc.AC120.015720
DOI: 10.1074/jbc.AC120.015720 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200924082656.htm

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