SAN ANTONIO, Oct.18, 2020
/PRNewswire-PRWeb/ -- American and Polish scientists,
reporting Oct. 16 in the journal
Science Advances, laid out a novel rationale for COVID-19 drug
design – blocking a molecular "scissor" that the virus uses for
virus production and to disable human proteins crucial to the
The researchers are from The University of
Texas Health Science Center at San
Antonio (UT Health San Antonio) and the Wroclaw University
of Science and Technology. Information gleaned by the American team
helped Polish chemists to develop two molecules that inhibit the
cutter, an enzyme called SARS-CoV-2-PLpro.
SARS-CoV-2-PLpro promotes infection by sensing and processing
both viral and human proteins, said senior author Shaun K. Olsen, PhD, associate professor of
biochemistry and structural biology in the Joe R. and Teresa Lozano Long School of Medicine at UT
Health San Antonio.
"This enzyme executes a double-whammy," Dr. Olsen said. "It
stimulates the release of proteins that are essential for the virus
to replicate, and it also inhibits molecules called cytokines and
chemokines that signal the immune system to attack the infection,"
Dr. Olsen said.
SARS-CoV-2-PLpro cuts human proteins ubiquitin and ISG15, which
help maintain protein integrity. "The enzyme acts like a molecular
scissor," Dr. Olsen said. "It cleaves ubiquitin and ISG15 away from
other proteins, which reverses their normal effects."
Dr. Olsen's team, which recently moved to the Long School of
Medicine at UT Health San Antonio from the Medical University of South Carolina, solved the
three-dimensional structures of SARS-CoV-2-PLpro and the two
inhibitor molecules, which are called VIR250 and VIR251. X-ray
crystallography was performed at the Argonne National Laboratory
"Our collaborator, Dr. Marcin Drag, and his team developed the
inhibitors, which are very efficient at blocking the activity of
SARS-CoV-2-PLpro, yet do not recognize other similar enzymes in
human cells," Dr. Olsen said. "This is a critical point: The
inhibitor is specific for this one viral enzyme and doesn't
cross-react with human enzymes with a similar function."
Specificity will be a key determinant of therapeutic value down
the road, he said.
The American team also compared SARS-CoV-2-PLpro against similar
enzymes from coronaviruses of recent decades, SARS-CoV-1 and MERS.
They learned that SARS-CoV-2-PLpro processes ubiquitin and ISG15
much differently than its SARS-1 counterpart.
"One of the key questions is whether that accounts for some of
the differences we see in how those viruses affect humans, if at
all," Dr. Olsen said.
By understanding similarities and differences of these enzymes
in various coronaviruses, it may be possible to develop inhibitors
that are effective against multiple viruses, and these inhibitors
potentially could be modified when other coronavirus variants
emerge in the future, he said.
Activity profiling and structures of inhibitor-bound
SARS-CoV-2-PLpro protease provides a framework for anti-COVID-19
Wioletta Rut, Zongyang Lv, Mikolaj
Patchett, Digant Nayak,
Scott J. Snipas, Farid El Oualid, Tony T.
Huang, Miklos Bekes, Marcin
Drag, Shaun K. Olsen
First published: Oct. 16, 2020,
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SOURCE UT Health San Antonio