Viral 'molecular scissor' is next COVID-19 drug target
Coronavirus uses enzymatic cutter for virus production and to disable essential immune proteins

Date:
October 16, 2020
Source:
University of Texas Health Science Center at San Antonio
Summary:
Inhibiting the SARS-CoV-2-PLpro enzyme is a novel avenue to explore
in rational design of COVID-19 drugs, according to new research.



FULL STORY ========================================================================== 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 immune response.


==========================================================================
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 near Chicago.

"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.


========================================================================== Story Source: Materials provided by University_of_Texas_Health_Science_Center_at_San_Antonio.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Wioletta Rut, Zongyang Lv, Mikolaj Zmudzinski, Stephanie Patchett,
Digant
Nayak, Scott J. Snipas, Farid El Oualid, Tony T. Huang, Miklos
Bekes, Marcin Drag, Shaun K. Olsen. Activity profiling and crystal
structures of inhibitor-bound SARS-CoV-2 papain-like protease:
A framework for anti- COVID-19 drug design. Science Advances,
Oct. 16, 2020; DOI: 10.1126/ sciadv.abd4596 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201016164310.htm

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