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Viral ‘molecular scissors’ are the next COVID-19 drug target

Viral 'molecular scissors' are the next COVID-19 drug target

The SARS-CoV-2-PLpro enzyme is visualized with an insert of viral inhibitor interaction. Blocking the effects of the enzyme may prove fruitful in stopping coronavirus infections. Credit: Shaun K. Olsen, PhD, Laboratory at the University of Texas Health Science Center in San Antonio (Joe R. and Teresa Lozano Long School of Medicine)

American and Polish researchers reporting October 1

6 in the journal Scientific progress, laid a new rationale for COVID-19 drug design – blocking a molecular “scissors” that the virus uses for virus production and for inactivating human proteins that are essential for the immune response.

The researchers are from the University of Texas Health Science Center in San Antonio (UT Health San Antonio) and Wroclaw University of Science and Technology. Information gathered by the US team helped Polish chemists develop two molecules that inhibit the cutter, an enzyme called SARS-CoV-2-PLpro.

SARS-CoV-2-PLpro promotes infection by detecting and treating both viral and human proteins, said senior author Shaun K. Olsen, Ph.D., associate professor of biochemistry and structural biology at Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio.

“This enzyme performs a double-whammy,” said Dr. Olsen. “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,” said Dr. Olsen.

SARS-CoV-2-PLpro cuts human proteins ubiquitin and ISG15, which help maintain protein integrity. “The enzyme acts as a molecular scissors,” said Dr. Olsen. “It cleaves ubiquitin and ISG15 away from other proteins, reversing their normal effect.”

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 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 effective in blocking the activity of SARS-CoV-2-PLpro, but do not recognize other similar enzymes in human cells,” said Dr. Olsen. “This is a critical point: the inhibitor is specific for this one viral enzyme and does not cross-react with human enzymes with a similar function.”

Specificity will be a key determinant of therapeutic value on the road, he said.

The US team also compared SARS-CoV-2-PLpro against similar coronavirus enzymes in recent decades, SARS-CoV-1 and MERS. They learned that SARS-CoV-2-PLpro treats ubiquitin and ISG15 very differently from its SARS-1 counterpart.

“One of the key questions is whether it accounts for some of the differences we see in how these viruses affect humans, if at all,” said Dr. Olsen.

By understanding the similarities and differences between these enzymes in different coronaviruses, it may be possible to develop inhibitors that are effective against multiple viruses, and these inhibitors can potentially be modified when other coronavirus variants occur in the future, he said.

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More information:
Activity profiling and structures of inhibitor-bound SARS-CoV-2-PLpro protease provide a framework for anti-COVID-19 drug design, Scientific progress (2020). DOI: 10.1126 / sciadv.abd4596

Provided by the University of Texas Health Science Center in San Antonio

Citation: Viral ‘molecular scissors’ is the next COVID-19 drug target (2020, October 16) retrieved October 17, 2020 from https://medicalxpress.com/news/2020-10-viral-molecular-scissor-covid-drug. html

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