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Next COVID-19 drug target: Viral “Molecular Scissor”

Deactivation of viral molecular scissors

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: Image courtesy of 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)

Coronavirus uses enzymatic cutter for virus production and to inactivate essential immune proteins.

American and Polish researchers reporting October 16, 2020 in the journal Scientific progress, laid a new justification for COVID-19 drug design – blocking a molecular “scissors” that the virus uses to produce viruses and to inactivate 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 collected 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, PhD, associate professor of biochemistry and structural biology at Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio.

Shaun K. Olsen

Shaun K. Olsen, PhD, is studying the enzyme SARS-CoV-2-PL pro and is collaborating with Polish chemists who have developed inhibitors of the enzyme. Dr. Olsen is a faculty researcher at Joe R. and Teresa Lozano Long School of Medicine at the University of Texas Health Science Center in San Antonio. Credit: 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.

Reference: “Activity Profiling and Crystal Structures of Inhibitor-Bound SARS-CoV-2 Papain-Like Protease: A Framework for Anti-COVID-19 Drug Design” by Wioletta Rut, Zongyang Lv, Mikolaj Zmudzinski, Stephanie Patchett, Digant Nayak, Scott J. Snipas, Farid El Oualid, Tony T. Huang, Miklos Bekes, Marcin Drag and Shaun K. Olsen, 16 October 2020, Scientific progress.
DOI: 10.1126 / sciadv.abd4596

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