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Next COVID-19 Drug Target: Viral “Molecular Scissor”

Disabling Viral Molecular Scissor

The enzyme SARS-CoV-2-PLpro is described in an inset of viral inhibitor interaction. Blocking the effects of the enzyme may prove effective in stopping coronavirus infections. Credit: Courtesy of photo 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 an enzymatic cutter for virus production and to disable essential immune proteins.

American and Polish scientists, reporting on October 16, 2020, in the journal Advances in Science, laid out a novel argument for COVID-19 drug design – blocking a “scissors” used by the virus for making the virus and to disable human proteins that are important in 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. The information obtained by the American 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 sensing and processing 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, studies the enzyme SARS-CoV-2-PL pro and works with Polish chemists who developed enzyme inhibitors. Dr. Olsen is a research professor 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 implements a double whammy,” Drs. Olsen. “It stimulates the release of proteins that are essential for virus replication, and it also inhibits molecules called cytokines and chemokines that signal the immune system to attack infection,” Drs. Olsen.

SARS-CoV-2-PLpro breaks down human proteins ubiquitin and ISG15, which help maintain protein integrity. “The enzyme acts like a molecular scissors,” Drs. Olsen. “It removes ubiquitin and ISG15 away from other proteins, reversing their normal effects.”

Dr.’s team. Olsen, who recently transferred to the UT School San Antonio Long School of Medicine from Medical University of South Carolina, solved the three-dimensional structures of SARS-CoV-2-PLpro and the two molecular inhibitors, called VIR250 and VIR251. X-ray crystallography was performed at the Argonne National Laboratory near Chicago.

Our partner, Dr. Marcin Drag, and his team developed inhibitors, which are very good at blocking SARS-CoV-2-PLpro activity, but do not identify other similar ones. enzyme 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 similar function.”

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

The American team also compared SARS-CoV-2-PLpro against similar enzymes from coronaviruses of the past decades, SARS-CoV-1 and MERS. They found 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 viruses affect humans, if at all,” Drs. Olsen.

By understanding the similarities and differences of these enzymes in different coronaviruses, it may be possible to produce inhibitors that are effective against many viruses, and these inhibitors can be modified when other coronaviruses appear in the future, he said.

Reference: “The activity of profiling and inhibitor-like crystal structures bound to SARS-CoV-2 such as papain protease: A framework for the design of anti-COVID-19 drug” 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, Advances in Science.
DOI: 10.1126 / sciadv.abd4596

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