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

The SARS-CoV-2-PLpro enzyme is visualized with an inset of viral inhibitor interactions. Blocking the enzyme’s effect in preventing coronovirus infection may prove fruitful. Credit: Sean Kay. Olsen, PhD, laboratory at the University of Texas Health Sciences Center in San Antonio (Joe R. and Teresa Lozano Long School of Medicine)

Reporting in Journal of American and Polish Scientists, 16 October Science advanceA novel justification has been set for COVID-19 drug design – blocking a molecular “scissor” that the virus uses for virus production and inactivating human proteins important for the immune response.

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

SARS-CoV-2-PLpro promotes infection by sensing and processing both viral and human proteins, senior author Sean Kay. Olsen, PhD, Joe R. And Teresa Lozano is Associate Professor of Biochemistry and Structural Biology of the Long School. Medicine at UT Health San Antonio.

“This enzyme performs a double-whammy,” Dr. Olsen said. “It stimulates the release of proteins that are required to replicate the virus, 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 the human proteins ubiquitin and ISG15, which help maintain protein integrity. “Enzyme acts like molecular scissors,” Dr. Olsen said. “It removes ubiquitin and ISG15 from other proteins, reversing their normal effects.”

Dr. Olson’s team, which recently moved from the Medical University of South Carolina to the Long School of Medicine at UT Health San Antonio, solved the three-dimensional structures of SARS-CoV-2-PLpro and three inhibitory molecules, called Goes VIR250 and VIR251. X-ray crystallography was performed at the Argon National Laboratory near Chicago.

“Our colleague, Dr. Marcin Drag, and his team developed 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 an important point: the inhibitor is specific to this one viral enzyme and does not cross-react with human enzymes for a similar function.”

He stated that specialty would be a major determinant of therapeutic value down the road.

The US team compared SARS-CoV-2-PLpro against similar enzymes from coronavir of recent decades, SARS-CoV-1 and MERS. They found that SARS-CoV-2-PLpro processes ubiquitin and ISG15 very differently from its SARS-1 counterpart.

“One of the main questions is whether we account for some of the differences we see in how those viruses affect humans, if at all.”

They stated that by understanding the similarity and differences of these enzymes in different coronaviers, it may be possible to develop effective inhibitors against many viruses, and potentially modify these inhibitors if other coronovirus variants emerge in the future.

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more information:
Activity modalities and structures of inhibitor-bound SARS-CoV-2-PLpro proteases provide a framework for anti-COVID-19 drug design, Science advance (2020). DOI: 10.1126 / Sciadv.abd4596

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

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