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Next target for drugs COVID-19: Viral “Molecular Scissors”

Deactivation of viral molecular scissors

The SARS-CoV-2-PLpro enzyme was visualized by interaction with a viral inhibitor. Blocking the effects of the enzyme can be beneficial in stopping coronavirus infections. Credit: Courtesy of Dr. Sean K. Olsen, Laboratory at the University of Texas Health Science Center in San Antonio (Joe R. and Teresa Lozano Long School of Medicine)

The coronavirus uses an enzyme knife to produce viruses and to deactivate essential immune proteins.

American and Polish scientists reporting on October 16, 2020 in the journal Scientific progress, set out a new rationale for COVID-19 drug design – blocking the molecular “scissors” that the virus uses to produce viruses and to deactivate human proteins, which are crucial for the immune response.

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

SARS-CoV-2-PLpro promotes infection by detecting and processing viral and human proteins, said senior author Sean K. Olsen, associate professor, associate professor of biochemistry and structural biology at Joe R. Medical School and Teresa Lozano at UT Health San Antonio.

Sean K. Olsen

Dr. Sean K. Olsen studied the enzyme SARS-CoV-2-PL pro and collaborated with Polish chemists who developed enzyme inhibitors. Dr. Olsen is a professor at the Joe R. and Teresa Lozano School of Medicine at the University of Texas at San Antonio School of Medicine. Credit: UT Health San Antonio

“This enzyme performs a double emphasis,” Dr. Olsen said. “It stimulates the release of proteins that are essential for virus replication, and also inhibits molecules called cytokines and chemokines, which signal the immune system to attack the infection,” Dr. Olsen said.

SARS-CoV-2-PLpro reduces the human proteins ubiquitin and ISG15, which help maintain protein integrity. “The enzyme acts like a molecular scissors,” said Dr. Olsen. “It releases 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 University of South Carolina Medical School, 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 Argon National Laboratory near Chicago.

“Our collaborator, Dr. Marcin Drag, and his team have developed inhibitors that 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 viral enzyme and does not cross-react with human enzymes with similar function.”

Specificity will be a key determinant of therapeutic value along the way, he said.

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

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

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

Reference: “Profiling the Activity and Crystal Structures of the SARS-CoV-2 Papain-Similar Protease Inhibitor: A Framework for the Design of COVID-19 Drugs” 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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