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

The SARS-CoV-2-PLpro enzyme is visualized with an inset of viral inhibitor interaction. Blocking the enzymes results may show rewarding in stopping coronavirus infections. Credit: Image courtesy Shaun K. Olsen, PhD, lab at The University of Texas Health Science Center at San Antonio (Joe R. and Teresa Lozano Long School of Medicine).
Coronavirus uses enzymatic cutter for virus production and to disable essential immune proteins.
Polish and american scientists, reporting October 16, 2020, in the journal Science Advances, set out a novel rationale for COVID-19 drug design– obstructing a molecular “scissor” that the virus uses for virus production and to disable human proteins crucial to the immune response.
The scientists are from The University of Texas Health Science Center at San Antonio (UT Health San Antonio) and the Wroclaw University of Science and Technology. Details gleaned by the American group assisted Polish chemists to develop 2 particles that inhibit the cutter, an enzyme called SARS-CoV-2-PLpro.
SARS-CoV-2-PLpro promotes infection by processing and noticing both human and viral proteins, stated senior author Shaun K. Olsen, PhD, associate professor of biochemistry and structural biology in the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio.
Shaun K. Olsen, PhD, studies the enzyme SARS-CoV-2-PL pro and is working together with Polish chemists who have established inhibitors of the enzyme. Dr. Olsen is a professors scientist in the Joe R. and Teresa Lozano Long School of Medicine at The University of Texas Health Science Center at San Antonio. Credit: UT Health San Antonio.
” This enzyme executes a double-whammy,” Dr. Olsen said. “It promotes the release of proteins that are necessary for the virus to duplicate, and it likewise hinders molecules called cytokines and chemokines that signify the body immune system to attack the infection,” Dr. Olsen stated.
SARS-CoV-2-PLpro cuts human proteins ubiquitin and ISG15, which assist keep protein stability. “The enzyme acts like a molecular scissor,” Dr. Olsen said. “It cleaves ubiquitin and ISG15 away from other proteins, which reverses their normal results.”.
Dr. Olsens team, which recently relocated to the Long School of Medicine at UT Health San Antonio from the Medical University of South Carolina, fixed the three-dimensional structures of SARS-CoV-2-PLpro and the two inhibitor molecules, which are called VIR250 and VIR251. X-ray crystallography was carried out at the Argonne National Laboratory near Chicago.
” Our collaborator, Dr. Marcin Drag, and his team established the inhibitors, which are extremely efficient at blocking the activity of SARS-CoV-2-PLpro, yet do not recognize other similar enzymes in human cells,” Dr. Olsen stated. “This is a crucial point: The inhibitor is particular for this one viral enzyme and doesnt cross-react with human enzymes with a comparable function.”.
Specificity will be a crucial factor of restorative worth down the roadway, he said.
The American group also compared SARS-CoV-2-PLpro versus similar enzymes from coronaviruses of recent years, SARS-CoV-1 and MERS. They found out that SARS-CoV-2-PLpro processes ubiquitin and ISG15 much in a different way than its SARS-1 counterpart.
” One of the crucial concerns is whether that accounts for some of the differences we see in how those viruses impact human beings, if at all,” Dr. Olsen said.
By understanding resemblances and differences of these enzymes in numerous coronaviruses, it may be possible to establish inhibitors that are efficient against several viruses, and these inhibitors possibly could be modified when other coronavirus versions emerge in the future, he said.
Recommendation: “Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: A structure for anti– COVID-19 drug style” 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, Science Advances.DOI: 10.1126/ sciadv.abd4596.

The SARS-CoV-2-PLpro enzyme is visualized with an inset of viral inhibitor interaction. Blocking the enzymes impacts may show worthwhile in stopping coronavirus infections. Shaun K. Olsen, PhD, studies the enzyme SARS-CoV-2-PL pro and is collaborating with Polish chemists who have established inhibitors of the enzyme. “The enzyme acts like a molecular scissor,” Dr. Olsen said.

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