A Viral ‘Molecular Scissor’ Identified As The Next Potential COVID-19 Drug Target

Viral Molecular Scissor for COVID-19

Potential Covid-19 Drug Target

For COVID-19 drug design, a new approach for inhibiting a molecular “scissor” used by the virus to incapacitate human proteins essential to the immune response and for virus production was provided by American (the University of Texas Health Science Center) and Polish (the Wroclaw University of Science and Technology) researchers, in their research reported in the Science Advances journal. Two molecules that inhibit an enzyme called SARS-CoV-2-PLpro, was developed by the Polish chemists with the help of the information obtained by the American team.

From the UT Health San Antonio’s Joe R. and Teresa Lozano Long School of Medicine, associate professor of biochemistry and structural biology, Shaun K. Olsen, Ph.D., the study’s senior author said that the infection is promoted by the SARS-CoV-2-PLpro by sensing and processing both viral and human proteins. Dr. Olsen said that this enzyme inhibits the molecules that signal the immune system to attack the infection, the cytokines, and chemokines molecules, along with stimulating the release of proteins that are essential for the replication of the virus.

As the enzyme cleaves the proteins in humans namely, ubiquitin and ISG15 away from other proteins, which aids in maintaining protein integrity and reversing their normal effects, the enzyme acts as a molecular scissor, added Dr. Olsen.

The two inhibitor molecules’ (VIR251 and VIR250), and the SARS-CoV-2-PLpro’s three-dimensional structures were solved by Dr. Olsen’s team and they performed X-ray crystallography.

Dr. Olsen said, “Inhibitors that are greatly effective at blocking the activity of SARS-CoV-2-PLpro and does not recognize other similar enzymes in human cells, were developed by Dr. Marcin Drag, our collaborator, and his team. The inhibitor does not cross-react with human enzymes with a similar function and is specific for this particular viral enzyme, this is an important point to be noted. A crucial factor for determining therapeutic value would be specificity.”

When the American team compared SARS-CoV-2-PLpro against similar enzymes from other coronaviruses, such as MERS and SARS-CoV-1, it was found that compared to its SARS-1 counterpart, ubiquitin and ISG15 is processed by the SARS-CoV-2-PLpro much differently.

Dr. Olsen said, “Finding out if that accounts for a few of the differences seen in how humans are affected by those viruses is one of the key questions.”

He added saying that developing inhibitors that are efficacious against multiple viruses could be possible by understanding the differences and similarities of these enzymes in various coronaviruses. In the future, when other coronaviruses variants emerge, these inhibitors could be potentially modified and used.

Source
Viral Molecular Scissor for COVID-19

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