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A team of American and Polish scientists have detailed a new approach to block an enzyme used by the novel coronavirus to disable the human immune system and replicate.
The novel coronavirus uses the enzymic cutter for virus production and to disable human proteins crucial to the immune response.
Researchers from the University of Texas Health Science Center at San Antonio (UT Health San Antonio) and the Wroclaw University of Science and Technology have laid out an approach to block this molecular "scissor" used by the novel coronavirus.
Methodology
They have developed two molecules that inhibit the cutter, an enzyme called SARS-CoV-2-PLpro. SARS-CoV-2-PLpro promotes infection, as per the report.
"This enzyme executes a double-whammy," said senior author Shaun K. Olsen, PhD, associate professor of biochemistry and structural biology. "It stimulates the release of proteins that are essential for the virus to replicate, and it also inhibits molecules called cytokines and chemokines that signal the immune system to attack the infection.”
The enzyme blocks human proteins ubiquitin and ISG15, which help maintain protein integrity.
"The enzyme acts like a molecular scissor," Dr Olsen explained. "It cleaves ubiquitin and ISG15 away from other proteins, which reverses their normal effects."
The researchers solved the three-dimensional structures of SARS-CoV-2-PLpro and the two inhibitor molecules, dubbed VIR250 and VIR251.
This was done with the help of X-ray crystallography.
"Our collaborator, Dr Marcin Drag, and his team developed the 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 a critical point: The inhibitor is specific for this one viral enzyme and doesn't cross-react with human enzymes with a similar function."
The team of American researchers also compared SARS-CoV-2-PLpro against similar enzymes from coronaviruses infections noted in recent decades, SARS-CoV-1 and MERS.
Conclusion
The comparison concluded that SARS-CoV-2-PLpro processes ubiquitin and ISG15 in a much manner than its SARS-1 counterpart.
"One of the key questions is whether that accounts for some of the differences we see in how those viruses affect humans, if at all," Dr Olsen said.
It may be possible to develop inhibitors that can work for multiple viruses by better understanding similarities and differences of these enzymes in various coronaviruses. The research can help determining a Covid-19 drug design and improve therapeutic value of these drugs down the road, as per the researchers.
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