Researchers, including those at the University of Texas Health Science Center at San Antonio (UT Health San Antonio) in the United States, developed two molecules that inhibit the “scissors” molecular enzyme used by the coronavirus SARS-CoV-2-PLpro.
According to the study published in the journal Science, SARS-CoV-2-PLpro promotes infection by recognizing and processing both viral and human proteins. “This enzyme does a double punch,” said lead study author Shaun K Olsen, associate professor of biochemistry and structural biology at UT Health San Antonio.
“It stimulates the release of proteins that are essential for the virus to replicate, and it also blocks molecules called cytokines and chemokines that signal the immune system to attack the infection,” said Olsen.
SARS-CoV-2-PLpro cuts the human proteins ubiquitin and ISG15, which help maintain protein integrity by acting as molecular scissors, he explained. The scientists developed inhibitors that block the activity of SARS-CoV-2-PLpro very effectively, but fail to recognize other similar proteins in human cells.
“This is a critical point: the inhibitor is specific to that one viral enzyme and does not react with human enzymes with a similar function,” he added. The researchers said this specificity was a key factor in the therapeutic value of the approach.
When the scientists compared SARS-CoV-2-PLpro with similar enzymes from coronaviruses of the past few decades, such as the SARS pandemic virus 2002-03, they found that ubiquitin and ISG15 are processed much differently than its counterpart. “One of the key questions is whether this is responsible for some of the differences we see, if any, in how these viruses affect humans,” said Olsen.
By understanding the similarities and differences of these enzymes in different coronaviruses, the researchers said it might be possible to develop inhibitors that are effective against multiple viruses. Olsen said these inhibitors could potentially be modified if other coronavirus variants emerge in the future.
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