Viral Molecular Scissors Could be Next Drug Target for COVID-19

A new study, published in Science Advances, laid out a novel method for COVID-19 drug design—blocking an enzyme called called SARS-CoV-2-PLpro that the virus uses to disable human proteins crucial to the immune response. The research was performed by a collaborative team from the University of Texas Health Science Center at San Antonio and the Wroclaw University of Science and Technology. 

SARS-CoV-2-PLpro promotes infection by sensing and processing both viral and human proteins, said senior author Shaun K. Olsen. "This enzyme executes a double-whammy," Olsen said. "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 cuts human proteins ubiquitin and ISG15, which help maintain protein integrity. "The enzyme acts like a molecular scissor," Olsen added. "It cleaves ubiquitin and ISG15 away from other proteins, which reverses their normal effects."

The team developed three-dimensional structures of SARS-CoV-2-PLpro and the two inhibitor molecules, which are called VIR250 and VIR251. "Our collaborator, 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," 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."

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