Better understanding of viral protein could lead to more effective COVID drug treatments with fewer side effects

Mark Paetzel, a molecular biologist at Simon Fraser University, Natalie Strynadka, a structural biologist at the University of British Columbia and colleagues Jaeyong Lee, Calem Kenward and Liam Worrall used the incredibly bright light of the Canadian Light Source at the University of Saskatchewan to study the structure and characteristics of one important viral protein that makes a tempting target for antiviral drugs.

Like many RNA viruses, SARS-CoV-2 synthesizes most of its non-structural proteins as one long chain, called a polyprotein, which it cleaves -- or splits up -- into individual units afterwards. “It’s a strategy to keep the viral genome small and concise, as well as providing a way to adjust the time and place for viral replication and assembly,” says Paetzel.

Paetzel and the team focused on the central enzyme that does that splitting, called the Main Protease (M^pro), and looked at how it interacts with the cut sites of each of the other proteins to cut them loose from the polyprotein.

The powerful X-rays of the CMCF-BM beamline at CLS were vital for this, because the team had to screen more than 500 protein crystals to find the ones they were looking for. “It was critical to have the CLS resources,” says Paetzel. “The resolution achieved by the intense X-rays produced, and the speed of data collection, allowed us to more efficiently analyze the many crystals needed to capture these complexes.”

They found that M^pro is remarkably adaptable; the pocket where it binds the target proteins can open and close like a catcher’s mitt to accommodate the wide variety of differently shaped proteins it has to bind with and cut. “There are multiple ways for molecules to bind in that pocket,” says Paetzel.

That’s an interesting discovery because M^pro is an important target for antiviral drugs. Blocking M^pro disables the virus’s ability to replicate. Learning more about how the protease binds to its targets will help drug developers design new treatments that can take advantage of the protein’s flexibility, potentially making them more effective at fighting the virus with fewer side effects and with potentially less downstream effects of drug resistance induced by future mutations of the virus.

“If we can see all the different ways to bind it, we can adjust our drugs to mimic them,” says Paetzel.

Lee, Jaeyong, Calem Kenward, Liam J. Worrall, Marija Vuckovic, Francesco Gentile, Anh-Tien Ton, Myles Ng, Artem Cherkasov, Natalie CJ Strynadka, and Mark Paetzel. "X-ray crystallographic characterization of the SARS-CoV-2 main protease polyprotein cleavage sites essential for viral processing and maturation." Nature communications 13, no. 1 (2022): 1-13. https://doi.org/10.1038/s41467-022-32854-4

Photos: Synchrotron | CMCF Beamline | Mark Paetzel / Research Team

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