The currently available COVID-19 vaccines provide hope that the spread of the disease can be stopped. But infection rates remain high, and for those infected with COVID-19, the search for effective treatments remains important.
Researchers investigating the atomic structure of SARS-CoV-2, the virus that causes COVID-19, have made significant discoveries that could contribute critical information in the design of safe and effective antiviral drugs to fight the virus.
Understanding enzymes goes hand in hand with understanding their atomic structures -; and the higher the resolution the better, because subtle differences can affect interpretation. We wanted the best possible data, so we went to the APS. “
Natalie Strynadka, University of British Columbia
Using a powerful X-ray to study the SARS-CoV-2 protein in crystallized form, a team from the University of British Columbia (UBC) observed -; first time ever -; the main protease of the virus, an important virus enzyme, which performs its function.
This widely persecuted antiviral target is a central enzyme that allows the virus to break down large proteins called polyproteins into smaller functional units, a process necessary for the virus to replicate and infect other human cells.
“What we captured in high resolution is one of the important steps in this process that has never been visualized before in any viral protease of this class,” said Natalie Strynadka, a UBC professor of biochemistry who led the research team with colleague Mark Paetzel.
The research was published in Nature.
The breakthrough was made possible by Advanced Photon Source (APS), the U.S. Department of Energy (DOE), the Office of Science, and Customer Service at DOE’s National Argonne Laboratory. APS produces X-rays that are approximately a billion times brighter than those used by doctors and dentists, allowing researchers to examine in detail the structure of the coronavirus protease at the atomic level.
The data were collected at the Department of Structural Biology of General Medical Sciences and the Cancer Institute on the 23-ID-B line at the APS.
The newly discovered information may be of particular interest to scientists around the world who are racing to develop antiviral treatments for COVID-19. If the major protease is inhibited by a small-molecule drug, the polyproteins will not be cleaved into functional parts, effectively blocking virus replication and subsequent transmission.
“We now have a much better blueprint of these mechanistic structures that will provide information on creating the best possible inhibitor,” Strynadka said. “Better knowledge of the structure as we are now helping to direct drug research, narrowing the field of potential targets, instead of having to check billions of potential molecules.”
Michael Becker, a protein crystallographer from Argonne’s Department of X-Ray Sciences, said Strynadka’s research stands out because the team focused on understanding the mechanism of protease.
“This understanding will improve the work of everyone else in drug design,” Becker said. “Because the deeper you understand how something works, the better chance you have of controlling or stopping it.”
Argonne’s remote access capabilities have enabled researchers from British Columbia to collect real-time data and manipulate an APS beam located about 2,200 miles away in Illinois. UBC team members Jaeyong Lee and Liam Worrall delivered SARS-CoV-2 major protease crystals stored in liquid nitrogen from Canada to Argonne.
APS workers were available to answer questions, ensure equipment correctness, and submit samples.
“The remote interface is fantastic. It’s almost like you’re there,” Strynadka said. “We are very grateful for the use of APS. Canada has a national synchrotron plant, but currently does not have the same capabilities as APS, which is a very high-level facility with micro-focused rays. Understanding enzymes goes hand in hand with understanding their atomic structures – and what the higher the resolution the better because subtle differences can affect interpretation. We wanted the best possible data, so we went to APS. “
Argonne National Laboratory
Lee, J., and others. (2020) Crystallographic structure of the major wild-type SARS-CoV-2 intermediate of the wild-type acyl-enzyme protease with a physiological site of self-processing at the C-terminal. Nature. doi.org/10.1038/s41467-020-19662-4.