The COVID-19 vaccines currently rolling out are providing hope that the spread of the disease can be halted. But infection rates are still high, and for those who contract COVID-19, the search for effective treatments remains important.
Researchers examining the atomic structure of SARS-CoV-2, the virus that causes COVID-19, have made a landmark discovery that could contribute critical information to the design of safe and effective antiviral drugs in the fight against the virus.
“Understanding enzymes goes hand in hand with understanding their atomic structures — and the higher resolution the better, because subtle differences can affect the interpretation. We wanted the best data possible, so we went to the APS.” — Natalie Strynadka, University of British Columbia
Using a powerful X-ray beam to study SARS-CoV-2 proteins in crystallized form, a team from the University of British Columbia (UBC) has observed — for the first time ever — the virus’s main protease, an important enzyme of the virus, performing its function.
This widely pursued antiviral target is a central enzyme that allows the virus to cut up large proteins called polyproteins into smaller functional units, a process necessary for the virus to be replicated and infect other human cells.
“What we’ve captured at high resolution is one of the important steps in that process that has never been visualized before in any viral protease of this class,” said Natalie Strynadka, the UBC biochemistry professor who led the research team with colleague Mark Paetzel.
The research was published in Nature.
The breakthrough was made possible by the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science User Facility at DOE’s Argonne National Laboratory. The APS produces X-rays that are roughly a billion times brighter than those used by doctors and dentists, allowing researchers to examine the structure of the coronavirus protease in very fine detail at the atomic level.
Data was captured at the General Medical Sciences and Cancer Institutes Structural Biology Facility at beamline 23-ID-B at the APS.
The newly uncovered information may be of particular interest to scientists worldwide who are racing to develop antiviral treatments for COVID-19. If the main protease is inhibited by a small molecule drug, the polyproteins won’t be clipped into functional pieces, effectively blocking viral replication and subsequent transmission.
“We now have a much better blueprint of these mechanistic structures that will inform making the best inhibitor possible,” Strynadka said. “Better knowing the structure as we now do helps guide drug research, narrowing the field of potential targets instead of having to screen billions of potential molecules.”
Michael Becker, a protein crystallographer with Argonne’s X-ray Science Division, said Strynadka’s research stands out because the team was focused on understanding the mechanism of the protease.
“This understanding will improve everyone else’s work in designing drugs,” Becker said. “Because the more deeply you understand how something works, the better the chance you have of controlling or stopping it.”
Remote access capabilities at Argonne made it possible for the researchers in British Columbia to collect data in real time and to manipulate the APS beamline located about 2,200 miles away in Illinois. UBC team members Jaeyong Lee and Liam Worrall shipped crystals of the SARS-CoV-2 main protease preserved in liquid nitrogen from Canada to Argonne. Workers at the APS were on hand to answer questions, ensure the working order of the equipment, and load the samples.
“The remote interface is fantastic. It’s almost like being there,” Strynadka said. “We’re very thankful for the use of the APS. Canada does have a national synchrotron facility, but it currently doesn’t have the same capability as the APS, which is a very high-level facility with micro-focused beams. Understanding enzymes goes hand in hand with understanding their atomic structures — and the higher resolution the better, because subtle differences can affect the interpretation. We wanted the best data possible, so we went to the APS.”
The Advanced Photon Source is a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory. Additional funding for beamlines used for COVID-19 research at the APS is provided by the National Institutes of Health (NIH) and by DOE Office of Science Biological and Environmental Research. Supplemental support for COVID-19 research was provided by the DOE Office of Science through the National Virtual Biotechnology Laboratory, a consortium of DOE national laboratories focused on response to COVID-19 with funding provided by the Coronavirus CARES Act.
About the Advanced Photon Source
The U. S. Department of Energy Office of Science’s Advanced Photon Source (APS) at Argonne National Laboratory is one of the world’s most productive X-ray light source facilities. The APS provides high-brightness X-ray beams to a diverse community of researchers in materials science, chemistry, condensed matter physics, the life and environmental sciences, and applied research. These X-rays are ideally suited for explorations of materials and biological structures; elemental distribution; chemical, magnetic, electronic states; and a wide range of technologically important engineering systems from batteries to fuel injector sprays, all of which are the foundations of our nation’s economic, technological, and physical well-being. Each year, more than 5,000 researchers use the APS to produce over 2,000 publications detailing impactful discoveries, and solve more vital biological protein structures than users of any other X-ray light source research facility. APS scientists and engineers innovate technology that is at the heart of advancing accelerator and light-source operations. This includes the insertion devices that produce extreme-brightness X-rays prized by researchers, lenses that focus the X-rays down to a few nanometers, instrumentation that maximizes the way the X-rays interact with samples being studied, and software that gathers and manages the massive quantity of data resulting from discovery research at the APS.
This research used resources of the Advanced Photon Source, a U.S. DOE Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02–06CH11357.
Argonne National Laboratory seeks solutions to pressing national problems in science and technology. The nation’s first national laboratory, Argonne conducts leading-edge basic and applied scientific research in virtually every scientific discipline. Argonne researchers work closely with researchers from hundreds of companies, universities, and federal, state and municipal agencies to help them solve their specific problems, advance America’s scientific leadership and prepare the nation for a better future. With employees from more than 60 nations, Argonne is managed by UChicago Argonne, LLC for the U.S. Department of Energy’s Office of Science.
The U.S. Department of Energy’s Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time. For more information, visit https://energy.gov/science.
