The COVID-19 pandemic has caused more than 600,000 deaths in the United States since the start of 2020 and more than 4 million globally. The search for effective treatments against the disease are ongoing, and one hurdle is that SARS-CoV-2, the virus that causes COVID-19, has a number of tricks up its molecular sleeve when it comes to infecting people.
In a recent study published in Nature Communications Biology, researchers from the U.S. Department of Energy’s (DOE) Argonne National Laboratory and the University of Chicago identified a way to interfere with a sneaky mechanism the virus uses to prevent a response from an infected person’s immune system.
“These structures will almost certainly be used by many other investigators for designing additional antiviral agents.” — Karen Anderson, Yale University
This new weapon against COVID-19 actually comes from the fight against cancer, as scientists have found that tipiracil, a drug used to treat colorectal cancer, can inhibit the action of one of the main proteins that make up SARS-CoV-2.
SARS-Cov-2 is a ribonucleic acid (RNA) virus. RNA is a type of genetic code that can be translated into proteins that allow the virus to replicate. During its RNA duplication, the virus would typically have a distinct chemical genetic signature — a string of molecules, or bases, that appends to one end of SARS-CoV-2’s RNA backbone.
This chemical signature would normally be recognizable by the body and produce an immune response, but the virus has a special way of hiding the extra molecules and sneaking into the body undetected. The research team used the resources of the Advanced Photon Source (APS), a DOE Office of Science User Facility at Argonne, to test a new treatment option that may foil this mechanism.
The research was led by Andrzej Joachimiak of Argonne and the University of Chicago, with Argonne protein crystallographer Youngchang Kim and University of Chicago structural biologist Natalia Maltseva and their colleagues. Joachimiak is the director of the Structural Biology Center (SBC) at the APS, and the research team used the high-powered X-ray beams generated there to study one of the virus’s proteins, called Nsp15.
This protein acts like a molecular scissors, cutting regions of the virus that are involved in its ability to make copies of itself. As more and more of those strings of molecules — made up of uridine, one of the main components of nucleic acid — are produced, the Nsp15 molecule removes them, essentially giving the virus the haircut it needs to pass undetected undercover.
“Not all the functions of these proteins are fully understood yet, but some of them serve to cut the larger poly-protein into smaller functional units. The RNA gives you the blueprint and encoded proteins act as the scissors,” Joachimiak said.
The virus uses strings of uridine to duplicate itself and translate those copies into protein. Those strings of uridine would typically create an immune response, but the Nsp15 cuts it off, allowing the virus to proliferate and infection to spread. The tipiracil inhibits the action of Nsp15 by binding in the place where Nsp15 otherwise would.
In addition to tipiracil, another drug used for an entirely different malady may have applications in treating COVID-19.
Scientists from Yale University have used the APS to study the structure of perampanel, an anti-seizure medication, as a starting point for inhibitor design. Modifying perampanel to create new configurations of the drug gave researchers new molecules that were effective against SARS-CoV-2. These new molecules would be used along with remdesivir, a current therapeutic agent for COVID-19.
The Yale researchers, William Jorgensen and Karen Anderson, used a combination of X-rays and computers to target the main SARS-CoV-2 protease, a key enzyme that plays an important role in COVID-19 infection. Perampanel was one of 14 drugs identified from a virtual screening effort to discover potential inhibitors of SARS-CoV-2, from an initial survey of about 2,000 known drugs. The research team found these new analogs of perampanel to be effective against the main protease, especially when combined with remdesivir.
The results of their research were published by the American Chemical Society.
“These structures will almost certainly be used by many other investigators for designing additional antiviral agents,” said Karen Anderson, a professor of pharmacology and molecular biophysics and biochemistry at Yale, and co-director of developmental therapeutics for the Yale Cancer Center and William Jorgensen, Sterling Professor of Chemistry in the Chemistry department at Yale.
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.