Biochemists have created the first 3-D, atomic-scale map of key proteins in the killer coronavirus, opening up new possibilities for developing treatments and a vaccine.
Researchers at the University of Washington and its Institute for Protein Design are among the sleuths who’ll be taking advantage of the new clues.
The map shows the 3-D arrangement of proteins in the molecular “spike” that the virus known as COVID-19 uses to force its way into the cells that it infects. Once the virus gains entry, it delivers genetic code that takes control of the cells to spread the infection.
Finding ways to stop the infection is a high-stake pursuit. Since the virus came to light in the Chinese city of Wuhan late last year, there have been more than 75,000 COVID-19 cases in 26 countries, resulting in more than 2,000 deaths.
“Coronavirus” refers to a class of viruses, including the common cold, that have a crown-shaped spike of proteins on top. (“Corona” is the Latin word for crown.) The symptoms associated with COVID-19 include fever, coughing and shortness of breath, on a level much more serious than that seen in cold sufferers.
Governments around the world have been using quarantines to reduce the spread of the virus, and health officials are using the best virus-fighting treatments they have on hand. But longer-term, researchers are racing to develop vaccines and other types of antiviral treatments that are specific to COVID-19. That’s where the 3-D map, published today by the journal Science, comes into play.
UW’s Institute for Protein Design has been at the forefront of protein engineering to fight disease. The institute’s technique looks at the 3-D structure of proteins, and then creates molecular “locks” and “keys” that fit onto those proteins — either to facilitate a molecular interaction or gum up the works and head off an interaction.
For COVID-19, the institute is looking for ways to gum up the works.
Researchers at the institute has already reported some success in developing a “Flu Glue” that binds itself to a protein on the outer coat of an influenza virus known as hemagglutinin or influenza HA. The newly released map could help them create similar mini-proteins for COVID-19.
Institute director David Baker said the authors of the Science study have already emailed him the coordinates for the COVID-19 map.
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“We are using them to design stable mini-protein binders to different sites on the spike protein, in collaboration with David Veesler here who is providing the protein and expertise,” Baker told GeekWire in an email. “By analogy with the mini-proteins we’ve designed against influenza HA, we expect (hope) high-affinity designs to neutralize the virus.”
If the binders work the way they do with the flu virus, they could be part of an effective virus-blocking treatment, or serve as the basis for new diagnostic tools.
Veesler and his teammates at UW are also among many researchers around the world who are working to develop a COVID-19 vaccine.
The vaccine hunters also include the researchers at the University of Texas at Austin and the National Institutes of Health who came up with the 3-D protein map for COVID-19. They drew upon their previous experience in locking down and mapping spike proteins for other coronaviruses, such as SARS and MERS.
“As soon as we knew this was a coronavirus, we felt we had to jump at it, because we could be one of the first ones to get this structure,” UT-Austin’s Jason McLellan, the senior author of the Science study, said in a news release. “We knew exactly what mutations to put into this, because we’ve already shown these mutations work for a bunch of other coronaviruses.”
The bulk of the research was done by the study’s principal authors, Daniel Wrapp and Nianshuang Wang of UT-Austin. Just two weeks after receiving the genome sequence of the virus from Chinese researchers, the team designed and produced samples of their stabilized spike protein. It took another 12 days to reconstruct the 3-D protein map and send the research to Science.
One of the key technologies behind the effort is cryogenic electron microscopy, or cryo-EM, which makes it possible to produce 3-D models of cellular structures, molecules and viruses. UT-Austin has a state-of-the-art cryo-EM facility at its Sauer Structural Biology Laboratory.
“We ended up being the first ones in part due to the infrastructure at the Sauer Lab,” McLellan said. “It highlights the importance of funding basic research facilities.”
In addition to facilitating the development of vaccines and synthetic antiviral mini-proteins, the 3-D map could help researchers come up with ways to isolate naturally occurring antibodies from COVID-19 patients who survive the disease. Like the mini-proteins, those antibodies could be used to treat an infection soon after exposure.
Authors of the study published by Science, “Cryo-EM Structure of the 2019-nCoV Spike in the Prefusion Conformation,” include Wrapp, Wang and McLellan as well as Kizzmekia Corbett, Jory Goldsmith, Ching-Lin Hsieh, Olubukola Abiona and Barney Graham.