Imagine being able to ward off COVID-19 just by spritzing a nasal spray into your nostrils. It may not be just your imagination: Researchers at the University of Washington have designed a batch of synthetic proteins that could conceivably block the coronavirus behind this year’s pandemic from gaining a foothold.
“Although extensive clinical testing is still needed, we believe the best of these computer-generated antivirals are quite promising,” Longxing Cao, a postdoctoral scholar at UW’s Institute for Protein Design, said in a news release.
Cao is the lead author of a study about the protein-building experiment, published today by the journal Science. It’s the latest innovation to come from the emerging field of protein engineering, and the technique could revolutionize how drugs are developed to counter future pandemics.
It may not be too late to counter COVID-19 as well. “We are working to get improved versions … deployed to fight the current pandemic,” senior study author David Baker, the director of the Institute for Protein Design, told GeekWire in an email.
The technique involves creating small-molecule proteins, or mini-binders, that are custom-designed to latch onto the spiky molecular structures that are scattered around the surface of SARS-CoV-2, the virus that causes COVID-19.
The spikes on the virus do their dirty work by fitting into molecular-scale receptors on the surfaces of cells, much like fitting a key into a lock to gain entry to someone’s house. Once the virus “unlocks” a receptor, it gains entry to the cell, hijacks its chemical machinery and churns out more virus particles to spread the infection.
Baker, Cao and their colleagues used high-powered computers to design more than 2 million candidate proteins that could conceivably gum up the works for the virus’ spike protein. More than 118,000 of the most promising candidates were synthesized and tested on lab-grown cells.
Agilent Technologies and Twist Bioscience manufactured the synthetic proteins for testing, and researchers at the Washington University School of Medicine in St. Louis used cryo-electron microscopy to document how the mini-binders interacted with the spike proteins. A distributed-computing network called Rosetta@home helped screen the candidates.
The best candidate, known as LCB1, blocked the effectiveness of the spike protein with six times the potency of monoclonal antibodies, which offer an alternate route for preventing infection. What’s more, Cao said the mini-binders are “much easier to produce and far more stable, potentially eliminating the need for refrigeration.”
The researchers say their mini-binders seem well-suited for a powdery aerosol or spray that could be delivered into the respiratory system through the nose. “There is not much precedent in protein antivirals that would be delivered directly into the respiratory system — this is the sweet spot for our designs, we believe,” Baker said.
Now LCB1 is being evaluated in rodents, and Baker said there’s interest in taking a candidate COVID-19 antiviral drug into human clinical trials. “We’re currently exploring that,” he said, without providing further details.
Once the technique is perfected and automated, protein antivirals could be designed and produced for testing with the first month of a viral outbreak, Baker said. The technique also could be adapted to create new types of diagnostics for viral infections.
In addition to Cao and Baker, authors of the paper published by Science, “De Novo Design of Picomolar SARS-CoV-2 Miniprotein Inhibitors,” include Inna Goreshnik, Brian Coventry, James Brett Case, Lauren Miller, Lisa Kozodoy, Rita Chen, Lauren Carter, Lexi Walls, Young-Jun Park, Lance Stewart, Michael Diamond and David Veesler.
The work was supported by the National Institutes of Health, the Defense Advanced Research Projects Agency, The Audacious Project at IPD, Eric and Wendy Schmidt by recommendation of the Schmidt Futures program, the Open Philanthropy Project, an Azure computing resource gift for COVID-19 research provided by Microsoft, and the Burroughs Wellcome Fund.
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