Computer-designed small proteins have now been shown to protect laboratory-grown human cells from SARS-CoV-2, the coronavirus that causes COVID-19.
The findings are reported today, September 9 Science.
In experiments, the main antiviral candidate, named LCB1, antagonized the neutralizing antibody to SARS-CoV-2, most well-known in its protective functions. LCB1 is currently being evaluated in rodents.
Coronaviruses are herbivorous with so-called spike proteins. They latch onto human cells to break down viruses and enable them to infect. The development of drugs that interfere with this insertion mechanism may lead to the treatment or even prevention of infection.
The Institute for Protein Design Researchers at the University of Washington University of Medicine used computers to generate new proteins that tightly bind the SARS-CoV-2 spike protein and disrupt it from infected cells.
In early January, more than two million candidate spike-binding proteins were designed on computers. More than 11,000,000 were produced and tested in the laboratory.
“Although extensive clinical trials are still needed, we believe that most of these computer-borne antivirals are quite promising,” said Leading Locksing Cao, a postdoctoral scholar at the Institute for Protein Design.
He stated, “They appear to minimize SARS-CoV-2 infection as well as block monoclonal antibodies, but are much easier to produce and far more stable, possibly eliminating the need for refrigeration. ,” They said.
Researchers created antiviral proteins in two ways. First, a segment of the ACE2 receptor, which SARS-CoV-2 naturally binds to the surface of human cells, was incorporated into a series of small protein scaffolds.
Second, the fully synthetic protein was designed from scratch. The latter method produced the most potent antivirals, including LCB1, which is about six times more potent on a per-mass basis than the most effective monoclonal antibodies reported so far.
Scientists at Washington University School of Medicine in Seattle and Washington University School of Medicine in St. Louis collaborated in this work.
Senior author and Howard Hughes Medical Institute Investigator David Baker, professor at UW School of Medicine, investigator David Baker of Howard Hughes Medical Institute said, “Our success in designing high-affinity antiviral proteins from scratch is evidence that computational Protein design can be used. ” And head of the Institute for Protein Design. In 2019, Baker gave a TED talk on how protein design can be used to prevent viruses.
To confirm that new antiviral proteins associated with coronavirus spike proteins, the team collected snapshots of the two molecules interacting using cryo-electron microscopy. These experiments were conducted by researchers in the laboratories of David Wessler, assistant professor of biochemistry at the UW School of Medicine, and Michael S. Diamond, Herbert S. Geser Professor in the Division of Infectious Diseases at Washington University School of Medicine in St. Louis.
The antiviral research team wrote in their study pre-print, “Hypertable minibinders provide promising starting points for new SARS-COV-2 therapies,” and computational to rapidly generate potential therapeutic candidates against pandemic hazards Proteins describe the power of design. ”
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Longing Cao et al, “De novo design of Pecomolar SARS-COV-2 miniprotein inhibitors”. Science 09 September 2020: eabd9909 DOI: 10.1126 / science .abd9909
Provided by University of Washington
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