Computer-designed Antiviral Proteins Inhibit SARS-CoV-2 in The Lab
Scientists have now shown computer-designed small proteins protecting lab-grown human cells from the COVID-19 causing coronavirus, the SARS-CoV-2 virus. The findings are reported in Science.
The lead antiviral candidate in the experiments, named LCB1, rivaled the best-known SARS-CoV-2 neutralizing antibodies in its protective actions. In rodents, LCB1 is being evaluated currently.
The so-called Spike proteins are studded onto the coronaviruses and these enable the virus to break in human cells and infect them as these latch onto human cells. Treatment or even prevention of infection could be achieved by the development of drugs that can interfere with this entry mechanism.
At the University of Washington School of Medicine, researchers from the Institute for Protein Design used computers to originate new proteins that obstruct SARS-CoV-2 Spike protein from infecting the cells by binding tightly to it.
More than two million candidate Spike-binding proteins were designed on the computer beginning in January. Then, over 118,000 produced and tested in the lab.
A postdoctoral scholar at the Institute for Protein Design, lead author Longxing Cao said, “We believe the best of these computer-generated antivirals are quite promising, although extensive clinical testing is still needed.”
He added
, “These antivirals appear to block SARS-CoV-2 infection at least as well as monoclonal antibodies, but are far more stable, potentially eliminating the need for refrigeration, and much easier to produce.”Two approaches were used by the researchers to create antiviral proteins. First, a segment of the ACE2 receptor was incorporated into a series of small protein scaffolds, and second, from scratch, completely synthetic proteins were designed. The potent antivirals were produced in the latter method. This included the antiviral which is roughly six times more potent on a per mass basis than the most effective monoclonal antibodies reported thus far, the LCB1.
This work was done in collaboration with scientists from the Washington University School of Medicine in St. Louis and the University of Washington School of Medicine in Seattle.
At the UW School of Medicine and head of the Institute for Protein Design, professor of biochemistry, senior author, and Howard Hughes Medical Institute Investigator David Baker, who had given a TED talk on how protein design might be used to stop viruses in 2019 said, “Proof that computational protein design can be used to create promising drug candidates can be seen from our success in designing high-affinity antiviral proteins from scratch.”
The research team collected snapshots of the coronavirus Spike protein and the new antiviral proteins interacting by using cryo-electron microscopy to confirm that the new antiviral proteins attached to the coronavirus Spike protein as intended.
The antiviral research team wrote in their study pre-print that promising starting points for new SARS-CoV-2 therapeutics are provided by the hyper stable mini binders, and also mentioned that for rapidly generating potential therapeutic candidates against pandemic threats, it illustrates the power of computational protein design.
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Computer-designed Antiviral Proteins Inhibit SARS-CoV-2 in The Lab
