Designed antiviral proteins inhibit SARS-CoV-2 in the lab
Computer design of synthetic proteins is creating potent, stable
antivirals that block infection at least as well as monoclonal antibodies

Date:
September 9, 2020
Source:
University of Washington Health Sciences/UW Medicine
Summary:
Computer-designed miniproteins have now been shown to protect
lab-grown human cells from SARS-CoV-2, the coronavirus that causes
COVID-19. The lead antiviral candidate rivals the best-known
SARS-CoV-2 monoclonal antibodies in its protective actions. The
synthetic antiviral candidates were designed to prevent infection
by interfering with the mechanism that coronaviruses use to break
into and enter cells.



FULL STORY ========================================================================== Computer-designed small proteins have now been shown to protect lab-grown
human cells from SARS-CoV-2, the coronavirus that causes COVID-19.


==========================================================================
The findings are reported today, Sept. 9, in Science In the experiments,
the lead antiviral candidate, named LCB1, rivaled the best- known
SARS-CoV-2 neutralizing antibodies in its protective actions. LCB1 is
currently being evaluated in rodents.

Coronaviruses are studded with so-called Spike proteins. These latch
onto human cells to enable the virus to break in and infect them. The development of drugs that interfere with this entry mechanism could lead
to treatment of or even prevention of infection.

Institute for Protein Design researchers at the University of Washington
School of Medicine used computers to originate new proteins that bind
tightly to SARS- CoV-2 Spike protein and obstruct it from infecting cells.

Beginning in January, more than two million candidate Spike-binding
proteins were designed on the computer. Over 118,000 were then produced
and tested in the lab.



========================================================================== "Although extensive clinical testing is still needed, we believe the
best of these computer-generated antivirals are quite promising," said
lead author Longxing Cao, a postdoctoral scholar at the Institute for
Protein Design.

"They appear to block SARS-CoV-2 infection at least as well as monoclonal antibodies, but are much easier to produce and far more stable,
potentially eliminating the need for refrigeration," he added.

The researchers created antiviral proteins through two approaches. First,
a segment of the ACE2 receptor, which SARS-CoV-2 naturally binds to
on the surface of human cells, was incorporated into a series of small
protein scaffolds.

Second, completely synthetic proteins were designed from scratch. The
latter method produced the most potent antivirals, including LCB1,
which is roughly six times more potent on a per mass basis than the most effective monoclonal antibodies reported thus far.

Scientists from the University of Washington School of Medicine in Seattle
and Washington University School of Medicine in St. Louis collaborated
on this work.

"Our success in designing high-affinity antiviral proteins from scratch
is further proof that computational protein design can be used to create promising drug candidates," said senior author and Howard Hughes Medical Institute Investigator David Baker, professor of biochemistry at the UW
School of Medicine and head of the Institute for Protein Design. In 2019,
Baker gave a TED talk on how protein design might be used to stop viruses.

To confirm that the new antiviral proteins attached to the coronavirus
Spike protein as intended, the team collected snapshots of the two
molecules interacting by using cryo-electron microscopy. These experiments
were performed by researchers in the laboratories of David Veesler,
assistant professor of biochemistry at the UW School of Medicine, and
Michael S. Diamond, the Herbert S. Gasser Professor in the Division
of Infectious Diseases at Washington University School of Medicine in
St. Louis.

"The hyperstable minibinders provide promising starting points for new
SARS- CoV-2 therapeutics," the antiviral research team wrote in their
study pre- print, "and illustrate the power of computational protein
design for rapidly generating potential therapeutic candidates against
pandemic threats."

========================================================================== Story Source: Materials provided by University_of_Washington_Health_Sciences/UW_Medicine.

Original written by Ian Haydon, Institute for Protein Design. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Longxing Cao, Inna Goreshnik, Brian Coventry, James Brett Case,
Lauren
Miller, Lisa Kozodoy, Rita E. Chen, Lauren Carter, Alexandra
C. Walls, Young-Jun Park, Eva-Maria Strauch, Lance Stewart, Michael
S. Diamond, David Veesler, David Baker. De novo design of picomolar
SARS-CoV- 2 miniprotein inhibitors. Science, Sept. 9, 2020; DOI:
10.1126/ science.abd9909 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200909140314.htm

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