New COVID-19 nasal spray outperforms current antibody treatments in mice
A single inhaled dose treated or even prevented infection by COVID-19 and
its variants

Date:
April 13, 2022
Source:
Northwestern University
Summary:
Current antibody treatments block SARS-CoV-2 by binding to one
of three binding sites on the spike protein. A new protein-based
antiviral binds to all three sites on the spike protein, making
it more effective than current therapies. The new therapy also
is low-cost, easy to manufacture, does not require complicated
supply chains with extreme refrigeration and potentially could
be self-administered.



FULL STORY ==========================================================================
A new protein-based antiviral nasal spray developed by researchers
at Northwestern University, University of Washington and Washington
University at St. Louis is being advanced toward Phase I human clinical
trials to treat COVID-19.


========================================================================== Designed computationally and refined in the laboratory, the new protein therapies thwarted infection by interfering with the virus' ability
to enter cells. The top protein neutralized the virus with similar or
greater potency than antibody treatments with Emergency Use Authorization status from the U.S.

Food and Drug Administration (FDA). Notably, the top protein also
neutralized all tested SARS-CoV-2 variants, something that many clinical antibodies have failed to do.

When researchers administered the treatment to mice as a nasal spray,
they found that the best of these antiviral proteins reduced symptoms
of infection - - or even prevented infection outright.

The findings were published yesterday (April 12) in the journal Science Translational Medicine.

This work was led by Northwestern's Michael Jewett; David Baker and David Veesler at the University of Washington School of Medicine; and Michael S.

Diamond at WashU.

To begin, the team first used supercomputers to design proteins that
could stick to vulnerable sites on the surface of the novel coronavirus, targeting the spike protein. This work was originally reported in 2020
in the journal Science.



==========================================================================
In the new work, the team reengineered the proteins -- called minibinders
-- to make them even more potent. Rather than targeting just one site
of the virus' infectious machinery, the minibinders simultaneously bind
to three sites, making the drug less likely to detach.

"SARS-CoV-2's spike protein has three binding domains, and common
antibody therapies may only block one," Jewett said. "Our minibinders
sit on top of the spike protein like a tripod and block all three. The interaction between the spike protein and our antiviral is among the
tightest interactions known in biology. When we put the spike protein and
our antiviral therapeutic in a test tube together for a week, they stayed connected and never fell apart." Jewett is a professor of chemical and biological engineering at Northwestern's McCormick School of Engineering
and director of Northwestern's Center for Synthetic Biology. Andrew
C. Hunt, a graduate research fellow in Jewett's laboratory, is the
paper's co-first author.

As the SARS-CoV-2 virus has mutated to create new variants, some
treatments have become less effective in fighting the ever-evolving
virus. Just last month, the FDA paused several monoclonal antibody
treatments, for example, due to their failure against the BA.2 omicron subvariant.

Unlike these antibody treatments, which failed to neutralize omicron,
the new minibinders maintained potency against the omicron variant
of concern. By blocking the virus' spike protein, the new antiviral
prevents it from binding to the human angiotensin-converting enzyme 2
(ACE2) receptor, which is the entry point for infecting the body. Because
the novel coronavirus and its mutant variants cannot infect the body
without binding to the ACE2 receptor, the antiviral also should work
against future variants.



==========================================================================
"To enter the body, the spike protein and ACE2 receptor engage in a
handshake," Jewett said. "Our antiviral blocks this handshake and,
as a bonus, has resistance to viral escape." In addition to losing effectiveness, current antibody therapies also come with several
problems: They are difficult to develop, expensive and require a
healthcare professional to administer. They also require complicated
supply chains and extreme refrigeration, which is often unavailable in low-resource settings.

The new antiviral solves all these problems. As opposed to monoclonal antibodies, which are made by cloning and culturing living mammalian
cells, the new antiviral treatment is produced large-scale in
microorganisms like E. coli, making them more cost-effective to
manufacture. Not only is the new therapy stable in high heat, which
could further streamline manufacturing and decrease the cost of goods for clinical development, it also holds promise for being self-administered
as a one-time nasal spray, bypassing the need for medical professionals.

The researchers imagine that it could be available at the pharmacy and
used as a preventative measure to treat infections.

This study, "Multivalent designed proteins neutralize SARS-CoV-2 variants
of concern and confer protection against infection in mice," was supported
by The Audacious Project at the Institute for Protein Design; Bill &
Melinda Gates Foundation (OPP1156262, INV-004949); Burroughs Wellcome
Fund; Camille Dreyfus Teacher-Scholar Program; David and Lucile Packard Foundation; Helen Hay Whitney Foundation; Open Philanthropy Project;
Pew Biomedical Scholars Award; Schmidt Futures; Wu Tsai Translational Investigator Fund; Howard Hughes Medical Institute, including a fellowship
from the Damon Runyon Cancer Research Foundation; Department of Defense (NDSEG-36373, W81XWH-21-1-0006, W81XWH-21-1- 0007, W81XWH-20-1-0270-2019, AI145296, and AI143265); Defense Advanced Research Project Agency
(HR0011835403 contract FA8750-17-C-0219); Defense Threat Reduction Agency (HDTRA1-15-10052, HDTRA1-20-10004); European Commission (MSCA CC-LEGO
792305); National Institutes of Health (1P01GM081619, R01GM097372,
R01GM083867, T32GM007270, S10OD032290); National Institute of Allergy
and Infectious Diseases (DP1AI158186, HHSN272201700059C, R37 AI1059371,
R01 AI145486); National Institute of Diabetes and Digestive and Kidney
Diseases (R01DK117914, R01DK130386, U01DK127553, F31DK130550); National Institute of General Medical Sciences (R01GM120553); NHLBI Progenitor
Cell Biology Consortium (U01HL099997, UO1HL099993); National Center for Advancing Translational Sciences (UG3TR002158); United World Antiviral
Research Network; Fast Grants; T90 Training Grant; and with federal funds
from the Department of Health and Human Services (HHSN272201700059C).


========================================================================== Story Source: Materials provided by Northwestern_University. Original
written by Amanda Morris. Note: Content may be edited for style and
length.


========================================================================== Journal Reference:
1. Andrew C. Hunt, James Brett Case, Young-Jun Park, Longxing Cao,
Kejia Wu,
Alexandra C. Walls, Zhuoming Liu, John E. Bowen, Hsien-Wei Yeh,
Shally Saini, Louisa Helms, Yan Ting Zhao, Tien-Ying Hsiang,
Tyler N. Starr, Inna Goreshnik, Lisa Kozodoy, Lauren Carter, Rashmi
Ravichandran, Lydia B. Green, Wadim L. Matochko, Christy A. Thomson,
Bastian Vo"geli, Antje Kru"ger, Laura A. VanBlargan, Rita E. Chen,
Baoling Ying, Adam L. Bailey, Natasha M. Kafai, Scott E. Boyken,
Ajasja Ljubetič, Natasha Edman, George Ueda, Cameron M. Chow,
Max Johnson, Amin Addetia, Mary Jane Navarro, Nuttada Panpradist,
Michael Gale, Benjamin S. Freedman, Jesse D.

Bloom, Hannele Ruohola-Baker, Sean P. J. Whelan, Lance Stewart,
Michael S. Diamond, David Veesler, Michael C. Jewett, David
Baker. Multivalent designed proteins neutralize SARS-CoV-2 variants
of concern and confer protection against infection in mice. Science
Translational Medicine, 2022; DOI: 10.1126/scitranslmed.abn1252 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220413203131.htm

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