Common FDA-approved drug may effectively neutralize virus that causes
COVID-19
Heparin could be used as a decoy to prevent SARS-CoV-2 from infecting
human cells

Date:
July 15, 2020
Source:
Rensselaer Polytechnic Institute
Summary:
A common drug, already approved by the Food and Drug Administration
(FDA), may also be a powerful tool in fighting COVID-19, according
to new research.



FULL STORY ==========================================================================
A common drug, already approved by the Food and Drug Administration
(FDA), may also be a powerful tool in fighting COVID-19, according to
research published this week in Antiviral Research.


========================================================================== SARS-CoV-2, the virus that causes COVID-19, uses a surface spike protein
to latch onto human cells and initiate infection. But heparin, a blood
thinner also available in non-anticoagulant varieties, binds tightly
with the surface spike protein, potentially blocking the infection from happening. This makes it a decoy, which might be introduced into the
body using a nasal spray or nebulizer and run interference to lower the
odds of infection. Similar decoy strategies have already shown promise
in curbing other viruses, including influenza A, Zika, and dengue.

"This approach could be used as an early intervention to reduce the
infection among people who have tested positive, but aren't yet suffering symptoms. But we also see this as part of a larger antiviral strategy,"
said Robert Linhardt, lead author and a professor of chemistry and
chemical biology at Rensselaer Polytechnic Institute. "Ultimately, we
want a vaccine, but there are many ways to combat a virus, and as we've
seen with HIV, with the right combination of therapies, we can control
the disease until a vaccine is found." To infect a cell, a virus must
first latch onto a specific target on the cell surface, slice through
the cell membrane, and insert its own genetic instructions, hijacking
the cellular machinery within to produce replicas of the virus. But the
virus could just as easily be persuaded to lock onto a decoy molecule,
provided that molecule offers the same fit as the cellular target.

Once bound to a decoy, the virus would be neutralized, unable to infect
a cell or free itself, and would eventually degrade.

In humans, SARS-CoV-2 binds to an ACE2 receptor, and the researchers hypothesized that heparin would offer an equally attractive target. In a binding assay, the researchers found that heparin bound to the trimeric
SARS- CoV-2 spike protein at 73 picomoles, a measure of the interaction
between the two molecules.

"That's exceptional, extremely tight binding," said Jonathan Dordick,
a chemical and biological engineering professor at Rensselaer who is collaborating with Linhardt to develop the decoy strategy. "It's hundreds
of thousands of times tighter than a typical antibody antigen. Once it
binds, it's not going to come off." Internationally recognized for his creation of synthetic heparin, Linhardt said that, in reviewing sequencing
data for SARS-CoV-2, the team recognized certain motifs on the spike
protein and strongly suspected it would bind to heparin. In addition
to the direct binding assay, the team tested how strongly three heparin variants -- including a non-anticoagulant low molecular weight heparin
-- bind to SARS-CoV-2, and used computational modeling to determine the specific sites where the compounds bind to the virus. All the results
confirm heparin as a promising candidate for the decoy strategy. The researchers have subsequently initiated work on assessments of antiviral activity and cytotoxicity in mammalian cells.

"This isn't the only virus that we're going to confront in a pandemic,"
Dordick said. "We don't really have great antivirals, but this is
a pathway forward. We need to be in a position where we understand
how things like heparin and related compounds can block virus entry."
In previous work, a team led by Linhardt and Dordick demonstrated the
decoy strategy on viruses with a mechanism similar to SARS-CoV-2. In 2019,
the team created a trap for dengue virus, attaching specific aptamers -- molecules the viral latches will bind to -- precisely to the tips and
vertices of a five- pointed star made of folded DNA. Floating in the bloodstream, the trap lights up when sprung, creating the world's most sensitive test for mosquito-borne diseases. In work prior to that, they
created a synthetic polymer configured to match the sialic acid latch
points on influenza virus, reducing influenza A mortality in mice from
100% to 25% over 14 days.

"This innovative approach to effectively trapping virusus is a prime
example of how biotechnology approaches developed at Rensselaer are
being brought forward to address challenging global health problems,"
said Deepak Vashishth, the director of the Center for Biotechnology
and Interdisciplinary Studies at Rensselaer, of which both Dordick
and Linhardt are a part. "Professors Dordick and Linhardt have worked collaboratively across disciplines, and their research shows promise even beyond this current pandemic." "Characterization of glycosaminoglycan and novel coronavirus (SARS-CoV-2) spike glycoprotein binding interactions"
was published in Antiviral Research. At Rensselaer, Linhardt and Dordick
were joined on the research by Fuming Zhang, and also by researchers
at the University of California San Diego, Duke University, and the
University of George, Athens with support from the National Institutes
of Health.


========================================================================== Story Source: Materials provided by
Rensselaer_Polytechnic_Institute. Original written by Mary
L. Martialay. Note: Content may be edited for style and length.


========================================================================== Related Multimedia:
*
YouTube_video:_Common_FDA-Approved_Drug_May_Effectively_Neutralize_Virus
That_Causes_COVID-19 ========================================================================== Journal Reference:
1. So Young Kim, Weihua Jin, Amika Sood, David W. Montgomery, Oliver C.

Grant, Mark M. Fuster, Li Fu, Jonathan S. Dordick, Robert J. Woods,
Fuming Zhang, Robert J. Linhardt. Characterization of heparin and
severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2)
spike glycoprotein binding interactions. Antiviral Research, 2020;
181: 104873 DOI: 10.1016/j.antiviral.2020.104873 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200715123203.htm

--- up 1 hour, 54 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1337:3/111)