Potential COVID-19 medication found among tapeworm drugs
Re-engineered compound fights both cytokine storm and viral replication, experiments show

Date:
August 6, 2021
Source:
Scripps Research Institute
Summary:
From a collection of molecules inspired by anti-parasitic medicines
comes a potential drug candidate against COVID-19.



FULL STORY ==========================================================================
A group of medications long prescribed to treat tapeworm has inspired
a compound that shows two-pronged effectiveness against COVID-19 in
laboratory studies, according to a new publication appearing online in
the journal ACS Infectious Disease.


==========================================================================
The compound, part of a class of molecules called salicylanilides,
was designed in the laboratory of Professor Kim Janda, PhD, the Ely
R. Callaway, Jr.

Professor of Chemistry and director of the Worm Institute for Research
and Medicine at Scripps Research, in La Jolla, CA.

"It has been known for 10 or 15 years that salicylanilides work against
certain viruses," Janda says. "However, they tend to be gut-restricted
and can have toxicity issues." Janda's compound overcomes both issues,
in mouse and cell-based tests, acting as both an antiviral and an anti-inflammatory drug-like compound, with properties that auger well
for its use in pill form.

Salicylanilides were first discovered in Germany in the 1950s and used to address worm infections in cattle. Versions including the drug niclosamide
are used in animals and humans today to treat tapeworm. They have also
been studied for anti-cancer and antimicrobial properties.

The modified salicylanilide compound that Janda created was one of about
60 that he built years ago for another project. When the SARS-CoV-2
virus became a global pandemic in early 2020, knowing that they may
have antiviral properties, he started screening his old collection,
first in cells with collaborators from Sorrento Therapeutics and The
University of Texas Medical Branch, and later, after seeing promising
results, working with Scripps Research immunologist John Teijaro, PhD,
who conducted rodent studies.



==========================================================================
One compound stood out. Dubbed simply "No. 11," it differs from the
commercial tapeworm medicines in key ways, including its ability to pass
beyond the gut and be absorbed into the bloodstream -- and without the worrisome toxicity.

"Niclosamide is basically digestive-track restricted, and that makes
sense, because that's where parasites reside," Janda says. "For
that reason, simple drug repurposing for a COVID treatment would be counterintuitive, as you want something that is readily bioavailable,
yet does not possess the systemic toxicity that niclosamide has."
About 80 percent of salicylanilide 11 passed into the bloodstream,
compared to about 10 percent of the antiparasitic drug niclosamide, which
has recently entered clinical trials as a COVID-19 treatment, Janda says.

The experiments showed that of the many modified salicylanilides he had
built in his laboratory, No. 11 affected pandemic coronavirus infections
in two ways.

First, it interfered with how the virus deposited its genetic material
into infected cells, a process called endocytosis. Endocytosis requires
the virus to form a lipid-based packet around viral genes. The
packet enters the infected cell and dissolves, so the infected
cell's protein-building machinery can read it and churn out new viral
copies. No. 11 appears to prevent the packet's dissolution.

"The compound's antiviral mechanism is the key," Janda says. "It blocks
the viral material from getting out of the endosome, and it just gets
degraded.

This process does not allow new viral particles to be made as readily." Importantly, because it acts inside cells rather than on viral spikes, questions about whether it would work in new variants like Delta and
Lambda aren't a concern, he adds.



========================================================================== "This mechanism is not dependent on the virus spike protein, so these new variants coming up aren't going to relegate us to finding new molecules
as is the case with vaccines or antibodies," Janda says.

In addition, No. 11 helped quiet potentially toxic inflammation in the
research animals, Janda says, which could be important for treating
acute respiratory distress associated with life-threatening COVID
infections. It reduced levels of interleukin 6, a signaling protein which
is a key contributor of inflammation typically found in advanced stages
of COVID-19.

Better medications against COVID-19 are urgently needed, as highly
infectious new variants drive renewed surges of illness and death
globally. But Janda says salicylanilide No. 11 was created long before
the pandemic.

After fighting an unpleasant bacterial infection called Clostridioides difficileabout 10 years ago,he saw a clear need for better treatment
options.

Multi-drug-resistant strains of C. difficilehave become a major cause of
drug- resistant diarrheal disease outbreaks in health care institutions globally, and among people using antibiotics. As director of the Worm Institute, which focused on parasitic infections, Janda was very familiar
with salicylanilides, and knew of their antimicrobial properties. His laboratory created a "library" of modified salicylanilides several of
which showed strong efficacy against C.

difficile, and the collection was subsequently licensed by pharmaceutical
firm Sorrento Therapeutics. Among them was salicylanilide 11.

"Salicylanilide 11 actually was placed on the back burner in my laboratory against C. difficile because it's not as gut-restricted as we would
like it to be," Janda says. "But salicylanilide 11 has got a lot of
really positive things going for it as a potential therapeutic for COVID." ========================================================================== Story Source: Materials provided by Scripps_Research_Institute. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Steven Blake, Namir Shaabani, Lisa M. Eubanks, Junki Maruyama,
John T.

Manning, Nathan Beutler, Slobodan Paessler, Henry Ji, John
R. Teijaro, Kim D. Janda. Salicylanilides Reduce SARS-CoV-2
Replication and Suppress Induction of Inflammatory Cytokines
in a Rodent Model. ACS Infectious Diseases, 2021; DOI:
10.1021/acsinfecdis.1c00253 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210806171924.htm

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