Medical drugs

Redesigned compound fights both cytokine storm and viral replication, experiments show – sciencedaily

A group of drugs long prescribed to treat tapeworm have inspired a compound that shows two-pronged efficacy against COVID-19 in laboratory studies, according to a new publication appearing online in the journal Infectious disease of ACS.

The compound, which is part of a class of molecules called salicylanilides, was engineered in the lab of Professor Kim Janda, PhD, Ely R. Callaway, Jr. Professor of Chemistry and Director of the Worm Institute for Research and Medicine at Scripps Research , in La Jolla, California.

“We have known for 10 or 15 years that salicylanilides work against certain viruses,” explains Janda. “However, they tend to be restricted to the gut and can have toxicity issues.”

Janda’s compound overcomes both problems, in mouse and cell tests, acting as both an antiviral and anti-inflammatory compound, with properties that bode well for its use in pill form.

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

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

One compound stood out. Dubbed simply “# 11,” it differs from commercial tapeworm medications in key ways, including its ability to pass beyond the gut and be absorbed into the bloodstream – and without the worrying toxicity.

“Niclosamide is basically limited to the digestive tract, and that makes sense because that’s where the parasites reside,” Janda explains. “For this reason, reusing a simple drug for COVID treatment would be counterintuitive, because you want something that is readily bioavailable, but does not have the systemic toxicity of niclosamide.”

About 80 percent of salicylanilide 11 is passed into the bloodstream, compared to about 10 percent of the antiparasitic drug niclosamide, which recently entered clinical trials as a COVID-19 treatment, Janda says.

Experiments showed that among the many modified salicylanilides he had built in his lab, No. 11 affected pandemic coronavirus infections in two ways. First, it interfered with the way the virus deposited its genetic material in infected cells, a process called endocytosis. Endocytosis requires the virus to form a lipid-based bundle around viral genes. The bundle enters the infected cell and dissolves, so that the infected cell’s protein-building machinery can read it and make new viral copies. # 11 seems to prevent the package from being dissolved.

“The compound’s antiviral mechanism is key,” Janda explains. “It prevents viral material from leaving the endosome and it just breaks down. This process does not allow new viral particles to be made as easily.”

Mainly, because it acts inside cells rather than viral spikes, questions of whether it would work in newer variants like Delta and Lambda are not an issue, he adds.

“This mechanism does not depend on the spike protein of the virus, so these upcoming new variants are not going to relegate us to finding new molecules as is the case with vaccines or antibodies,” explains Janda.

Additionally, # 11 has helped calm potentially toxic inflammation in 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 that is a key contributor to inflammation typically found in the advanced stages of COVID-19.

Better COVID-19 drugs are urgently needed as new, highly infectious variants lead to new outbreaks of disease and death around the world. But Janda says Salicylanilide # 11 was created long before the pandemic.

After battling a nasty bacterial infection called Clostridioides difficile About 10 years ago, he saw a clear need for better treatment options. Multidrug-resistant strains of It’s hard have become a major cause of epidemics of drug-resistant diarrheal disease in healthcare facilities around the world and among people using antibiotics. As the director of the Worm Institute, which specializes in parasitic infections, Janda was very familiar with salicylanilides and was familiar with their antimicrobial properties. His laboratory has created a “library” of modified salicylanilides, several of which have shown strong efficacy against It’s hard, and the collection was subsequently licensed by the pharmaceutical company Sorrento Therapeutics. Among them was salicylanilide 11.

“Salicylanilide 11 has actually been put on the back burner in my lab against It’s hard because it’s not as small as we would like, ”says Janda. “But salicylanilide 11 has a lot of really positive things going for it as a potential therapy for COVID. “

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