Extract of Sea Squirt Shows Promise as COVID-19 Treatment

Drug focuses on a protein in human cells the virus needs to replicate.

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An extract from a rare undersea creature will soon be put to the test in clinical trials after initial studies showed effectiveness in stopping COVID-19 infections, according to a pharmaceutical company and a California-based researcher who has been studying it.

"It's a little crazy when you think about where this drug has come from," said Nevan Krogan, Phd, co-author of the promising study published this week and Director of the Quantitative Biosciences Institute at UC San Franciso -- half a world away from the home of the drug's source: a type of sea squirt, Aplidium Albicans. It is found only in the Mediterranean Sea, in the waters around the island of Ibiza off the coast of Spain.

The extract, known as Aplidin or Plitidepsin, was actually discovered several years ago by the Spanish Pharmaceutical PharmaMar, which specializes in exploring marine resources for potential therapeutics. Before COVID-19 emerged, Aplidin won approval as a treatment for a rare form of cancer.

Laboratory studies show effectiveness in preventing coronavirus from replicating.

"In human cells it was about 30 times more potent than Remdesivir, which is the standard of treatment right now," Dr. Krogran said.

So how on earth did a sea squirt get enlisted into the struggle to rein in the worst pandemic the world has seen in a century?

The answer is a methodical approach that began with Dr. Krogan's Coronavirus Research Group at QBI looking not only at the proteins of the SARS-CoV-2 virus, but at the human cell proteins with which they interact.

"The virus can't live by itself. It needs our genes and proteins to live and replicate and infect us," Dr. Krogran explained. Working with collaborators, including several based at the Icahn School of Medicine at Mt. Sinai Hospital in New York City, they found reason to pursue one protein in particular, eEF1A. "The virus hijacks it to make its own proteins."

The next step was to survey the existing drugs which neutralize that protein, and that is how the team came across Aplidin, which had been approved 2018 to treat Multiple Myeloma, primarily in Australia. The team reached out to PharmaMar, and the collaboration expanded.

"PharmaMar is discussing with different regulatory agencies the start of the anticipated Phase III trials," the company stated after the study results were published in the Journal Science.

Because Aplidin is targeting a protein in human cells, that lessens opportunity for the virus developing resistance.

"It doesn't matter if the virus mutates, because it's never going to be able to get around relying on that human protein," Dr. Krogran said.

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Targeting the human cell does raise the issue of potential toxic effects. But Aplidin was found to be safe in the trials for cancer use, and Dr. Krogran noted the cumulative dosage for treating cancer is higher than would be used for treatment of COVID-19 as an acute disease.

In the research, the collaborators also indentified other drugs with the potential to inhibit SARS-CoV-2, including Zotatifin, developed by San Diego-based eFFECTOR Therapeutics. The Department of Defense is providing funding for clinical trials, Dr. Krogan said.

But in part because of its previous successful trials, and more so because of the in vitro results showing 99% reduction of viral load, Aplidin is the front-runner.

“Of all the SARS-CoV-2 inhibitors that we have been characterizing in tissue culture and animal models since we started our studies with SARS-CoV-2, plitidepsin has been the most potent one," stated Icahn Microbiology Prof.
Adolfo García-Sastre, Ph.D, using Aplidin's other name.

On a strategic level, beyond finding potential therapeutics, even more concerted effort and funding has gone into developing vaccines, and establishing vast mechanisms for mass vaccination in the hope that "herd" immunity can be built within a matter of months. But no matter the timetable, Dr. Krogran believes there will still be a need for therapeutics, not only for treating cases of SARS-CoV-2, but at some point in the future for dealing with the next coronavirus to make the jump to humans and threaten another epidemic.

"We're going to need multiple vaccines. We're going to need multiple anti-virals, collectively, to help us deal with this coronavirus, without a doubt," Dr. Krogan said. He also foresees development of a combination of therapeutics, a so-called "cocktail," as has had success treating HIV.

He has been struck by the spirit of collaboration in response to COVID-19, and said he hopes "when the dust settles," that will extend to the development of therapeutics for other diseases.

But a final question:

Why is the potential silver bullet for COVID-19 to be found inside an obscure sea
squirt that resides only one in small corner of the earth? Is it just serendipity?

Dr. Krogan speculates the compound may assist the sea creature in fending off other viruses, but acknowledges no one yet really knows.

"Maybe if we further understand why it has it, this could help us further
develop it."

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