Team recreates scarce ‘sea creature’ drug in lab

Supplies of a promising drug for cancer and HIV—provided by a feathery creature of the sea—is about half what it was in the 1990s. Now, scientists have come up with a synthetic alternative.

As reported in Science, the new synthetic supply will be enough to continue ongoing trials testing its effectiveness as a cancer immunotherapy and for treating Alzheimer’s disease and HIV.

Principal investigator Paul Wender, a professor of chemistry at Stanford University, says he got so excited about the project at one point, “I put on my lab coat and did some crystallizations,” one of the basic steps of chemistry lab work usually left to students, not full professors.

For him, the findings are the result of decades of work and an accident in the Gulf of Mexico almost 50 years ago.

“It’s basically three elephants going down to a salt shaker.”

Like many other naturally occurring chemicals put into service as pharmaceuticals, bryostatin was discovered following what was essentially a fishing expedition. In the 1960s, having had some success developing drugs from terrestrial flora and fauna, scientists began to shift attention to marine life.

The story of bryostatin itself began in 1968, when a marine biologist working in the Gulf of Mexico collected a plethora of marine organisms and sent them to the National Cancer Institute for analysis. One of those organisms, Bugula neritina, a pest best known for fouling up marine environments, showed some promise as an anti-cancer agent.

A decade and a half later, researchers reported the structure of the active ingredient, which they dubbed bryostatin 1 after the animal’s common name, brown bryozoan.

Unfortunately, bryostatin 1 is very hard to come by. When scientists went back and swept up 14 tons of B. neritina, they managed to extract just 18 grams of bryostatin. “It’s basically three elephants going down to a salt shaker,” Wender says.

“That’s it, we’re going to roll up our sleeves and make bryostatin because it is now in demand.”

Worse, subsequent studies showed that B. neritina produces bryostatin only in depths greater than about 10 feet and in warmer seas closer to the equator, and only during certain times of the year. (In fact, the NCI’s 14-ton collection came from California, because subsequent samples from the Gulf of Mexico proved inactive.) And while there was a way to synthesize bryostatin in the lab, it took 57 steps and wasn’t very efficient.

Wender and his group have been working with bryostatin analogs—chemicals inspired by bryostatin, but not quite the same—since the 1980s but only recently began thinking about how to make bryostatin itself in a lab.

“Ordinarily, we’re in the business of making chemicals that are better than the natural products” such as bryostatin, Wender says. In other words, they try to come up with chemicals inspired by nature, but more effective.

“But when we started to realize that clinical trials a lot of people were thinking about were not being done because they didn’t have enough material, we decided, ‘That’s it, we’re going to roll up our sleeves and make bryostatin because it is now in demand,’” Wender says.

After decades of experience with bryostatin analogs and two years of concerted effort, the lab came up with a much shorter, 29-step process and a yield of 4.8 percent, tens of thousands of times more efficient than extracting bryostatin from B. neritina, and substantially simpler and more efficient than the previous synthetic approach.

“…we have an opportunity to start in earnest a clinical conversation about eradicating HIV/AIDS.”

The team members have now produced over 2 grams of bryostatin 1, and once production is scaled up, they expect manufacturers could produce about 20 grams per year, enough to cover clinical and research needs. That is a bit more than was ever extracted from B. neritina and enough to treat about 20,000 cancer patients or 40,000 Alzheimer’s patients.

The results could also be a boon for HIV/AIDS research. In late September, researchers reported that a bryostatin 1 analog could help wake latent HIV-infected cells, making them more susceptible to attack by HIV drugs or the immune system.

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With new insight into—and a new supply of –bryostatin 1, Wender says, “we have an opportunity to start in earnest a clinical conversation about eradicating HIV/AIDS.”

The National Institutes of Health, the National Science Foundation, the American Cancer Society, and the National Cancer Institute funded the work.

Stanford University has filed a provisional patent application on the technology, which Neurotrope BioScience has licensed for the treatment of neurological disorders. Stanford has granted an option to license to Bryologx Inc. for use in HIV/AIDS eradication and cancer immunotherapy. Wender is an adviser to both companies and a co-founder of the latter.

Source: Stanford University

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