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A rare marine molecule that shows promise for treating cancer and HIV

Stanford University chemist Paul Wender and his colleagues are working to improve treatments for cancer, HIV and Alzheimer’s – and they are betting that a drab, weedy marine invertebrate is the means to achieving that end. They have focused on this seemingly unremarkable organism, called Bugula neritina, because it cooperates with a bug in its gut to produce bryostatin (specifically, bryostatin-1), a molecule that can manipulate cellular activity in crucial and controllable ways.

Faced with dwindling natural supplies, the Wender lab produced synthetic bryostatin in 2017. Now, they are developing a suite of related synthetic analogs while continuing to explore the many uses of bryostatin for medical treatments, such as enhanced cancer immuno-therapy and eradication of HIV/AIDS.

“If you search long enough, somewhere, someplace, somehow you’re going to find a solution to a problem that originally appeared impossible, and our work with bryostatin has led to those kinds of moments many times,” said Wender. “What we have now are pretty remarkable results that will hopefully be driving clinical trials.

In a paper published on April 20 in Nature Communications, researchers from the Wender lab and the labs of Jerome Zack and Matthew Marsden at the University of California, Los Angeles describe the first synthetic forms of bryostatin that are subtly different from the natural molecule – called “close-in analogs.” Tests of these 18 analogs on lab-grown human cancer cells indicated that many could boost the effectiveness of cell therapies at a level similar to or better than bryostatin, opening the door for disease-specific optimization.

In a second study, published April 27 in Proceedings of the National Academy of Sciences, the same researchers collaborated with Tae-Wook Chun at the National Institutes of Health to modify bryostatin into a prodrug that can pay out the active drug – and its medicinal effect – over time. This prodrug was found to be significantly more effective and better tolerated than bryostatin in animal models and infected cells from HIV positive individuals. The same success in humans would mean a reduction in treatment frequency and drug side effects for patients with HIV.

More precious than gold

In 1968, naturalist Jack Rudloe provided the National Cancer Institute with the first sample of Bugula neritina. Scientists later processed 14 tons of the invertebrate – only to produce a mere 18 grams of bryostatin. That makes bryostatin nearly 350,000 times more valuable than gold (at current prices). Scientists continue to be interested in this scarce material because bryostatin-based drugs have the potential to make existing state-of-the-art cell and combination therapies more effective for a wider diversity of people and diseases. Bryostatin and its analogs could also serve as treatments on their own.

Bryostatin’s exciting prospects come from its ability to alter signaling pathways in cells to promote or block genes involved in protein production. And it can make these changes in several different ways that could be useful for a wide range of medical applications. In the case of cancer and HIV,

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