The seabed is full of mysteries, but scientists recently uncovered one of its best-kept secrets. For 25 years, drug hunters have been searching for the source of a natural chemical that early studies have shown promise in treating cancer. Now researchers at the University of Utah Health report that easy-to-find soft corals make the hard-to-reach stuff.
Identifying the source allowed the researchers to go a step further and find the animal’s DNA code for synthesizing the chemical. By following these instructions, they were able to take the first steps towards recreating the soft coral chemical in the laboratory.
“This is the first time we’ve been able to do this with a prodrug on Earth,” says Dr. Eric Schmidt, Professor of Medicinal Chemistry at U of U Health. He led the study together with Dr. Paul Scesa, postdoc and first author, and Dr. Zhenjian Lin, Assistant Professor of Research.
The advance opens up the possibility of making the compound in the large quantities needed for rigorous testing, and might one day lead to a new cancer-fighting agent.
A second research group led by Bradley Moore, Ph.D., of the Scripps Institution of Oceanography at the University of California San Diego, has independently shown that corals make similar molecules. Both studies are published in the May 23 issue of Nature Chemical Biology.
A world of possibilities
Soft corals have thousands of drug-like compounds that might act as anti-inflammatory agents, antibiotics, and more. However, a major obstacle in developing drugs for clinical use has been obtaining enough of these compounds. Schmidt says these other compounds should now also be accessible with this new approach.
Corals aren’t the only animals harboring potential therapeutics. Nature abounds with snakes, spiders, and other animals known to carry chemicals with healing properties. However, the compounds from soft corals offer distinct advantages for drug development, says Schmidt.
Unlike toxic chemicals injected into prey, corals use their chemicals to repel predators trying to eat them. Because they are made to be eaten, the chemicals found in soft corals are easily digested. Likewise, medications derived from these compounds should be able to be taken as pills with a glass of water, rather than being taken through injections or other more invasive means. “These compounds are harder to find, but they’re easier to make in the lab and easier to take as medicine,” says Schmidt.
These possibilities had been unattainable for decades. Getting to this point took the right know-how and a bit of luck.
In search of the source
Scesa found the long-sought connection in a common species of soft coral that lives off the coast of Florida — just a mile from his brother’s home. In the 1990s, marine scientists reported that a rare coral near Australia contained a chemical, eleutherobin, with anti-cancer properties. The chemical disrupts the cytoskeleton, an important scaffolding in cells, and soft corals use it to defend once morest predators. However, laboratory studies showed that the compound also potently inhibited the growth of cancer cells.
In the decades that followed, scientists searched but might not find the fabled “holy grail” in the quantities needed for drug development and might not solve the problem without understanding how the chemical was made. The dogma held that, similar to other types of marine life, the chemical is synthesized by symbiotic organisms that live inside the animals.
“It didn’t make sense,” says Scesa. “We knew that corals need to make eleutherobin.” He and Schmidt concluded that some species of soft coral do not have symbiotic organisms, yet their bodies contain the same class of chemicals.
Solving the riddle seemed to be a task for Scesa. As a boy growing up in Florida, the ocean was his playground and he spent countless hours exploring its depths and wildlife. During his studies, he developed a passion for organic chemistry and combined these two interests to better understand the chemical diversity of the oceans.
He later entered the laboratory of natural products researcher Schmidt to track down the source of the drug lead. Scesa suspected familiar coral species might provide the answer, so he brought small live specimens from Florida to Utah — and the real hunt began.
The decoding of the recipe
The next step was to find out if the coral’s genetic code contained instructions for making the compound. Recently, thanks to advances in DNA technology, it has been possible to quickly decipher the genetic code of any species. The difficulty was that the scientists didn’t know what the instructions for making the chemical should be.
They tackled the problem by finding areas of coral DNA that resembled the genetic instructions for similar types of compounds from other species. After programming lab-grown bacteria to follow soft coral-specific coral DNA instructions, the microorganisms were able to replicate the initial steps in manufacturing the potential cancer therapeutic.
This proved that soft corals are the source of eleutherobin. It also showed that it should be possible to make the connection in the lab. Her work now focuses on completing the missing steps in the drug’s formulation and finding the best way to manufacture large quantities of the potential drug.
