Could venomous snails be part of the solution to the opioid epidemic?

April 2, 2018 — Opioids are powerful pain relievers, but their addictive nature also creates powerful trouble for those who misuse them. Worldwide, millions of people suffer from opioid dependency. Each day more than 1,000 people are treated in emergency rooms across the United States for misusing prescription opioids. In the U.S, alone, roughly 46 people died each day from overdoses involving prescription opioids in 2016.

Researchers across the world are searching for solutions to the opioid epidemic. In looking for safer and more effective painkillers, some now are making use of an unusual source — venomous sea snails.

Unexpected Discovery

Humans have a long history of turning to nature for pain remedies. One of the world’s oldest preserved medical texts, the ancient Egyptian Ebers Papyrus, recommended the application of dried myrtle leaves to achy joints. The ancient Greek physician Hippocrates prescribed extract of willow tree bark — a precursor to aspirin — to treat fever and labor pains. In South America, the Quechua used the bark of the cinchona tree to treat malaria-induced fever. Europeans later would take extracts from the bark to make quinine. The Sumerians of ancient Mesopotamia cultivated a red flower called the opium poppy, from which scientists derived the suite of chemically enhanced opioid painkillers we have today. However, the ocean and its inhabitants remained largely unexplored as a potential source of pain relief.

Nature has long been a source of pain relievers. The Ebers Papyrus, one of the oldest known medical texts, recommended the use of myrtle leaves to treat joint ache. Photo courtesy of Jeff Dahl/Wikimedia Commons

Then in 1979, Baldomero “Toto” Olivera, a professor of biology at the University of Utah, and J. Michael McIntosh, a student working in his lab, changed that. Growing up in the Philippines, Olivera had collected the large, colorful shells of cone snails from the shores of Manila Bay. Years later, he turned his childhood fascination with the venomous marine mollusks that could kill a fish — or human — with a single sting into a quest to learn how the snails’ venom worked. Olivera and McIntosh isolated some intriguing neurotoxins from the venom of fish-eating cone snails. Researchers in Olivera’s lab later found that some of them could block certain signaling pathways in the brain — acting as potent pain-relievers.

The discovery led to the development of a new type of pain medication called Prialt (ziconotide). In 2004, Prialt became the first U.S. Food and Drug Administration–approved pain drug to come from the ocean. The powerful analgesic works on different brain receptors than opioids. It helps relieve chronic nerve pain in people with HIV, multiple sclerosis or spinal cord injuries without the overdose and addiction risks posed by narcotics.

“There are few classes of medications that are useful for chronic pain. That’s why opioids are often prescribed despite the side effects and problems that go with them,” explains McIntosh, now a professor of psychiatry and biology at the University of Utah.

Opioid receptors in the brain become less sensitive to the drug the longer you use it, meaning users need to keep increasing the dose to get the same effect. Medicine from the cone snail venom worked differently. “With the cone snail venom, we see a greater effect the longer the medication is given,” McIntosh says.

McIntosh, Olivera and colleagues at the University of Utah are now searching for other cone snail venom molecules that could be developed into opioid alternatives — with the help of a US$10 million grant from the U.S. Department of Defense.

Once the researchers figure out the chemical structure of the natural venom molecules, they can build similar molecules in the lab to test as drugs. That way they don’t have to harvest and kill snails each time they want to use the molecules. They’ve identified and synthesized a few promising venom molecules that they’re now modifying to make “more drug-like,” by tweaking the chemical structure to optimize the way the molecules are absorbed and excreted, says McIntosh. The researchers are looking for large molecules that could be used to develop injectable painkillers — and also smaller molecules that could be taken orally.

“I think our research shows why it’s important to protect natural resources,” says McIntosh. “These cone snails have gone through millions of years of evolution to refine the compounds they use for offense or defense. The solutions they’ve found have medical applications that we can learn from.”

More Mollusks

Prialt was made from one molecule found in one species of cone snail — Conus magus. More than 800 species of cone snails produce their own venomous cocktails — each containing 50 to 200 different, potentially useful, molecules.

And snails are just the start. Mollusks are an enormous group of spineless critters that includes snails, slugs, mussels and octopuses. Many of the estimated 52,000 known species are venomous. Most live in the ocean and are poorly studied.

One major challenge for scientists is figuring out which of the thousands of different venom molecules might make suitable drug targets.“Each species has an entire book of knowledge encoded in its genome,” says Kirsten Benkendorff, a marine biologist at Southern Cross University in Australia who studies mollusks.

One major challenge for scientists is figuring out which of the thousands of different venom molecules might make suitable drug targets.

Mandë Holford uses evolution to help. The biochemist studies therapeutic molecules in marine snail venom at CUNY-Hunter College and the American Museum of Natural History in New York City. With the help of genetic sequencing, she’s creating a family tree for terebrid snails — another group of tiny marine snails that lives in the world’s tropical oceans.  By showing which snail species are close relatives, the tree can provide clues as to which snails might be producing similar compounds in their venom.

“If we know what we’re looking for before we go out into the field, we can collect fewer specimens and leave a smaller environmental footprint,” says Holford.

Holford and her research team patented their first peptide from terebrid snail venom in 2017. While they initially were investigating molecules that could act on pain receptors in the brain, they found one that could modulate certain signaling pathways that are very active in tumor cells. The patent is for a method of using the peptide as an anti-tumor live cancer drug.

“There’s a cornucopia of peptides in venom that can be applied to various problems or diseases if we can figure out how to unlock their potential,” says Holford.