Deadly toxin from sea snails could hold key to making better drugs

Scientists are finding clues to how to treat diabetes and hormonal disorders in an unexpected place: a toxin from one of the most venomous animals on the planet.

A multinational research team led by scientists at the University of Utah has identified a component in the venom of a deadly marine snail, the geographic cone snail, that mimics a human hormone called somatostatin, which regulates blood sugar levels and various hormones in the body. The specific and long-lasting effects of this toxic hormone, which helps the snail hunt its prey, could also help scientists design better drugs for people with diabetes or hormonal disorders, diseases that can be serious and sometimes fatal.

The results are published in Nature Communications.

A plan for better medicines

The somatostatin-like toxin characterized by the researchers could hold the key to improving drugs for people with diabetes and hormonal disorders.

Somatostatin acts as a brake on many processes in the human body, preventing levels of blood sugar, various hormones, and many other important molecules from rising dangerously. The researchers found that the cone toxin, called consomatin, works in a similar way, but consomatin is more stable and specific than the human hormone, making it a promising model for drug design.

By measuring how consomatin interacts with somatostatin targets in human cells in a petri dish, the researchers found that consomatin interacts with one of the same proteins as somatostatin. But while somatostatin interacts directly with several proteins, consomatin interacts with only one. This precise targeting means that the cone toxin affects hormone and blood sugar levels, but not the levels of many other molecules.

In fact, the cone toxin is more precisely targeted than the more specific synthetic drugs designed to regulate hormone levels, such as growth hormone-regulating drugs. These drugs are an important therapy for people whose bodies produce too much growth hormone. Consomatine’s effects on blood sugar could make it dangerous to use as a treatment, but by studying its structure, researchers could begin to design endocrine-disorder drugs that have fewer side effects.

Consomatine is more specific than high-end synthetic drugs, and it also stays in the body much longer than the human hormone, thanks to the inclusion of an unusual amino acid that makes it difficult to break down. That’s a useful trait for pharmaceutical researchers looking for ways to make drugs that will have long-term benefits.

Learning about cone snails

Finding better drugs by studying deadly venoms may seem counterintuitive, but Helena Safavi, Ph.D., associate professor of biochemistry at the University of Utah Spencer Fox Eccles School of Medicine (SFESOM) and lead author of the study, explains that the lethality of toxins is often facilitated by precise targeting of specific molecules in the victim’s body. That same precision can be extremely useful in treating diseases.

“Venomous animals have, over the course of evolution, fine-tuned the components of their venom to hit a particular target in the prey and disrupt it,” Safavi says. “If you take an individual component out of the venom mixture and look at how it disrupts normal physiology, that pathway is often very relevant in disease.” For medicinal chemists, “it’s a bit of a shortcut.”

Consomatin shares an evolutionary lineage with somatostatin, but over millions of years of evolution, the cone snail weaponized its own hormone.

For the cone snail’s prey, consomatine’s deadly effects depend on its ability to prevent blood sugar levels from rising. And importantly, consomatine doesn’t work alone. Safavi’s team had already discovered that cone snail venom contains another toxin that resembles insulin, lowering blood sugar levels so quickly that the cone snail’s prey becomes unresponsive. Consomatine then prevents blood sugar levels from rising again.

“We think the cone snail evolved this highly selective toxin to work in concert with the insulin-like toxin to reduce blood sugar to a really low level,” says Ho Yan Yeung, Ph.D., a postdoctoral researcher in biochemistry at SFESOM and first author of the study.

The fact that several parts of the cone venom target blood sugar regulation suggests that the venom may include many other molecules that do similar things.

“This means that the venom could contain not only insulin- and somatostatin-like toxins,” Yeung says. “It could also contain other toxins with glucose-regulating properties.” These toxins could be used to design better diabetes drugs.

It may seem surprising that a snail could outperform the best human chemists when it comes to drug design, but Safavi says cone snails have evolutionary time on their side.

“We’ve been trying to do medicinal chemistry and develop drugs for several hundred years, sometimes poorly,” she says. “Cone snails have had a long time to do it really well.”

Or, as Yeung puts it, “cone snails are just really good chemists.”