Diabetes, Hormone Disorder Drugs Could Be Derived from Deadly Sea Snail Toxin

A toxin from one of the most venomous animals on the planet is giving scientists new clues about how to treat some serious, and potentially fatal human disorders. A multinational research team led by University of Utah scientists identified a component of the venom produced by a deadly marine cone snail, the geography cone (Conus geographus), which mimics human somatostatin (SS), a peptide hormone that regulates levels of blood sugar and various hormones in the body. The toxin produced by the geography cone has specific, long-lasting hormone-like effects that help the snail hunt its prey, but this “weaponized” somatostatin mimic could also hold the key to improving treatment for diabetes and hormone disorders.

“Venomous animals have, through evolution, fine-tuned venom components to hit a particular target in the prey and disrupt it,” explained Helena Safavi, PhD, associate professor of biochemistry in the Spencer Fox Eccles School of Medicine (SFESOM) at the University of Utah. “If you take one individual component out of the venom mixture and look at how it disrupts normal physiology, that pathway is often really relevant in disease.” For medicinal chemists, Safavi suggested, “it’s a bit of a shortcut.”

Safavi is senior author of the team’s published paper in Nature Communications, titled “Fish-hunting cone snail disrupts prey’s glucose homeostasis with weaponized mimetics of somatostatin and insulin.” In their paper, the team concluded, “The discovery of a venom peptide that closely resembles a synthetic SS drug analog exemplifies the potential of natural compounds to serve as alternatives to human-engineered drugs.”

Venomous animals have evolved “a diversity of toxins” to incapacitate prey and defend against predators, the authors wrote, and many of these toxins represent valuable tools in basic and biomedical research, and have been developed as drug leads, drugs, and diagnostic agents. “… predatory marine cone snails have provided a vast array of small bioactive peptides, termed conopeptides or conotoxins, that mostly target the prey’s nervous and locomotor system,”  the team continued. And each of the 1000 or so species of cone snail expresses a unique library of perhaps hundreds of peptide toxins.

The team at the University of Utah, and other researchers have shown that as well as neurotoxins, some cone snail toxins mimic hormones to “hijack” important signaling systems in prey or predators. “We refer to these toxins as doppelgänger peptides, or simply doppelgängers,” the authors stated.

Safavi’s team had previously found that cone snail venom includes a toxin that resembles insulin, lowering the level of blood sugar so quickly that the cone snail’s prey becomes nonresponsive. “… we previously showed that cone snails express specialized insulins (con-insulins) to rapidly induce dangerously low blood glucose in prey thereby impairing locomotion and facilitating prey capture,” they wrote. The team’s studies also suggested that the geography cone snail may also use weaponized somatostatins to sustain the dangerously low blood glucose induced by the venom insulins.

Somatostatin acts like a brake pedal for many processes in the human body, preventing the levels of blood sugar, various hormones, and many other important molecules from rising dangerously high. The researchers’ newly reported work found that the cone snail toxin, consomatin, works similarly, but is more stable and specific than the human hormone, which makes it a promising blueprint for drug design. “Collectively, these findings provide a stunning example of chemical mimicry,” they stated.

“We think the cone snail developed this highly selective toxin to work together with the insulin-like toxin to bring down blood glucose to a really low level,” said Ho Yan Yeung, PhD, a postdoctoral researcher in biochemistry in SFESOM and the first author on the study.

The team’s collective experiments in human cells and using rodent tissues indicated that consomatin interacts with one of the same protein targets as does somatostatin itself. The studies found that while somatostatin directly interacts with several proteins, consomatin only interacts with one. “… we show that, in addition to insulins, the deadly fish hunter, Conus geographus, uses a selective somatostatin receptor 2 (SSTR2) agonist that blocks the release of the insulin-counteracting hormone glucagon, thereby exacerbating insulin-induced hypoglycemia in prey,” they noted.

This fine-tuned targeting means that the cone snail toxin affects hormone levels and blood sugar levels but not the levels of many other molecules. In fact, the cone snail toxin is more precisely targeted than the most specific synthetic drugs designed to regulate hormone levels, such as existing drugs that regulate growth hormone. These drugs offer an important therapy for people whose bodies overproduce growth hormone.

And while consomatin’s effects on blood sugar could make it dangerous to use as a therapeutic, by studying its structure researchers may be able to look at designing drugs for treating endocrine disorders, which have fewer side effects.

Consomatin is more specific than top-of-the-line synthetic drugs—and it also lasts far longer in the body than the human hormone, thanks to the inclusion of an unusual amino acid that makes it difficult to break down. This is a useful feature for pharmaceutical researchers looking for ways to make drugs that will have long-lasting benefits.

Finding better drugs by studying deadly venoms may seem unintuitive, but Safavi explains that the toxins’ lethality is often aided by pinpoint targeting of specific molecules in the victim’s body. That same precision can be extraordinarily useful when treating disease.

Consomatin shares an evolutionary lineage with somatostatin, but over millions of years of evolution, the cone snail turned its hormone into a weapon. The fact that multiple parts of the cone snail’s venom target blood sugar regulation hints that the venom could include many other molecules that target normoglycemia. “Future identification of these potential peptides may provide novel drug leads and enhance our understanding of the complex physiological mechanisms guiding glucose control,” the authors wrote.

“It means that there might not only be insulin and somatostatin-like toxins in the venom,” Yeung added. “There could potentially be other toxins that have glucose-regulating properties too.” Such toxins could be used to design better diabetes medications.

It may seem surprising that a snail can outperform the best human chemists at drug design, but Safavi noted that the cone snails have evolutionary time on their side. “We’ve been trying to do medicinal chemistry and drug development for a few hundred years, sometimes badly,” she said. “Cone snails have had a lot of time to do it really well.” Or, as Yeung put it, “Cone snails are just really good chemists.”