Medicines for diabetes and hormone disorders could be derived from deadly sea snail venom

A venom from one of the world's most venomous animals is giving scientists new clues to treating some serious and potentially fatal human diseases. A multinational research team led by scientists from the University of Utah identified a component of the venom of a deadly cone snail, the Geography Cone Snail (Conus sylvatica) that mimics human somatostatin (SS), a peptide hormone that regulates blood sugar levels 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 the treatment of diabetes and hormone disorders.

“Venomous animals have fine-tuned venom components over the course of evolution to hit and disrupt a specific target in the prey,” explains Dr. Helena Safavi, associate professor of biochemistry at the University of Utah's Spencer Fox Eccles School of Medicine (SFESOM). “If you take a single component out of the venom mix and look at how it disrupts normal physiology, that pathway is often really relevant in disease.” For medicinal chemists, says Safavi, “it's a kind of shortcut.”

Safavi is lead author of the team’s published paper in Nature communicationentitled “Fish-hunting cone snail disrupts glucose homeostasis of its prey through weaponized mimics of somatostatin and insulin.” In their article, the team concludes: “The discovery of a venom peptide that closely resembles a synthetic SS drug analogue illustrates the potential of natural compounds as alternatives to human-developed drugs.”

Venomous animals have evolved “a variety of toxins” to incapacitate their prey and defend themselves against predators, the authors write, and many of these toxins represent valuable tools in basic and biomedical research and have been developed as drugs, medicines, and diagnostics. “…predatory marine cone snails have yielded a wide range of small bioactive peptides, called conopeptides or conotoxins, that primarily target the nervous and locomotor systems of prey,” the team continues. And each of the 1,000 or so cone snail species expresses a unique library of possibly hundreds of peptide toxins.

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

Safavi's team had previously found that cone snail venom contains an insulin-like toxin that lowers blood sugar levels so quickly that the cone snail's prey becomes unresponsive. “…we have previously shown that cone snails produce special insulins (con-insulins) to rapidly induce dangerously low blood sugar levels 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 somatostatins as weapons to maintain the dangerously low blood sugar levels caused by the venom insulins.

Somatostatin acts like a brake pedal for many processes in the human body, preventing blood sugar levels, levels of various hormones and many other important molecules from rising to dangerous levels. In their new work, the researchers found that the cone snail venom consomatin acts similarly but is more stable and specific than the human hormone, making it a promising model for drug development. “Taken together, these findings represent an astonishing example of chemical mimicry,” they explained.

“We believe that the cone snail evolved this highly selective toxin to work together with the insulin-like toxin to lower blood sugar to very low levels,” said Ho Yan Yeung, PhD, postdoctoral fellow in biochemistry at SFESOM and lead author of the study.

The team's joint experiments on human cells and rodent tissue showed that consomatin interacts with one of the same protein targets as somatostatin itself. The studies found that somatostatin interacts directly with several proteins, but consomatin only interacts with one. “… we show that in addition to insulins, the deadly fish hunter, Conus sylvaticauses a selective somatostatin receptor 2 (SSTR2) agonist that blocks the release of the insulin-inhibiting hormone glucagon, thereby exacerbating insulin-induced hypoglycemia in the prey,” they noted.

This fine-tuned targeting means that cone snail venom affects hormone levels and blood sugar levels, but not the levels of many other molecules. In fact, cone snail venom is more targeted than the most specific synthetic drugs for regulating hormone levels, such as existing drugs for regulating growth hormone. These drugs offer important therapy for people whose bodies produce too much growth hormone.

And although consomatine's effects on blood sugar could make its use as a therapeutic agent dangerous, by studying its structure, researchers may be able to develop drugs to treat endocrine disorders that have fewer side effects.

Consomatin is more specific than top-of-the-line synthetic drugs – and it also stays in the body much longer than the human hormone, thanks to an unusual amino acid that makes it harder to break down. This is a useful property for pharmaceutical researchers looking for ways to create drugs with long-lasting effects.

Developing better drugs by studying deadly poisons may seem counterintuitive, but Safavi explains that the lethality of the toxins is often aided by the ability to target specific molecules in the victim's body. This precision can be extremely useful in treating disease.

Consomatin shares a common evolutionary ancestry with somatostatin, but over millions of years of evolution, the cone snail has weaponized its hormone. The fact that several parts of the cone snail's venom target blood sugar regulation suggests that the venom may contain many other molecules that target normoglycemia. “Future identification of these potential peptides could yield new drugs and improve our understanding of the complex physiological mechanisms that govern glucose control,” the authors wrote.

“This means that the venom may not only contain insulin and somatostatin-like toxins,” Yeung added. “It may also contain other toxins that regulate blood sugar levels.” Such toxins could be used to develop better diabetes drugs.

It may seem surprising that a snail can outperform the best human chemists at developing drugs, but Safavi noted that 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 with failure,” 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.”