A deadly, sluggish marine snail may have revealed the key to fast-acting diabetes therapies.
The geography cone snail (Conus geographus) is a fish-hunting mollusk that kills its prey by flooding their gills with an ultra-fast-acting insulin that sends the fish into hypoglycemic shock. Researchers have now shown that the geography cone’s weaponized insulin binds with human insulin receptors, and they have uncovered the molecular structure that’s responsible for its lethal speed.
Researchers from Utah and Australia discovered that the snail insulin works more quickly than human insulin because it lacks a “hinge” structure at the molecular level, which they describe in a recent paper published in Nature Structural and Molecular Biology. In human insulin, the hinge slows activity in two ways: one, by causing the molecules to clump together in groups—which must break apart before the individual insulin molecules can bind with receptors—and two, by preventing binding until the hinge is open. Scientists looking to develop faster insulin have seen the hinge as an obstacle, but simply removing it hasn’t been an option.
“If you chop that off, the human insulin is dead, it doesn’t work,” said Mike Lawrence, an associate professor at Melbourne’s Walter and Eliza Hall Institute of Medical Research and corresponding author of the study. Since past attempts to remove the hinge have rendered insulin useless, scientists were struck by the fact that the snail insulin lacks the human version’s hinge piece entirely, but still activates human insulin receptors.
“The question is, how does it get around not having that piece?” Lawrence said. “And the answer is that by putting one residue—one amino acid at another point in the protein—that serves the purpose of the hinge.
Lawrence said that while researchers have experimented with removing the hinge in the past, it’s unlikely that anyone might have tried removing it while also adding the additional amino acid at the location where it occurs in the snail insulin.
“There would have been no logic to doing that,” Lawrence said. “But through evolution, the cone snail has developed this methodology of creating a very fast-acting insulin.”
This research builds on a 2015 paper that detailed the insulin-based nature of the geography cone’s venom. It is the first known use of insulin in venom, and scientists found that the weaponized insulin paralyzes the prey because it is structured like fish insulin rather than the snail’s own insulin. Since fish insulin is similar to human insulin, researchers saw the possibility that the snail’s weaponized version would bind with human insulin receptors.
It is not unusual for researchers to look to animal venoms as a source of potential medical therapies because, like many drugs, venoms tend to be both potent and highly targeted to specific molecules. There are at least six FDA-approved drugs derived from animal venoms, including a diabetes drug derived from Gila monster saliva and a pain medication derived from another species of cone snail. Other medications come from various snakes and a leech.
For Helena Safavi-Hemami, an author on the paper, the decision to study cone snail venoms had to do with their unusual richness. She said that in cone snail venom “there is a great diversity of venom peptides that’s really not seen in other venomous animals,” and that many of these peptides are highly targeted to specific receptors. Those factors make the venom more likely to contain something medically useful.
The team’s paper concludes that their discovery could aid in developing fast-acting insulin therapies for humans, and Lawrence said a next phase of research has already begun.
“There is a very, very long way from this finding to a clinically useful, novel insulin,” said Peter Kurtzhals, senior vice president and head of global research at Novo Nordisk, a pharmaceutical company specializing in diabetes treatments. He said that the next step would be to study the many aspects of how the insulin would work in the human body. Even so, he recognized the significance of understanding the structure of the cone snail’s hinge-free insulin.
“It’s an inspiration to what you could engineer,” he said.