An international team of researchers headed by scientists at the University of Copenhagen has discovered that venoms produced by one group of fish-hunting deep sea cone snails contain compounds similar to analogs of the hormone somatostatin (SS). Studies showed that one of these cone snail venom SS analogs, which the team called Consomatin Ro1, alleviated pain in two different mouse models. The scientists aim to investigate the origin of Consomatin Ro1 in snails, as well as gain a better understanding of the potential to use the compound, or modified versions of it, as an anti-inflammatory or pain reliever.

Moreover, they claimed, each of this diverse set of cone snail SS analogs is optimized to elicit specific systemic physiological effects in prey. And their properties, including increased metabolic stability, SS receptor activation profiles, and chemical diversity make them “suitable leads for therapeutic applications, potentially including pain, cancer, and endocrine disorders.”

In addition to providing potential therapeutic avenues for cone snail somatostatin analogs, the study results highlight the wide variety of drug leads that are produced and refined in venomous animals over millions of years, the team said. “We have to broaden the scope of what we expect that these venomous animals make, assuming that they could really be making anything,” said Helena Safavi-Hemami, PhD, an adjunct assistant professor at the University of Utah and associate professor at the University of Copenhagen. “We should look very broadly and keep an open eye for completely new compounds.” Added University of Copenhagen researcher, Iris Bea Ramiro, PhD, “Cone snail venom is like a natural library of compounds. It is just a matter of finding what is in that library.”

Safavi, Ramiro, and colleagues reported on their discoveries in a paper in Science Advances, titled, “Somatostatin venom analogs evolved by fish-hunting cone snails: From prey capture behavior to identifying drug leads.” Safavi is also the corresponding author of research published earlier this month, describing a fast-acting insulin designed with properties of another cone snail venom compound.

Cone snails comprise a large family of venomous marine predators. These mollusks lack offensive mechanical weaponry, but have evolved what the team describes as “highly sophisticated pharmacological strategies for prey capture.” And because of the stability, chemical diversity, and target selectivity of cone snail toxins (conotoxins), these compounds have been developed as biomedical tools, and drug leads, including one approved drug, the researchers pointed out.

There are about 1,000 species of cone snail living today, including those that hunt fish for prey. Some use a “taser-and-tether” hunting strategy, shooting a barbed hook into a fish and delivering a jolt of venom that chemically electrocutes and paralyzes the fish. “The underlying molecular mechanisms of taser-and-tether toxins have been well characterized and have provided a rich set of pharmacological tools and drug leads, including an approved therapeutic for the treatment of chronic pain,” the authors noted.

Some fish-eating cone snails are known to use an alternative, net hunting strategy, releasing into the water a cloud of venom that contains compounds that leave the fish sensory deprived and disoriented. “The mixture of compounds that elicits this response was called the nirvana cabal because it makes fish appear as if under the influence of narcotic drugs,” the scientists further explained. But so far, this hunting technique has only been observed in two cone snail species, Conus geographus and Conus tulipa.

“Nirvana-cabal toxins have proven biomedical applications, including a diagnostic tool for an autoimmune disorder and a family of insulins that have inspired the design of fast-acting drug leads for diabetes,” the investigators further pointed out. “C. geographus venom has also provided one of the most widely used pharmacological tools in molecular neuroscience for studying synaptic transmission …”

Interestingly, of the estimated eight groups of fish hunting cone snails, only half have been extensively studied. Among the least-studied lineages are the Asprella cone snails. Unlike the shallow-water snails, these cone snails like deeper waters. Found at depths of 200–800 feet (60–250 m), they have been less accessible to scientists.

Ramiro grew up in the Philippines, on the island of Bohol. As a graduate student at the University of the Philippines, Ramiro began studying Conus rolani, a species of Asprella snail. “No one in our lab was working on it at that time,” she says. “I was just looking to identify any small peptide (chain of amino acids) from the venom of C. rolani that had unusual or interesting activity in mice.”

She discovered a small peptide from the C. rolani venom that caused mice to act sluggishly or become unresponsive. But it was slow acting, which wasn’t an expected effect, given that other cone snails produced venoms that acted almost immediately. The venom peptide had a few similarities to the hormone somatostatin, but not enough to say conclusively that it and the human hormone were functionally related.

While exploring how and why the venom worked, Ramiro made a visit to the University of Utah, a hub of cone snail research. The University of Utah researchers have been studying cone snails and their venom since 1970, following the arrival of Baldomero “Toto” Olivera, who brought with him the cone snail research he’d started in his native Philippines.

Decades of study have provided an abundance of information about how venom compounds act in the bodies of prey fish, including how they interact with receptors and overwhelm natural biochemical processes. Olivera and colleagues investigated whether those effects could be employed as pharmaceuticals in humans. One effort yielded a pain medication, Prialt. Another, in which Safavi played a leading role at the University as an assistant professor, investigated how insulin analogs produced by cone snails might be adapted as a fast-acting insulin for people with diabetes.

“Somehow cone snails take some of their hormones and turn them into weapons,” Safavi said. So she and other researchers helped Ramiro compare the peptide she’d found, Consomatin Ro1, to known human proteins.

Frank Whitby, a research associate professor in the department of biochemistry, used X-ray crystallography to determine the structure of Consomatin Ro1. “This was an important contribution because it showed that Consomatin Ro1 does not resemble somatostatin but rather resembles a drug analog of somatostatin called octreotide,” said Christopher Hill, D.Phil, distinguished professor of biochemistry at the University of Utah.

Meanwhile, the research team also worked with local fishermen off Cebu, an island near Bohol, to bring Asprella specimens to the lab to observe their behavior and learn more about their biochemistry. It took a year, Ramiro said, to confirm that the peptide that she’d originally isolated from the C. rolani snail activates two of the five human receptors for somatostatin “with unique selectivity,” she noted. “To the best of our knowledge, Consomatin Ro1 represents the first SS-like peptide to be isolated from venom,” the scientists stated.

“Then,” Safavi added, “we really wanted to understand what it’s doing and how it could be better than somatostatin.” In humans and many other vertebrates, somatostatin generally acts as an inhibitor. It’s the main inhibitor of growth hormone, and can be used to treat the excessive growth disorder, acromegaly. Somatostatin also inhibits hormones in the pancreas and signals of pain and inflammation. “So it’s this hormone that has many, many different functions in the human body,” Safavi commented, “but it’s always blocking something. And because of that, it had been an interesting hormone for drug development for some time.”

The discovery of Consomatin Ro1 led the team to search for additional SS-like peptides in cone snail venom. Their search through more than 600,000 assembled venom gland transcriptomes from Asprella and dozens of other cone snail species led to the identification of another 18 consomatins. “… we show that through predator-prey evolution, venomous snails have mastered SS drug design to likely induce diverse physiological endpoints in prey,” the authors noted.

But how can a hormone like somatostatin work as a weaponized venom, especially when it acts slowly? The best way to understand that, the researchers suggest, is to look to another predator, the rattlesnake, that also exploits a slow-acting venom.

Rattlesnakes, vipers, and cobras have developed a hunting strategy to protect themselves against dangerous prey that could possibly fight back. The snakes strike, injecting their venom, and then retreat. They then wait and follow their prey until the venom takes its full effect and the prey is dead or nearly dead and are then safe to approach and eat.

Observations of cone snails in tanks showed similarities to the rattlesnakes’ strike-and-release hunting strategy. After injecting venom, the snails would wait, sometimes up to three hours, before delivering a second injection and waiting again.

“And only when the prey is really incapacitated and unable to swim, they come and eat it,” Safavi said. “If you don’t catch the prey immediately, you have the advantage of just waiting until the prey can no longer move. That’s particularly important if the prey can fight back.”

How a venom component that mimics somatostatin can help with that strategy is still unclear. The study showed that Consomatin Ro1 can block pain in mice with efficiency similar to morphine, and it may be used to block pain so that prey doesn’t know it’s been struck, Safavi suggested. “ … these data demonstrate that Consomatin Ro1 represents a new lead for the potential development of an analgesic that acts via opioid receptor–independent pathways,” the authors further stated in their paper.

As a somatostatin analog, Consomatin Ro1 is structured “as if it was designed by drug makers,” Safavi noted. The molecule is short, stable, and efficient in the receptors it targets. That’s likely a reflection of evolutionary processes. Cone snails may have started out using their own somatostatin in venom and then, across generations the compound was refined to maximum effectiveness. That could be an advantage thinking for clinical applications, given that the biology of fish and humans is similar enough that a compound that’s highly effective in fish will likely be effective in humans.

It’s yet to be seen whether Consomatin Ro1 is more effective than somatostatin analog drugs that are already on the market for treating growth disorders or tumors. “The advantage with the cone snails, though, is that there are so many species,” Safavi pointed out. “And we know that many of these species make somatostatin, so the chances of finding the best analog might be pretty high.”

Next, the research team wants to investigate the origin of Consomatin Ro1 in snails, as well as better understand the potential of the compound as an anti-inflammatory or pain reliever. They’ll also look to see if modifications to the compound could make it even more useful.

The reported results show how venomous animals can turn a hormone into a weapon and suggest that the range of biochemical tools in venom might be broader than previously thought. “ … this study provides a powerful example of the evolution of optimized, drug-like evologs of human hormones in venomous predators,” the authors wrote. “.… we show that through predator-prey evolution, venomous snails have mastered SS drug design to likely induce diverse physiological endpoints in prey … It may be that different species of fish hunters may use these toxins for different purposes.”

“There’s evidence that viruses also turn hormones into weapons,” Safavi said. “We can spend a lot of time trying to design good hormone drugs, or we could try to look at nature more often. And I think if we did the latter, we might be more successful or we might be faster in our drug development efforts.” Safavi will continue this work when she returns to the Unversity of Utah as an associate professor of biochemistry in summer 2022.

“This gives insight to the development of next-generation therapeutics,” added Hill. “More generally, this is a great example of how evolution in the natural world has already developed drug-like natural products that have great potential to improve human health.” As the authors further noted, “With hundreds of cone snail species yet to be sequenced, we anticipate the future discovery of many more consomatins with diverse receptor activation profiles that exert distinctive systemic effects.”

“Discovering new peptides from the cone snails is fun and exciting but it could be a long and difficult journey,” Ramiro said, adding that the integration of various disciplines including biology, biochemistry, and pharmacology have made this study successful. “There is still so much we can find, discover, and learn from the cone snails and their venom.” In their paper, the investigators concluded, “Our findings not only establish the existence of SS-like peptides in animal venoms but also serve as a model for the synergy gained from combining molecular phylogenetics and behavioral observations to optimize the discovery of natural products with biomedical potential.”

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