The Cone Snail: beautiful but deadly

The cone snail shell is known for its beauty. The organism that resides inside is a highly adapted predator that uses a complex mixture of toxic peptides to trap and disable its prey.  

The cone snail shell is known for its beauty. The organism that resides inside is a highly adapted predator that uses a complex mixture of toxic peptides to trap and disable its prey.  

The cone snail shell is a lovely and familiar item. Displaying a stunning diversity of patterns and colors, artists, jewelers and shell collectors have long admired these little ocean gems. In fact, in 1796, a cone snail shell (Conus cedonulli, shown below), measuring just 5 cm, sold at auction for over 5 times the price of the Vermeer painting Woman in Blue Reading a Letter. While innocuous as a display item, when occupied by the feisty cone snail, these shells become armor for one of the most venomous of the oceans critters. 

C. cedonulli - the same type of shell that outshined a Vermeer at auction

C. cedonulli - the same type of shell that outshined a Vermeer at auction

When you look at a cone snail, it doesn’t really look that scary. Ranging in length from a few to ~10 centimeters, and displaying the aforementioned beauty, one might actually feel compelled to pick it up and peer closely at it. I would advise against this. These snails, which generally feed on small fish, worms, or other mollusks, are fierce hunters. Generally (though the exact order of events can vary from species to species), the snail attacks its prey by luring it in with an enticing-looking long proboscis. When the prey draws near, the snail shoots out a venom-filled “harpoon” thus rendering its target paralyzed, disoriented, and just generally helpless. Once it has immobilized its prey, the worm extends its large sucker-like mouth around the helpless victim and ingests it. Pretty grim stuff.  The venom injection of a cone snail is sufficiently potent to kill a human (though reports of fatalities from cone snail poisonings are rare); this toxic venom causes a range of neuromuscular effects such as paralysis, numbness, disorientation and difficulty breathing.

But what is in this venom? Why is it so potent? These are, of course, the first questions a natural products chemist might ask when learning about the extreme biological effects of this mysterious substance. Baldomero Olivera, a professor at the University of Utah, has dedicated his research career to these questions. Olivera first became aware of this marine organism while growing up in the Philippines where cone snails are ubiquitous. He has since published numerous research articles on a wide variety of neurotoxins (mostly called “conotoxins”) exuded in the cone snail venom. His research has revealed that the venom is primarily composed of peptides - strings of 10-30 amino acids - often containing multiple intramolecular connections (mainly disulfide bonds) that give the molecules their three dimensional shape.

Over the last 25 years the Olivera lab has identified a huge number of these cone snail neurotoxins. Perhaps not surprisingly, many of these molecules (mostly those identified from fish-eating species like Conus geographicus or C. magnus) have been shown to affect mammalian neurological and neuromuscular systems. The toxins are divided up into three major classes based on their identified vertebrate targets:  the α-conotoxins bind the acetylcholine receptor, µ-conotoxins block sodium ion channels and ω-conotoxins block calcium ion channels.

Two representations of the ω-conotoxin ziconotide (Prialt®). In the 3D form on the right the disulfide bonds that give the molecule its shape are marked in yellow. This analgesic is currently used in the clinic primarily for pain control in cancer patients.  

Two representations of the ω-conotoxin ziconotide (Prialt®). In the 3D form on the right the disulfide bonds that give the molecule its shape are marked in yellow. This analgesic is currently used in the clinic primarily for pain control in cancer patients.  

What makes these molecules truly special, however, is that they can be tissue specific. Many molecules (including approved drugs) that target neurological transmission pathways cause severe side effects because they interact with closely related proteins in a large variety of tissues. Studies on the binding affinity of the conotoxins suggest that they may be able to discriminate between highly similar binding pockets of closely related protein subtypes expressed in different tissue types. For example, µ-conotoxins bind more strongly to voltage-gated sodium channels in skeletal muscle than the subtypes of these channels found in neurons, whereas previously identified sodium channel inhibitors, like tetrodotoxin (TTX), cannot discriminate between receptors in these two tissues.

Since selectivity is a desirable characteristic of human therapies, this property of conotoxins makes them an intriguing source of new drugs. In fact, ziconotide (or Prialt®) is a ω-conotoxin isolated from C. magnus, which specifically binds voltage gated calcium ion channels in neuronal tissues. This molecule is an FDA approved pain reliever and is often used in cases where morphine is ineffective or insufficient. Ziconotide, however, is not a first-line analgesic, as it has to be administered directly into the spinal fluid - a process that is invasive and presents additional risks to the patient. Currently researchers are hoping to develop variants of this molecule with properties that would allow for intravenous or even oral administration.  

To isolate novel conotoxins, researchers extract the venom and run it over a column that separates the components by physical property. Each peak is a different conotoxin, and as depicted above, each conotoxin may cause a different phenotype when injected in mice.  Note: the trace shown above is just a representation, not data from a real experiment.

To isolate novel conotoxins, researchers extract the venom and run it over a column that separates the components by physical property. Each peak is a different conotoxin, and as depicted above, each conotoxin may cause a different phenotype when injected in mice.  Note: the trace shown above is just a representation, not data from a real experiment.

The toxin delivery strategy of cone snails is also fascinating because of its molecular complexity. The venom is a mixture of a variety of conotoxin subtypes (termed a “nirvana cabal”), meaning these molecules are delivered in concert and can hit multiple targets simultaneously. In other words, cone snails were using the drug cocktail approach long before combination therapies were put into use by humans. Further understanding the full biological effect of the venom could provide insight into the interconnectedness of the distinct molecular pathways targeted by each conotoxin.  

Analysis of the many venom contents of a diverse species of cone snails has uncovered a large variety of novel peptides that may one day provide novel therapeutics for pain relief or neuromuscular disorders. Yet cone snail venom has also been shown to contain the familiar. In a recent study by the Safavi-Hemami lab at University of Utah researchers found that some fish-eating cone snails inject their prey with insulin (as a component of the venom mixture). Much like in humans, this rush of insulin causes a plummet in blood sugar making their target fish lethargic and susceptible to cone snail predation. It’s remarkable to consider how varying the ecological context in which a molecule is produced could so completely alter its biological role.

Just within the genera Conus there are already >500 distinct known species.  But there are also other families of marine gastropods closely related to cone snails that could provide hundreds of thousands more unique venom sources. These small, resourceful marine creatures are a gold mine for short peptides with potent neurological effects. And whether they become drugs, or biological probes, or just molecules that can cause weird phenotypes in mice, they have the potential to broaden how we view the beauty of the cone snail.

-AMC