Deadly toxins from the sea

Intaglio print of conotoxin protein structures from the PDB
01 November 2019

Have you ever wondered what the most dangerous animal living in the sea is? The neurotoxin from one particularly dangerous creature became an inspiration for the November artwork in our 2019 calendar, but it’s probably not the creature you’re thinking of.

Sharks get a bad reputation for killing unsuspecting divers, but did you know there is a higher chance of being attacked by a hippo than by a shark? The world’s oceans are teeming with life. A lot of beautiful and fascinating creatures live there, but it can be a pretty dangerous place to live, too. Some animals have evolved poisons that can be used to catch their next dinner or as protection against predators. Thinking about the most dangerous ocean creatures, snails are quite unlikely to come to mind. Despite their small size, and often beautiful shells, they possess deadly neurotoxins. So if you accidently disturb or frighten a cone snail, you might be stung and possibly die without feeling any pain.

Cone snails can be found among rocks, coral reefs or on sand where they bury themselves for a protection. Typically they live in warm and tropical seas from the Indian and Pacific oceans to the Caribbean and Red seas, also along the coast of Florida. Some species are adapted to the cooler waters of southern California or Mediterranean Sea. The bright colours and patterns of cone snail shell are attractive for shell collectors, but picking up a live creature might be pretty risky. The smallest cone snails have a sting that is about as powerful as a bee sting, but the sting of a larger species can kill an adult human in a matter of hours. It is believed that species living in the Indo-Pacific region tend to have more harmful toxin than the others.

Cone snails are predators. Despite the fact that snail are very slow moving animals, these snails have evolved very skilful techniques to hunt and catch their prey (marine worms, small fish, molluscs, and even other cone snails). Cone snails use a radula tooth (made of chitin and filled with a venom) as a harpoon-like weapon that can be fired in any direction. When the cone snail detects prey nearby, it quickly prepares the tooth to be fired. Once the prey is hit and the venom is injected, the prey becomes paralyzed and unable to get away. The cone snail then slowly pulls the immobilized meal inside the shell to digest it whole. Each tooth is discarded after use and immediately replaced by another.

What makes the cone snails so venomous are an extensive group of hundreds of short peptide toxins called conotoxins. These peptides are 15-30 amino acids long and generally have 2-3 disulfide bridges. Five main types of conotoxins have been classified (alpha, delta, kappa, mu and omega) based on the number and position of disulfide bonds and the sequence of the amino acids. Conotoxins work by effecting the action of ion channels and neurotransmitter receptors causing muscle paralysis leading to respiratory arrest. Different types of conotoxins target different channels or receptors, for example the alpha-conotoxin in PDB entry 2br8 is bound to the receptor for the neurotransmitter acetylcholine.

Structures of conotoxin peptide classes and their conserved disulphide bonds

Graphical and structural (yellow bars) representation of the position of disulfide bridges which play a key role in the ability of conotoxins to selectively block particular ion channels and neuronal receptors.

 

How the cone snail’s deadly venom can help us build better medicines

The ability of conotoxins to selectively block the activity of ion channels and neuronal receptors mean that these peptides are of great pharmacological interest. Finding answers to why cone snail venom is able to penetrate another animal’s nervous system and paralyze a victim so quickly and so effectively might lead to novel drugs that move through a patient’s body more quickly and effectively.

So far, the research into conotoxins has mainly focused on the treatment of different forms of pain. A synthetic form of ω-conotoxin under the generic name Ziconotide prevents the propagation of pain signals to the brain by blocking neurotransmission at synapses. It is 1000 times stronger than morphine yet lacks the addictive side effects.

Other therapeutic applications of conotoxins include the treatment of schizophrenia, epilepsy, neuromuscular disorders, certain types of cancer, and many more diseases. Other potential uses of conotoxins are in anaesthetics and cosmetic anti-wrinkle products, thanks to their fast action (muscle relaxation) after being injected. There is even a worry that they may be used in bioterrorism.

Whatever their eventual use, these small sea creatures produce peptides that can have a big impact on our lives.

About the artwork

William Rayner from Impington Village College is the artist of this intaglio print for November. This artwork displays α-conotoxin PnlB (PDB entry 1akg) in comparison with α-conotoxin PnlA (PDB entry 1pen) and α-conotoxin Gl (PDB entry 1xgb).

Romana Gáborová