Their Venom

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Geography Cone

C. geographus is thought to be the deadliest cone shell. Click on the picture to learn more!

Cone shell venom is probably one of the cone shells’ most fascinating features. Its target specificity and chemical diversity make it the subject of continuing biomedical and pharmacological research.

What are conotoxins?

Cone shells, being snails, aren’t the quickest predators in their marine environment. As a result, they’ve developed methods of hunting and self-defense that act rapidly once deployed. When a cone shell senses prey (or danger), it releases a harpoon coated in venom that can quickly paralyze and kill its target (Jin et. al 2019).

All cone shells produce venomous proteins known as conotoxins, but they vary in effect, partly due to their great chemical diversity. In fact, research shows that some cones may use different venom combinations for self-defense and hunting. The most poisonous cone shells, piscivores, or fish-hunters, are known to be deadly to humans in a matter of hours. Conus geographis, pictured above, is thought to be the deadliest cone shell.

Conotoxin Diversity

As discussed earlier, the complexity of conotoxins is directly related to species diversity. Each species of cone shell exhibits about 1,000 different conotoxins, and while scientists have sequenced around 10,000 of those proteins, that likely only accounts for about 1% of all conotoxins in existence (Jin et. al 2019). Even fewer have been pharmacologically characterized. Also consider that, because the genes that code for cone shell venom mutate so rapidly, there’s very little similarity in venom across the genus (Holmes 2014). Amazingly, even venom samples taken from cone shells of the same species can diverge tremendously (Jin et. al 2019).

So, what contributes to that diversity?

(1) Venom mix-n-match

The genes that code for conotoxins are organized for maximum efficiency, allowing cone shells to produce a stunning number of different proteins. A study of these venom genes showed that a basic signal sequence is highly conserved, meaning that it appears the same across all studied cone shells (Olivera 2006).

The mature toxin sequence, however, is located much farther down the gene, and is subject to much higher mutation rates than naturally occur. This allows cone shells to “experiment” with different venoms without losing the basic venom structure. The human immune system works in a similar way, producing endless variations of immune cells by mixing and matching different components.

(2) Add-ons and powerups

In addition to mutating unusually quickly, conotoxins also often undergo extensive post-translation modifications– that is, after the initial protein is created, machinery in the cell adds and/or removes pieces to optimize the protein’s function or prepare it for transport (Jin et. al 2019).

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Magical Cone (Click on the picture to learn more!)

Research Interest in Conotoxins

In addition to being highly diverse, conotoxins also exhibit a high degree of specificity. This means that a certain protein often has one very precise target. Scientists use this specific structure of conotoxins to sort them into groups identified by a single Greek letter an a common cellular target– for example, ⍺-conotoxins target nAchRs (nicotinic acetylcholine receptors). These receptors stimulate muscle movement and enable nerve-muscle communication, so blocking these receptors causes paralysis and eventual death (Kapil 2022). Furthermore, μ-conotoxins act on sodium channels, preventing nerves from firing. Even more conotoxins have been found to mimic human hormones like insulin, oxytocin and ADH.

The specificity of conotoxins is a source of interest and frustration for scientists. On one hand, it’s nearly impossible to develop an effective anti-venom for conotoxins because they’re so varied. Every conotoxin has such a specific target that it’s impossible to neutralize every toxin.

Pharmaceutical Applications

On the other hand, that same specificity has led to new discoveries in cell biology. Studying the effects of a conotoxins on mammals allows scientists to identify the function of specifically targeted receptors. In one case, scientists discovered a new cellular target for pain medications by studying the path of an analgesic μ-conotoxin (Holmes, 2014).

As it becomes clear that synthetic painkillers aren’t ideal, naturally occurring analgesics like conotoxins are currently being explored for potential pharmaceutical uses. One drug, Ziconitide (developed from the venom of Conus magus, pictured to left), has already been authorized by the FDA for the treatment of intractable pain (Holmes, 2014).

However, there are drawbacks– as David Holmes writes for the Lancet, conotoxins make “good drug leads” but they don’t make good drugs (p. 867).  Their structure is difficult to replicate and tends to be unstable. As a result, Ziconotide can’t be delivered orally– it must be delivered through a spinal pump– and is only authorized for those with late-stage cancer or AIDS. Stabilizing or hybridizing conotoxins using other natural proteins could allow drug developers to take advantage of conotoxins’ analgesic properties while also making them easier to distribute.

Their Venom