Natural Products Chemistry Featuring conus magus

Who is Conus Magus? Conus Magus is one of approximately 700 species of cone snails. Cone snails are indigenous to coral reefs in the Indo-Pacific regions of southern Asia and northern Australia. They can also be found in the Mediterranean and Hawaii.

Cone snails are CARNIVORES, and each cone snail contains a cocktail of approximately 200 different toxins- more than any other creature- which is used to incapacitate their prey. Cone snails range in size from four to six inches long and have varying colors and patterned shells. Mmm… this leaf is delicious… Like normal snails, cone snails are slow- moving, depending mainly on their protective exterior for defense from predators. Ordinary Garden Snail:

What?! A Killer Snail?! How?

The cone snail’s harpoon fires with enough force to pierce through a 3 mm wetsuit. Although many species’ stings are no worse than that of a bee, stings from some of the larger species can lead to paralysis, respiratory failure, and death. There is no known anti-venom. Being stung by a cone snail “is like being bitten by a cobra and eating fugu at the same time.” (BALDOMERA OLIVERA, PHD) Note: The fugu’s toxin is more than a thousand times deadlier to humans than cyanide.

“Eddie Carr: I loaded the enhanced venom of Conus purpurascens, the South Sea cone snail. Most powerful neurotoxin in the world. Acts within a two-thousandth of a second. Faster than the nerve-conduction velocity. The animal's down before it feels the prick of the dart. Ian Malcolm: Is there an antidote? Eddie Carr: What, like if you shot yourself in the foot? Don't do that. You'd be dead before you realized you'd had an accident. “ In Jurassic Park 2, cone snail venom was used as a weapon strong enough to take down a tyrannosaurus rex.

Cone snail venom, called conotoxin, is a mixture developed in a special gland and delivered to the hollow harpoon, which contains approximately 200 different toxins.

Each species of cone snail produces it’s own cocktail of toxins, and there is no overlap of toxins between species at all. 700 species x 200 toxins= 140,000 compounds

How does one collect lethal mollusk venom? Cone snails can be “milked” in the laboratory, often using fish fins for bait attached to a non-lubricated condom in which the venom can be collected and then analyzed.

small peptides, 10 to 30 amino acid residues in length, which target Chemically conotoxins are made up of small peptides, 10 to 30 amino acid residues in length, which target ion receptors and channels in the neuromuscular system. Less than 1% of these cono-peptides have been pharmacologically characterized. However, several are currently in the process of undergoing clinical trials and many more are being investigated for varying uses.

Conopeptides being developed for pain treatment:

Individual peptides are separated out via High Performance Liquid Chromatography (HPLC), which provides a chromatogram of the different components. This allows us to isolate a pure peptide and determine it’s amino acid sequence, as well as to determine the effects of each individual conotoxin. Each peak represents a different peptide, with a different absorbance value.

This is a chromatogram from one cone snail (conus geographus) which shows the varying effects of choice peptides that were isolated from this mixture (on mice).

FDA approved analgesic via the cone snail, marketed as “Prialt,” in This particular peptide was isolated from the conotoxin of Conus Magus. It’s synthetic form, ziconotide, was used to create the first FDA approved analgesic via the cone snail, marketed as “Prialt,” in Prialt is 1,000 times more potent than morphine, at lower doses, yet is without morphine’s addictive properties. Prialt is 1,000 times more potent than morphine, at lower doses, yet is without morphine’s addictive properties.

In fish, this conotoxin targets ion channels between the muscles and the brain, blocking the transmission of signals which leads to flaccid paralysis. However, in the human body, these particular ion channels are resistant to prialt, even at high concentrations. Instead, prialt is effective on ion channels in pain fibers.

Prialt lodges in the calcium channels, blocking the calcium from entering the cell. The Fiber continues to fire, but the signal is not transmitted to nerve so the brain does not receive it. Therefore, we do not perceive the pain. How does Prialt work as a pain killer? Electrical signals sent along the pain fibers cause calcium channels to open Calcium passes through the ion channels, triggering a release of neurotransmitters Neurotransmitters communicate with nerves which signal pain to the brain

High Affinity + Narrow Specificity Side effects of many drugs are caused by drug binding not only to the target receptor with therapeutic value, but also to other receptors which may cause undesirable responses. In contrast, conotoxins can discriminate among closely related receptor sub-types. The omega- conotoxin used in prialt binds only to a specific subtype of calcium channels in neuronal tissue, and excludes those in skeletal or cardiac muscle, with a discrimination ratio up to 100,000,000.

Dizziness (47%), Nausea (41%), Confusion (18-33%), Weakness (22%), Speech Disorder (9-14%), Muscle Spasms (16%), Drowsiness (22%), Memory Impairment (7-22%), Diarrhea (19%), Vomiting (16%), Headache (15%), Abnormal Gait (15%), Headache (13%), Aphasia (8-12%), Hallucinations (12%), Blurred Vision (12%) Side Effects:

Alpha-conotoxins investigated for blocking of nicotinic acetylcholine receptors, which aids in overcoming nicotine addiction. Potential Uses for Conotoxins: Alpha-Conotoxin ACV1 in phase II clinical trials developed for treatment of sciatica, shingles, and diabetic neuropathy. This specific conotoxin also has potential for accelerating the functional recovery of injured nerves and tissues.

Alpha- and kappa-conotoxins investigated for treating neuroprotection, schizophrenia, depression, and cancer. Potential Uses for Conotoxins: Other conotoxins show prospects for being potent pharmaceuticals in the treatment of Alzheimer’s disease, Parkinson’s disease, and epilepsy.

QUESTIONS

Newman, D.J., Cragg, G.M. (2007). Natural Products as Sources of New Drugs over the Last 25 Years. Journal of Natural Products, Volume 70 (3), Dobson, R., Collodoro, M., et al. (2012). Secretion and maturation of conotoxins in the venom ducts of Conus textile. Toxicon, Volume 60 (8), Olivera, B.M., Rivier J., et al. (1990). Diversity of Conus Neuropeptides. Science, Volume 249 (4966), Olivera, B.M. (2009), From Venom to Drugs, HHMI Holiday Lectures on Science, Lecture conducted from Howard Hughes Medical Institute, Chevy Chase, Maryland. References:

Fan, Y., Song, J., et al. (2011) PREDCSF: An integrated feature- based approach for predicting conotoxin superfamily. Peptide and protein letters, volume 18 (3), Kirtan, D., Lahiry, A., (2012) Conotoxins: review and docking studies to determine potentials of conotoxin as anticancer drug molecule, Current topics in medicinal chemistry, volume 12 (8), References: