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.
Slide 3
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:
Slide 4
What?! A Killer Snail?! How?
Slide 5
The cone snails 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 fugus toxin is more than a thousand times deadlier to
humans than cyanide.
Slide 6
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.
Slide 7
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.
Slide 8
Each species of cone snail produces its own cocktail of toxins,
and there is no overlap of toxins between species at all. 700
species x 200 toxins= 140,000 compounds
Slide 9
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.
Slide 10
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.
Slide 11
Conopeptides being developed for pain treatment:
Slide 12
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 its 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.
Slide 13
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).
Slide 14
FDA approved analgesic via the cone snail, marketed as Prialt,
in 2004. This particular peptide was isolated from the conotoxin of
Conus Magus. Its synthetic form, ziconotide, was used to create the
first FDA approved analgesic via the cone snail, marketed as
Prialt, in 2004. Prialt is 1,000 times more potent than morphine,
at lower doses, yet is without morphines addictive properties.
Prialt is 1,000 times more potent than morphine, at lower doses,
yet is without morphines addictive properties.
Slide 15
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.
Slide 16
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
Slide 17
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.
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.
Slide 20
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 Alzheimers disease,
Parkinsons disease, and epilepsy.
Slide 21
QUESTIONS
Slide 22
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), 461-477. Dobson, R., Collodoro, M., et al. (2012).
Secretion and maturation of conotoxins in the venom ducts of Conus
textile. Toxicon, Volume 60 (8), 1370-1379. Olivera, B.M., Rivier
J., et al. (1990). Diversity of Conus Neuropeptides. Science,
Volume 249 (4966),257-263. Olivera, B.M. (2009), From Venom to
Drugs, HHMI Holiday Lectures on Science, Lecture conducted from
Howard Hughes Medical Institute, Chevy Chase, Maryland.
http://media.hhmi.org/hl/09Lect1.html References:
Slide 23
Fan, Y., Song, J., et al. (2011) PREDCSF: An integrated
feature- based approach for predicting conotoxin superfamily.
Peptide and protein letters, volume 18 (3), 261-267. 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), 845-851.
References:
