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 IndoPacific regions of southern Asia and northern Australia They can also be found in the Mediterranean and Hawaii ID: 697706
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Slide1
Natural Products Chemistry
Featuring
conus
magusSlide2
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. Slide3
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:Slide4
What?! A Killer Snail?! How?Slide5
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.Slide6
“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
.Slide7
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
. Slide8
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 compoundsSlide9
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.Slide10
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.Slide11
Conopeptides
being developed for pain treatment:Slide12
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.Slide13
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).Slide14
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 2004.
Prialt
is
1,000
times more potent than morphine, at lower doses, yet is without morphine’s addictive properties.Slide15
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
.Slide16
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
PRIALTSlide17
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
.Slide18
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:Slide19
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.Slide20
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.Slide21
QUESTIONS
?Slide22
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:Slide23
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: