A Conotoxin Derived Analgesic
The search for new & better drugs for treating infectious diseases, cancer & other ailments is never ending. Most people are not aware that the richest & often only sources of new compounds are of biological origin. This can include fungi, plants & surprisingly, a wide range of marine organisms. Of these, some of the most interesting come from snails, in particular from the genus Conus. In this article, we give a brief description of this gastropod mollusc and the drug Prialt (Ziconotide) that was produced from its venom.
The analgesics of choice for treating severe pain are mainly derivatives of the poppy plant extract opium. These include morphine, heroin, & others. Unfortunately, many people adapt to these drugs, especially in the late stages of cancer treatment making pain management very difficult.
Conopeptides (contoxins) produced by the marine snail Conus sp. are very selective in the ion channels they block which is very useful to both basic research & the search for novel drugs. One such drug, Prialt (Ziconotide) has been approved for use in humans for treating intractable pain. It targets voltage gated calcium channels associated with pain receptors & is estimated to be 1000 times more effective than morphine in this regard. However, because of severe side effects it cannot be administered by conventional means, oral or intravenous. It must instead be injected directly into spinal fluid.
Ziconotide: From our 3D Molecular Model Builder
The model shown below is the largest we have done to date with our 3D Molecular Model Builder. The structure has 102 carbons & is also distinguished by its 4 pairs of disulphide bridges created by the amino acid cysteine.
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Cone Snail Conus magus (Magic Cone)
The shells of these snails are 15-100mm long & are strikingly beautiful. They have been collected since antiquity with many valued highly as objets d’art. The snail whose venom was used for development of the new drug is Conus magus, section C, 2nd from the right.
The range of Conus magus is tropical & subtropical occurring within 40 degrees latitude on either side of the equator & is found along the shores of countries such as Australia, the Philippines, India & Mexico.
There are over 500 species in this genus, each with roughly 100 different toxins in their “arsenals”. These venoms have been adapted for prey animals including other snails, worms & even fish. Each venom is specific for the many types of ion channels (receptors) in prey species but interestingly the receptors in fish are very similar to those found in other vertebrates including mammals.
The delivery mechanism of these venoms is a particularly ingenious product of evolution. Most snails obtain nutrition by scraping off algae & other organic material from the surfaces they crawl over. They have a feeding structure called a radula that is loosely comparable to a tongue with teeth; see below left. These “teeth” have been modified to resemble harpoons which are injected into their target prey; see below right. The harpoons are hollow through which the venom is injected.
These snails are remarkable products of evolution & perfect examples of the need for preserving species diversity. They and many other species hold precious secrets we have yet to discover.
1) Cone snails general information: Wikipedia.
2) Ecological information: U. Wisconsin Lacrosse.
3) Biochemistry & pharmacology information: Heinrich Terlau, Baldomero M. Olivera in Physiological Reviews 1 January 2004, Vol. 84 No. 1.
4) Ion channel general information. Wikipedia