Conus magus, conotoxins from

NMR Structure of Ziconotide A Novel Treatment for Pain. MVIIA, now known as Ziconotide, is a 25-amino acid peptide originally discovered from the venom of the marine cone snail. Conus magus. Like other to-conotoxins it is a potent blocker of N-type calcium channels, giving it a wide range of potential therapeutic applications. When delivered intrathecally (i.e., through spinal infu-... 

FIGU RE 5.1 Upper panel shows the sequence of CO-conotoxins isolated from Conus geographus (GVIA), Conus magus (MVllA, MVllC, and MVllD) and Conus Striatus (SVIA). Lower panel shows the arrangement of the cys residues that constitutes the four-loop structure. 

This compotmd, discovered in 1979, is in Phase III clinical trials, and a request for NDA approval submitted in 1999 was granted on 28th June 2000. On 28th December 2004, the FDA approved Prialt for the treatment of chronic pain by intrathecal injection. It is a very powerful analgesic (painkiller), approximately a thousand-fold more effective than morphine, but does not provoke any dependence effects. It was extracted from the venom of the mollusk Conus magus, collected in the Philippines. These cones are carnivorous sea snails that kill their prey (fish, moUusks and worms) by means of a very sophisticated system that is a true natural blowpipe. The microscopic arrows launched by the mollusk are coated with very powerful venoms, of which there are two principal types, a- and / -conotoxin. 

R., Varga, J., Gray, W. R. and Rivier, J. 1987. Neuronal calcium channel antagonists. Discrimination between calcium channel subtypes using co-conotoxins from Conus magus venom. Biochemistry 26 2086-2090. 

Olivera, B.M., 1987, Neuronal Calcium channel Antagonists. Discrimination between Calcium Channel Subtypes using co-Conotoxin from Conus magus Venom, In Biochemistry, 26, 2086-209. 

As indicated, co-conotoxins are found in almost aU fish-hunting Conus species examined up to now. The most thoroughly studied are the venoms from C. geographus, C. magus, and C. striatus. Several of these peptides have been purified, sequenced, and synthesized (with similar potency as the natural toxins) and they have become important tools for the identification and characterization of the different subtypes of voltage-dependent Ca channels found in neuronal tissues. 

With the exception of a-conotoxin SII from Conus striatus, all a-conotoxins have the cysteine pattern, CC—C—C (Myers et al., 1993) (see Table 4). Peptides from the fish-hunting species, C geographus, C. striatus and C. magus, have the consensus core sequence CC(N/H)PACGXX(Y/F)XC and two disulfide bonds that connect Cys to Cys and Cys to Cys. Comparison with the a-conotoxins recently isolated from C. pennaceus, a mollusc-hunter, and C. imperialism a worm-hunter, indicates variations in the size of the intercysteine loops. The second loop has seven amino acid residues in a-conotoxins PnIA and PnIB from C pennaceus (Fainzilber et al., 1994), and only three residues in a-conotoxin Iml from C. imperialis (McIntosh et al., 1994), compared to five residues in the other a-conotoxins. 

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