Conotoxin peptides

Cone snails, Conus spp., have been investigated because of their production of conotoxin peptides. From an evolutionary standpoint, the production of conotoxins is quite interesting due to their wide range of neurophysiological activities. The conotoxins are small peptides, 10-30 amino acids, with conformations constrained by multiple disulfide bonds that target a number of receptors in vertebrate and invertebrate nervous systems. Cone snails use these toxins to immobilize prey, which allows the relatively slow-moving cone snails to feed on fish and worms. The wide variety of conotoxins isolated and the hypervariability within peptide sequences has led some to hypothesize a combinatorial biosynthetic approach for the production of conotoxins.116117... 

The Nayl a-subunit is a large protein, and several receptor sites for natural product neurotoxins have been identified by photoaffinity labeling and site-directed mutagenesis [79]. The small hydrophilic guanidines TTX and STX and the p,-conotoxin peptides bind at the extracellular mouth of the conduction pathway and are thought to physically occlude the pore. Binding of these toxins shows little state- or use-dependence. A number of a scorpion, sea anemone, and spider toxins also bind to an extracellular site, but act as... 

Finally, an outstanding example of research into marine bioactive peptides is that of the conotoxin peptides derived from the venom of marine snails of the genus Conus [159]. The initial propeptide is processed by both post-translational modification and proteolytic cleavage into a variety of small peptides which are 10-50 amino acids in length [160, 161]. Research into potential therapeutic applications of the conotoxins has shown that a number of these peptides interact uniquely with ion channels to induce a wide variety of pharmacological effects in mammalian systems [162-164]. General reviews of the conotoxins are available [160, 165], as well as more-detailed reviews of their structures [166] and potential therapeutic uses [166-168]. 

Conotoxins are the venoms of the marine cone snails. The >500 Conus species produce >10,000 different toxins. All are cysteine-rich peptides of 10-30 amino... 

Certain occluders also discriminate among Na channels from neuronal and skeletal muscle. But in this case the blocking ligands are small peptides, the x-conotoxins from the mollusc Conus geo aphus. This molecule binds tightly to muscle Na channels, effectively reducing Na current (55 see Figure 6A), and also can displace bound... 

Conotoxins Targeted Peptide Ligands from Snail... 

OLIVERA ET AL, Conotoxins Targeted Peptide Ligands from Snail Venoms 2<>3... 

When a cone snail envenomates its prey, the latter is invariably paralyzed. In all cases, the paralytic toxins in the venom ("conotoxins") appear to be small peptides, most commonly with 3 disulfide bonds (although conotoxins with 2 or 4 S-S bonds... 

Between 6 and 10 homologous peptides have been extensively characterized for each toxin class. Although uj- and a-conotoxins have been isolated from several fish-hunting Conus species, x-conotoxins have so far been isolated only from C. geographus venom. 

Peptides in the a-conotoxin family are inhibitors of nicotinic acetylcholine receptors. They were first isolated from C. geographus venom as components which cause paralysis in mice and fish when injected intraperitoneally (27). Early physiological experiments (28) indicated that a-conotoxins GI, GII, and GIA (see Table III) all act at the muscle end plate region. Mini end-plate potentials and end plate potentials evoked in response to nerve stimulation are inhibited in the presence of a-conotoxins in the nM to pM range. a-Conotoxin GI was subsequently shown to compete with rf-tubocurarine and a-bungarotoxin for the acetylcholine receptor (29). 

The a -, /z-, and a-conotoxins are the best characterized of the peptides isolated from Conus venoms so far. However, a large number of other peptides are found in these venoms. These comprise both paralytic toxins to immobilize the prey of the cone snail, and other biologically active peptides which are not themselves directly paralytic. Only the briefest overview of these peptide components will be presented here. 

Another potentially paralytic conotoxin was recently described this was a peptide purified from Conus geographus venom, which like / -conotoxin appeared to target to voltage-sensitive Na channels. However, the structure of "conotoxin GS" [nomenclature of Yanagawa et al. (J7)] was less homologous to / -conotoxins than to the w-conotoxins, which are Ca channel blockers. The same peptide was purified and characterized using a different assay, the induction of highly aberrant behavior upon ic injection of mice (L. J. Cruz, unpublished data). 

Xen-2174 (220) (isolated from the snail Conus marmoreus) 13-Amino-acid peptide (a conotoxin) Xen-2174 (220) Neurology (Pain) Inhibits norepinephrine transporter (NET) Phase II (against acute postoperative pain and chronic pain in cancer patient) Xenome 970-973... 

GrantMA, MorelliXJ, Rigby AC, Conotoxins and structural biology A prospective paradigm for drug discovery, Curr Protein and Peptide Sci 5 235—248, 2004. 

Armishaw CJ, Alewood PE, Conotoxins as research and drug leads, Curr Protein and Peptide Sci 6 221-224, 2005. 

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