Marine cone snails

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... 

Figure 6 Venomous marine cone snails, (a) Geography cone Conus geographus (Public domain)) (b) Queen Victoria cone [Conus victoriae)-, (c) cloth of gold cone [Conus textile), (d) marble cone [Conus marmoreus (Public domain)) (e) closing view of proboscis with toxoglossan cone snail (f) microscope picture of toxoglossan from Conus consors. Photos (b), (c), (e),...

Bacteria, protozoa, and venomous animals synthesize numerous toxins that are used to kill their prey or to defend themselves. Sea anemones, jellyfish, cone snails, insects, spiders, scorpions, and snakes all make potent and highly specific neurotoxins. Plants form a host of alkaloids and other specialized products, some of which are specifically neurotoxic and able to deter predators. More than 500 species of marine cone snails of the genus Conus synthesize a vast array of polypeptide toxins (conotoxins), 487-489 some with unusual posttranslational modifications.490 491 The slow-moving snails are voracious predators that use their toxins, which they inject with a disposible harpoonlike tooth,492 to paralyze fish, molluscs, or worms.493... 

NMR is particularly suitable for the study of peptidic toxins because these molecules are typically small in size (less than 50 amino acids), are usually highly soluble and very often have well-defined structures stabilised by disulphide bonds, which predispose them to have excellent dispersion in their NMR spectra. Indeed, small disulphide-rich peptides are perhaps the one area of structural biology where NMR dominates over X-ray crystallography as the preferred structural technique. The Protein Data Bank (PDB), for example, shows that of the approximately 50,000 structures deposited, less than 20% have been determined by NMR, but if the analysis is done over peptides smaller than 50 amino acids then the proportion of NMR structures is approximately 90%. An example of the important role of NMR in structure determination of peptide toxins involves those from marine cone snails known as conotoxins. Of the 125 conotoxin structures... 

One of the most extensively studied families of peptide toxins, the conotoxins, is isolated from marine cone snails.140 141 Each snail produces a suite of 100-200 peptides in its venom, which is used for the capture of prey, and given that more than 500 species of cone snails are thought to exist, conotoxins represent an enormous diversity of peptide toxins. They have been classified into families, based on their target receptor specificity, and superfamilies, according to their... 

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-... 

Conotoxim (cone toxins). Peptide toxins from subtropical and tropical marine cone snails (shells) (Co-... 

The cone snails from all marine environments (Phylum Mollusca, Class Gastropoda, Order Sorbeoconcha) represent a large genus of approximately 700 carnivorous predator species (Figure 6). They are classified... 

Prialt [Fig. 6] is a synthetic copy of a toxin from the Magician s cone snail. Conus magus, a mollusk from the Indo-Pacific region. This is also one of the first pharmaceuticals that demonstrate the promise that marine life, particularly invertebrates, holds for drug developers. 

Conotoxins are small (10-30 amino acids), disulphide-rich, conformationally constrained peptides produced by marine mollusks such as cone snails. The fish-hunting snails, in particular Conus geographus, have been extensively studied. Depending upon the arrangement of disulphide bonds and the number of residues between cysteines, five or more classes of conotoxin can be structurally identified ... 

The genus Conus comprises approximately five hundred species of predatory cone snails and is therefore, one of the largest, if not the largest, single genus of marine animals alive. Each species of snail produces a unique venom with between 50 and 200 components. These sulfur-rich peptides or conotoxins are neuropharmacologically active and modulate ion channel function [235]. Any attempt to deal with these toxins within this review would not be feasible and the reader is referred to other excellent reviews on the subject [235,236]. 

Marine sponges contain a host of bioactive compounds, particularly small molecules, and also contain a range of peptides that are non-ribosomally synthesised, often containing non-native amino acids. However, there are examples of peptides of ribosomal origin, including, for example, asteropine A isolated from the sponge Asteropus simplex.133 This peptide comprises 36 residues and three disulphide bonds. It has potent sialidase inhibitory activity and thus has applications in the design of novel viral inhibitors. Structural analysis of asteropine A with NMR spectroscopy revealed a cystine-knot motif, similar to that already described for plant toxins. This observation emphasises the fact that the cystine-knot motif is extremely prevalent in disulphide-rich peptides.134 Asteropine A, discovered in 2006, was the first reported cystine-knot peptide isolated from marine invertebrates other than from cone snails, which are described in more detail below. 

Generally speaking, the peptide toxins from marine animal sources are more natural product-like than their terrestrial counterparts, as on average they are smaller in size and more heavily modified. For this reason, in this chapter, we will concentrate on the peptide toxins expressed by cone snails and sea anemones as quintessential examples of natural peptide toxins suitable for therapeutic uses. 

The precise composition of cone snail venom is species-specific with significant intraspecies variability. The venom is an extremely complex concoction (20-200 components) of modified peptides (conopeptides) that elicit a wide range of strong neurophysiological responses in a variety of organisms. The development of such extremely potent and biochemically diverse venom is likely to be an evolutionary adaptation designed to compensate for the lack of mobility of cone snails when compared to other marine predators. 

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