Conotoxins toxins

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... 

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. 

Like the other paralytic toxins from Conus venom, a-conotoxins are small and very tightly folded, structural features which may be advantageous for rapid paralysis of prey (1). a-Conotoxins are typically 13 to 15 amino acids long with two disulfide bridges (see Table III). In addition to the five a-conotoxins shown, two new a-conotoxins (SIA and SIB) from C. striatus have recently been isolated, sequenced, and chemically synthesized. SIA is very unusual because it is 19 amino acid residues long and it contains 6 cysteine residues, three of which are contiguous near the amino terminus (C. Ramilo et al., unpublished results). 

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. 

In the light of such considerations, it is possible to discuss toxins which have already been analyzed in terms of their sites of action. Such a discussion is best conducted by categorizing the various possible cellular sites at which a toxin might act. The most obvious sites are the membrane channels for ions, receptors for neurotransmitters, membrane pumps, and the membrane itself. Invertebrate toxins acting on membrane channels include the conotoxins (10) and several of the sea anemone toxins (97). 

Another possible target for toxins are the receptors for neurotransmitters since such receptors are vital, especially for locomotion. In vertebrates the most strategic receptor is that for acetylcholine, the nicotinic receptor. In view of the breadth of action of the various conotoxins it is perhaps not surprising that alpha-conotoxin binds selectively to the nicotinic receptor. It is entirely possible that similar blockers exist for the receptors which are vital to locomotion in lower species. As mentioned previously, lophotoxin effects vertebrate neuromuscular junctions. It appears to act on the end plate region of skeletal muscle (79,59), to block the nicotinic receptor at a site different from the binding sites for other blockers (81). 

Synthetic drugs of comparable selectivity and affinity to the 1,4-dihydropyridines do not yet exist for the other channel types, T, N, P/Q, and R these remain characterized by complex polypeptide toxins of the aga- and conotoxin classes. Neuronal pharmacology, including that of the central nervous system (CNS), is dominated by the N, P/Q, and R channels. This underscores the normally weak effect of L-channel antagonists on CNS function. Drugs that act at the N, P, and R channels with comparable selectivity and affinity to the 1,4-dihydropyridines may be expected to offer major potential for a variety of CNS disorders, including neuronal damage and death from ischemic insults. 

Of this family of peptides containing two intramolecular disulfide bonds the most studied in terms of oxidative refolding are a-conotoxins with two adjacent cysteine residues, i.e. with m = 0, the bee venom toxins, for example apamin and mast cell degranulating peptide, and snake venom toxins, exemplified by sarafotoxins, and endothelins, mammalian peptide hormones with the characteristic Cys-(Xaa)rCys/Cys-(Xaa)3-Cys motif (Scheme 2). With m = 0 or 1 all these peptides are expected to show a weak tendency to form the isomer 3 with a disulfide bond between two proximal cysteine residues. This was fully confirmed by oxidative refolding experiments. 

Although it is a general rule to operate at high dilution (10-4-10 5M) in oxidative folding reactions to avoid formation of intermolecular disulfide-bonded species, p.-conotoxin GIIIB offers an opposite example (Scheme 10). This toxin belongs to a family of conotoxins from marine snails consisting of 22 amino add residues with three intramolecular disulfide bonds.185 ... 

DHPs, dihydropyridines (eg, nifedipine) sFTX, synthetic funnel web spider toxin m-CTX, conotoxins extracted from several marine snails of the genus Conus -aga-IIIA and co-aga-IVA, toxins of the funnel web spider, Agelenopsis aperta SNX-482, a toxin of the African tarantula, Hysterocrates gigas. 

Com shell is carnivorous snail belongs to the world s largest genus of marine invertebrates (Conus) under the phylum of mollusks (Bingham et al., 2010). Com shell species are able to secrete venom, which contains com shell toxins (conotoxins) of bioactive peptides called as conopeptides (Layer and McIntosh, 2006). Different structural classes of... 

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