Cone snail toxins, conotoxins, are small peptides with disulfide connectivity,
that target ion-channels or G-protein coupled receptors. Based on the number
and pattern of disulfide bonds and biological activities, conotoxins can be
classified into several families . Omega, delta and kappa families of
conotoxins have a knottin or inhibitor cystine knot scaffold. The knottin
scaffold is a very special disulfide through disulfide knot, in which the III-VI disulfide bond crosses the macrocycle formed by two other disulfide bonds
(I-IV and II-V) and the interconnecting backbone segments, where I-VI
indicates the six cysteine residues starting from the N-terminus [2,E1].
Conotoxins represent a unique arsenal of neuropharmacologically active
peptides that have been evolutionarily tailored to afford unprecedented and
exquisite selectivity for a wide variety of ion-channel subtypes. The toxins
derived from cone snails are currently being investigated for the treatment of
chronic pain, epilepsy, cardiovascular diseases, psychiatric and movement
disorders, spasticity, cancer, stroke as well as an anesthetic agent. Several
potential analgesic and anti-inflammatory peptides from conotoxin families
have been identified and patented [3,4]:
Conus magus omega-conotoxin MVIIa (Ziconotide) is used for the treatment of
Conus catus omega-conotoxin CVID is tested for treating severe morphine-
resistant pain stress.
Conus geographus omega-conotoxin GVIA may exert antagonistic effects
against β-endorphin induced anti-nociception.
The disulfide bonding network as well as specific amino acids in inter-cysteine loops provide specificity of conotoxins . The cysteine arrangement
[C-C-CC-C-C] is the same for omega and delta families, which belong to the O-superfamily. The omega conotoxins are calcium channel blockers, whereas delta
conotoxins delay the inactivation of sodium channels . The M-superfamily Mu
conotoxins have two types of cysteine arrangement [CC-C-C-CC] and
[CC-C-C-C-C], but knottin scaffold is not observed. Mu conotoxins target the
voltage-gated sodium channels  and are useful probes for investigating
voltage-dependent sodium channels of excitable tissues . α conotoxins
belong to the A-superfamily and have two types of cysteine arrangement
[CC-C-C] and [CCC-C-C-C] . α conotoxins are competitive nicotinic
acetylcholine receptor antagonists. The I-superfamily of conotoxins is
characterized by a pattern of eight cysteine residues that form four disulfide
bridges. The arrangement of cysteine residues is similar to the Janus-faced
atracotoxin peptides characterized from spider venoms (see <PDOC60020>) [8,9].
Three signature patterns were developed for omega, delta and mu conotoxin
families. The patterns each include six conserved cysteines thought to be
important for the maintenance of the tertiary structure of the conotoxins. We
have defined a pattern for the common part of the cysteine arrangement
[CC-C-C] in all members of α conotoxin family. The pattern includes four
conserved cysteines thought to be important for the maintenance of the
tertiary structure of α conotoxins. The pattern for the I-superfamily
conotoxin covers the eight conserved cysteines.
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