The marine environment has proven to be a valuable source of interesting and unusual natural products with a diverse range of biological activities. Of particular interest are marine snails belonging to the genus Conus, which contains an estimated 700 species, each possessing a unique cocktail of pharmacologically active peptides within its venom [1,2,3]. These marine snails have evolved into efficient predators, using their venom to hunt and paralyze worms, molluscs or fish. Conotoxins, isolated from the venom ducts of cone snails, constitute a large family of small, disulfide-rich peptides that have evolved to target a range of ion channels and receptors throughout the nervous system, usually with high potency and selectivity [4,5,6,7]. As such, many of these conotoxins have been used to gain further information about their target at the pharmacological, physiological or structural level [8,9,10,11]. They are relatively small peptides, typically eight to thirty amino acid residues in length that have been divided into different structural and pharmacological classes. A nomenclature for the conotoxins classifies the peptides according to the source, cysteine framework and biological target . The more recent availability of nucleic acid sequences from cDNA and transcriptomics analyses is enabling systematic classification into superfamilies on the basis of pre- and pro-peptide sequences [13,14].
Conotoxins serve not only as valuable pharmacological tools but potential drug candidates. While several conotoxins have advanced to clinical trials [15,16,17], ω-conotoxin MVIIA (ziconotide) was the first to be approved by the FDA for therapeutic use in humans . Marketed as Prialt®, it possesses potent and selective N-type calcium channel activity and is used to treat patients suffering from severe chronic pain . Although Prialt® represents a major milestone for conotoxins, its use is limited to intrathecal administration. Nonetheless, it highlights the potential of neurotoxic peptides as starting points for the development of therapeutics. Despite their desirable biological activities, peptides generally have several limitations that have restricted their progression as drug candidates, amongst which are short circulating half-life, poor proteolytic stability, and low oral bioavailability [20,21]. The challenge remains to capture the favorable bioactive properties of peptide toxins within drug-like molecules that can be administered in the clinic. This review summarizes current strategies for the development of conotoxins and their mimetics as leads for novel therapeutics.