Conus Venom Peptides, Receptor and Ion Channel Targets, and Drug Design: 50 Million Years of Neuropharmacology

The predatory cone snails (Conus) are among the most successful living marine animals (;500 living species). Each Conus species is a specialist in neuropharmacology, and uses venom to capture prey, to escape from and defend against predators and possibly to deter competitors. An individual cone snail’s venom contains a diverse mixture of pharmacological agents, mostly small, structurally constrained peptides (conotoxins). Individual peptides are selectively targeted to a specific isoform of receptor or ion channel. A variety of such targets have been identified, including many voltage-gated and ligand-gated ion channel subtypes, as well as G protein-linked receptors. Although there are only a few widely shared structural motifs in conotoxins (the majority of the .25,000 peptides in these venoms probably belong to only half a dozen gene superfamilies), the sequences of peptides are remarkably divergent from one Conus species to another. We suggest that cone snails undergoing speciation have, in effect, a mutator phenotype which acts specifically on the gene segment encoding the mature toxin region. In their 50 million years of evolution, cone snails anticipated many features of the modern drug industry: disposable hypodermic needles, combination drug therapy, and combinatorial strategies for drug discovery. Recent results indicate that the Conus peptide system may provide a novel paradigm for designing ligands that discriminate between closely related members of large families of receptors and ion channels. Many Conus peptides may be “Janus-ligands,” with two distinct recognition faces oriented in different directions, a design which should make far greater target specificity possible. BIOLOGY OF CONE SNAILS: WHY A NEUROPHARMACOLOGICAL STRATEGY?