E.E. Just Lecture, 1996

The predatory cone snails (Conus) are among the most successful living marine animals (ϳ500 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 Ͼ25,000 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.