Venomous marine snails (superfamily Conoidea) are a remarkably biodiverse marine invertebrate lineage (featuring more than 10,000 species). Conoideans use complex venoms (up to 100 different components for each species) to capture prey and for other biotic interactions. Molecular phylogeny and venom peptide characterization provide an unusual multidisciplinary view of conoidean biodiversity at several taxonomic levels. Venom peptides diverge between species at an unprecedented rate through hypermutation within gene families. Clade divergence within a genus occurs without recruiting new gene families when a saltatory event, such as colonization of new prey types (e.g., fish), leads to a new radiation. Divergence between genera in the same family involves substantial divergence in gene families. In the superfamily Conoidea, the family groups recruited distinct sets of different venom gene superfamilies. The associated morphological, behavioral, and prey-preference changes that accompany these molecular changes are unknown for most conoidean lineages, except for one genus, Conus, for which many associated phenotypic changes have been documented.

The fish-hunting marine cone snail Conus geographus uses a specialized venom insulin to induce hypoglycemic shock in its prey. We recently showed that this venom insulin, Con-Ins G1, has unique characteristics relevant to the design of new insulin therapeutics. Here, we show that fish-hunting cone snails provide a rich source of minimized ligands of the vertebrate insulin receptor. Insulins from C. geographus, Conus tulipa and Conus kinoshitai exhibit diverse sequences, yet all bind to and activate the human insulin receptor. Molecular dynamics reveal unique modes of action that are distinct from any other insulins known in nature. When tested in zebrafish and mice, venom insulins significantly lower blood glucose in the streptozotocin-induced model of diabetes. Our findings suggest that cone snails have evolved diverse strategies to activate the vertebrate insulin receptor and provide unique insight into the design of novel drugs for the treatment of diabetes.

Somatostatin (SS) is a peptide hormone with diverse physiological roles. By investigating a deep-water clade of fish-hunting cone snails, we show that predator-prey evolution has generated a diverse set of SS analogs, each optimized to elicit specific systemic physiological effects in prey. The increased metabolic stability, distinct SS receptor activation profiles, and chemical diversity of the venom analogs make them suitable leads for therapeutic application, including pain, cancer, and endocrine disorders. Our findings not only establish the existence of SS-like peptides in animal venoms but also serve as a model for the synergy gained from combining molecular phylogenetics and behavioral observations to optimize the discovery of natural products with biomedical potential.

Cone snails (genus Conus) are venomous marine snails that inject prey with a lethal cocktail of conotoxins, small, secreted, and cysteine-rich peptides. Given the diversity and often high affinity for their molecular targets, consisting of ion channels, receptors or transporters, many conotoxins have become invaluable pharmacological probes, drug leads, and therapeutics. Transcriptome sequencing of Conus venom glands followed by de novo assembly and homology-based toxin identification and annotation is currently the state-of-the-art for discovery of new conotoxins. However, homology-based search techniques, by definition, can only detect novel toxins that are homologous to previously reported conotoxins. To overcome these obstacles for discovery, we have created ConusPipe, a machine learning tool that utilizes prominent chemical characters of conotoxins to predict whether a certain transcript in a Conus transcriptome, which has no otherwise detectable homologs in current reference databases, is a putative conotoxin. By using ConusPipe on RNASeq data of 10 species, we report 5148 new putative conotoxin transcripts that have no homologues in current reference databases. 896 of these were identified by at least three out of four models used. These data significantly expand current publicly available conotoxin datasets and our approach provides a new computational avenue for the discovery of novel toxin families.

Venomous animals hunt using bioactive peptides, but relatively little is known about venom small molecules and the resulting complex hunting behaviors. Here, we explored the specialized metabolites from the venom of the worm-hunting cone snail, Conus imperialis. Using the model polychaete worm Platynereis dumerilii, we demonstrate that C. imperialis venom contains small molecules that mimic natural polychaete mating pheromones, evoking the mating phenotype in worms. The specialized metabolites from different cone snails are species-specific and structurally diverse, suggesting that the cones may adopt many different prey-hunting strategies enabled by small molecules. Predators sometimes attract prey using the prey’s own pheromones, in a strategy known as aggressive mimicry. Instead, C. imperialis uses metabolically stable mimics of those pheromones, indicating that, in biological mimicry, even the molecules themselves may be disguised, providing a twist on fake news in chemical ecology.