Venoms of predatory marine cone snails are intensely studied because of the biomedical applications of the neuropeptides that they contain, termed conotoxins. Meanwhile some gastropod lineages have independently acquired secretory glands strikingly similar to the venom gland of cone snails, suggesting that they possess similar venoms. Here we focus on the most diversified of these clades, the genus Vexillum . Based on the analysis of a multi-species proteo-transcriptomic dataset, we show that Vexillum species indeed produce complex venoms dominated by highly diversified short cysteine-rich peptides, vexitoxins. Vexitoxins possess the same precursor organization, display overlapping cysteine frameworks and share several common post-translational modifications with conotoxins. Some vexitoxins show sequence similarity to conotoxins and adopt similar domain conformations, including a pharmacologically relevant inhibitory cysteine knot motif. The Vexillum envenomation gland (gL) is a notably more recent evolutionary novelty than the conoidean venom gland. Thus, we hypothesize lower divergence between vexitoxin genes, and their ancestral ‘somatic’ counterparts compared to that in conotoxins, and we find support for this hypothesis in the evolution of the vexitoxin cluster V027. We use this example to discuss how future studies on vexitoxins can inform the origin of conotoxins, and how they may help to address outstanding questions in venom evolution.

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Venoms of predatory marine cone snails (the family Conidae, order Neogastropoda) are intensely studied because of the broad range of biomedical applications of the neuropeptides that they contain, conotoxins. Meanwhile anatomy in some other neogastropod lineages strongly suggests that they have evolved similar venoms independently of cone snails, nevertheless their venom composition remains unstudied. Here we focus on the most diversified of these lineages, the genus Vexillum (the family Costellariidae). We have generated comprehensive multi-specimen, multi-tissue RNA-Seq data sets for three Vexillum species, and supported our findings in two species by proteomic profiling. We show that venoms of Vexillum are dominated by highly diversified short cysteine-rich peptides that in many aspects are very similar to conotoxins. Vexitoxins possess the same precursor organization, display overlapping cysteine frameworks and share several common post-translational modifications with conotoxins. Some vexitoxins show detectable sequence similarity to conotoxins, and are predicted to adopt similar domain conformations, including a pharmacologically relevant inhibitory cysteine-know motif (ICK). The tubular gL of Vexillum is a notably more recent evolutionary novelty than the conoidean venom gland. Thus, we hypothesize lower divergence between the toxin genes, and their somatic counterparts compared to that in conotoxins, and we find support for this hypothesis in the molecular evolution of the vexitoxin cluster V027. We use this example to discuss how future studies on vexitoxins can inform origin and evolution of conotoxins, and how they may help addressing standing questions in venom evolution.