![]() ![]() Much less well-recognized is the emerging evidence that non-peptidic small molecules are used by certain lineages of cone snails as part of their strategy of envenomation. The purpose of this article is to balance the perception that the bioactive components of cone snail venoms are all small peptides (typified by the α-conopeptides). Cone snail venom peptides of this type have now been studied for many decades and are increasingly well characterized ( Azam and McIntosh, 2009). The gene structure that encodes this family of venom components is conserved a large fraction of the peptides encoded by this gene superfamily share their general targeting specificity-these inhibit nicotinic acetylcholine receptors of various types ( McIntosh et al., 1999). The mature peptides are encoded at the C-terminal end of a canonical precursor with a conserved signal sequence and an intervening propeptide region. One such example of a well-characterized group of venom peptides are the α-conopeptides that belong to the A-gene superfamily: the bioactive post-translationally processed gene products are typically small (10–25 amino acids) peptides with two disulfide bonds ( Puillandre et al., 2010). No matter what the prey type, many venom components are encoded by a few well-characterized gene superfamilies expressed in the venom glands and distributed through all of the diverse lineages of cone snails ( Robinson and Norton, 2014). The venom is injected by extending a proboscis from the anterior gut, through a highly -specialized radular tooth that serves as a hypodermic needle ( Kohn et al., 1999). The venoms are produced in a long venom gland, lined with secretory epithelial cells where the biosynthesis of venom components takes place. Despite the enormous range of biology evolved across the entire group, there is a general feature characteristic of the entire family (Conidae): all cone snails have complex venoms each with its own distinctive complement of typically 100–200 bioactive venom components ( Olivera et al., 2014). ![]() The cone snails can be grouped into distinct clades, based on molecular phylogenetic data these divisions generally correlate with the prey specialization of each clade ( Nam et al., 2009 Kraus et al., 2011). The venomous cone snails comprise a biodiverse lineage of marine gastropods (∼1,000 living species) that specialize on the spectrum of prey (fish, other gastropod molluscs, or polychaete worms) envenomated by each species. Thus, in analogy to the incredible pharmacopeia resulting from studying venom peptides, these small molecules may provide a new resource of pharmacological agents. The compounds so far characterized are active on neurons and thus may potentially serve as leads for neuronal diseases. In contrast to standing dogma in the field that peptide and proteins are predominantly used for prey capture in cone snails, these small molecules also contribute to prey capture and push the molecular diversity of cone snails beyond peptides. In particular, a basal clade of cone snails ( Stephanoconus) that prey on polychaetes produce genuanine and many other small molecules in their venoms, suggesting that this lineage may be a rich source of non-peptidic cone snail venom natural products. Since the initial discovery of genuanine as the first bioactive venom small molecule with an unprecedented structure, a broad set of cone snail venoms have been examined for non-peptidic bioactive components. In this review, we describe how it has recently become clear that to varying degrees, cone snail venoms also contain bioactive non-peptidic small molecule components. These venom components (“conotoxins, conopeptides”) have been widely studied in many laboratories, leading to pharmaceutical agents and probes. Prior characterization of cone snail venoms established that bioactive venom components used to capture prey, defend against predators and for competitive interactions were relatively small, structured peptides (10–35 amino acids), most with multiple disulfide crosslinks. ![]() Venomous molluscs (Superfamily Conoidea) comprise a substantial fraction of tropical marine biodiversity (>15,000 species). 4Interdisciplinary Centre of Marine and Environmental Research, CIIMAR/ CIMAR, Faculty of Sciences, University of Porto, Porto, Portugal.3Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.2Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.1Departments of Medicinal Chemistry and Biochemistry, School of Biological Sciences, University of Utah, Salt Lake City, UT, United States.Neves 4, Samuel Espino 1, Manju Karthikeyan 1, Baldomero M. Imperial 1, Jortan Tun 1, Helena Safavi-Hemami 1,2, Rocio K. Torres 1, Maren Watkins 1, Noemi Paguigan 1, Changshan Niu 1, Julita S. ![]()
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