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More than 100 species of venomous cone snails (genus Conus ) are highly effective predators of fish. The vast majority of venom components identified and functionally characterized to date are neurotoxins specifically targeted to receptors, ion channels, and transporters in the nervous system of prey, predators, or competitors. Here we describe a venom component targeting energy metabolism, a radically different mechanism. Two fish-hunting cone snails, Conus geographus and Conus tulipa , have evolved specialized insulins that are expressed as major components of their venoms. These insulins are distinctive in having much greater similarity to fish insulins than to the molluscan hormone and are unique in that posttranslational modifications characteristic of conotoxins (hydroxyproline, γ-carboxyglutamate) are present. When injected into fish, the venom insulin elicits hypoglycemic shock, a condition characterized by dangerously low blood glucose. Our evidence suggests that insulin is specifically used as a weapon for prey capture by a subset of fish-hunting cone snails that use a net strategy to capture prey. Insulin appears to be a component of the nirvana cabal, a toxin combination in these venoms that is released into the water to disorient schools of small fish, making them easier to engulf with the snail’s distended false mouth, which functions as a net. If an entire school of fish simultaneously experiences hypoglycemic shock, this should directly facilitate capture by the predatory snail. Significance The discovery and characterization of insulin, a key hormone of energy metabolism, provided a life-saving drug for diabetics. We show that insulin can be subverted for nefarious biological purposes: Venomous cone snails use specialized insulins to elicit hypoglycemic shock, facilitating capture of their fish prey. This finding extends our understanding of the chemical and functional diversity of venom components, such that the snail’s arsenal includes a diverse set of neurotoxins that alters neuronal circuitry, as well as components that override glucose homeostasis. The highly expressed venom insulins are distinct from molluscan insulins and exhibit remarkable similarity to fish insulins. They are the smallest of all insulins characterized from any source, potentially providing new insights into structure-function elements of insulin action.

α-Conotoxins are well-known probes for the characterization of the various subtypes of nicotinic acetylcholine receptors (nAChRs). Identifying new α-conotoxins with different pharmacological profiles can provide further insights into the physiological or pathological roles of the numerous nAChR isoforms found at the neuromuscular junction, the central and peripheral nervous systems, and other cells such as immune cells. This study focuses on the synthesis and characterization of two novel α-conotoxins obtained from two species endemic to the Marquesas Islands, namely Conus gauguini and Conus adamsonii. Both species prey on fish, and their venom is considered a rich source of bioactive peptides that can target a wide range of pharmacological receptors in vertebrates. Here, we demonstrate the versatile use of a one-pot disulfide bond synthesis to achieve the α-conotoxin fold [Cys 1-3; 2-4] for GaIA and AdIA, using the 2-nitrobenzyl (NBzl) protecting group of cysteines for effective regioselective oxidation. The potency and selectivity of GaIA and AdIA against rat nicotinic acetylcholine receptors were investigated electrophysiologically and revealed potent inhibitory activities. GaIA was most active at the muscle nAChR (IC50 = 38 nM), whereas AdIA was most potent at the neuronal α6/3 β2β3 subtype (IC50 = 177 nM). Overall, this study contributes to a better understanding of the structure–activity relationships of α-conotoxins, which may help in the design of more selective tools.

Small peptides isolated from the venom of the marine snails belonging to the genus Conus have been largely studied because of their therapeutic value. These peptides can be classified in two groups. The largest one is composed by peptides rich in disulfide bonds, and referred to as conotoxins. Despite the importance of conotoxins given their pharmacology value, little is known about the protein disulfide isomerase (PDI) enzymes that are required to catalyze their correct folding. To discover the PDIs that may participate in the folding and structural maturation of conotoxins, the transcriptomes of the venom duct of four different species of Conus from the peninsula of Baja California (Mexico) were assembled. Complementary DNA (cDNA) libraries were constructed for each species and sequenced using a Genome Analyzer Illumina platform. The raw RNA-seq data was converted into transcript sequences using Trinity, a de novo assembler that allows the grouping of reads into contigs without a reference genome. An N50 value of 605 was established as a reference for future assemblies of Conus transcriptomes using this software. Transdecoder was used to extract likely coding sequences from Trinity transcripts, and PDI-specific sequence motif \"APWCGHCK\" was used to capture potential PDIs. An in silico analysis was performed to characterize the group of PDI protein sequences encoded by the duct-transcriptome of each species. The computational approach entailed a structural homology characterization, based on the presence of functional Thioredoxin-like domains. Four different PDI families were characterized, which are constituted by a total of 41 different gene sequences. The sequences had an average of 65% identity with other PDIs. Using MODELLER 9.14, the homology-based three-dimensional structure prediction of a subset of the sequences reported, showed the expected thioredoxin fold which was confirmed by a \"simulated annealing\" method.

Conusis the largest genus of animals in the sea, occurring throughout the world's tropical and subtropical oceans and contributing significantly to marine biodiversity. The shells of these marine mollusks are prized for their amazing variety and extraordinary beauty. The neurotoxic venoms they produce-injected by a hollow, harpoon-like tooth into prey animals that are then paralyzed and swallowed whole-have a range of pharmaceutical applications, from painkillers to antidepressants. This beautifully illustrated book identifies 53 valid species of the southeastern United States and the Caribbean, a region that supports a diverse but taxonomically challenging group ofConus. Introductory chapters cover the evolution and phylogeny of the genus, and notes on methodology are provided. Detailed species accounts describe key identification features, taxonomy, distribution, ecology, toxicology, life history, and evolutionary relationships. The book includes more than 2,100 photos of shells on 109 splendid color plates; more than 100 additional photos, many depicting live animals in color; and 35 color distribution maps. Identifies 53 valid species-the first reassessment of western AtlanticConusin more than seventy yearsFeatures more than 2,100 photos of shells on 109 color platesBlends the traditional shell-character approach to identification with cutting-edge shell and radular tooth morphometrics and molecular genetic analysesIncludes color images of live animals as well as color distribution maps

Marine drugs have developed rapidly in recent decades. Cone snails, a group of more than 700 species, have always been one of the focuses for new drug discovery. These venomous snails capture prey using a diverse array of unique bioactive neurotoxins, usually named as conotoxins or conopeptides. These conotoxins have proven to be valuable pharmacological probes and potential drugs due to their high specificity and affinity to ion channels, receptors, and transporters in the nervous systems of target prey and humans. Several research groups, including ours, have examined the venom gland of cone snails using a combination of transcriptomic and proteomic sequencing, and revealed the existence of hundreds of conotoxin transcripts and thousands of conopeptides in each Conus species. Over 2000 nucleotide and 8000 peptide sequences of conotoxins have been published, and the number is still increasing quickly. However, more than 98% of these sequences still lack 3D structural and functional information. With the rapid development of genomics and bioinformatics in recent years, functional predictions and investigations on conotoxins are making great progress in promoting the discovery of novel drugs. For example, ω-MVIIA was approved by the U.S. Food and Drug Administration in 2004 to treat chronic pain, and nine more conotoxins are at various stages of preclinical or clinical evaluation. In short, the genus Conus, the big family of cone snails, has become an important genetic resource for conotoxin identification and drug development.

The a-Conotoxins are peptide toxins that are found in the venom of marine cone snails and they are potent antagonists of various subtypes of nicotinic acetylcholine receptors (nAChRs). Because nAChRs have an important role in regulating transmitter release, cell excitability, and neuronal integration, nAChR dysfunctions have been implicated in a variety of severe pathologies. We describe the isolation and characterization of α-conotoxin MilIA, the first conopeptide from the venom of Conus milneedwardsi. The peptide was characterized by electrophysiological screening against several types of cloned nAChRs that were expressed in Xenopus laevis oocytes. MilIA, which is a member of the α3/5 family, is an antagonist of muscle type nAChRs with a high selectivity for muscle versus neuronal subtype nAChRs. Several analogues were designed and investigated for their activity in order to determine the key epitopes of MilIA. Native MilIA and analogues both showed activity at the fetal muscle type nAChR. Two single mutations (Met9 and Asn10) allowed for MilIA to strongly discriminate between the two types of muscle nAChRs. Moreover, one analogue, MilIA [∆1,M2R, M9G, N10K, H11K], displayed a remarkable enhanced potency when compared to native peptide. The key residues that are responsible for switching between muscle and neuronal nAChRs preference were elucidated. Interestingly, the same analogue showed a preference for α9α10 nAChRs among the neuronal types.

The venom of each species of Conus contains different kinds of pharmacologically active peptides which are mostly unique to that species. Collectively, the ~500–700 species of Conus produce a large number of these peptides, perhaps exceeding 140,000 different types in total. To date, however, only a small fraction of this diversity has been characterized via transcriptome sequencing. In addition, the sampling of this chemical diversity has not been uniform across the different lineages in the genus. In this study, we used high-throughput transcriptome sequencing approach to further investigate the diversity of Conus venom peptides. We chose a species, Conus tribblei, as a representative of a poorly studied clade of Conus. Using the Roche 454 and Illumina platforms, we discovered 136 unique and novel putative conopeptides belonging to 30 known gene superfamilies and 6 new conopeptide groups, the greatest diversity so far observed from a transcriptome. Most of the identified peptides exhibited divergence from the known conopeptides, and some contained cysteine frameworks observed for the first time in cone snails. In addition, several enzymes involved in posttranslational modification of conopeptides and also some proteins involved in efficient delivery of the conopeptides to prey were identified as well. Interestingly, a number of conopeptides highly similar to the conopeptides identified in a phylogenetically distant species, the generalist feeder Conus californicus, were observed. The high diversity of conopeptides and the presence of conopeptides similar to those in C. californicus suggest that C. tribblei may have a broad range of prey preferences.

Animal venoms represent a vast library of bioactive peptides and proteins with proven potential, not only as research tools but also as drug leads and therapeutics. This is illustrated clearly by marine cone snails (genus Conus), whose venoms consist of mixtures of hundreds of peptides (conotoxins) with a diverse array of molecular targets, including voltage- and ligand-gated ion channels, G-protein coupled receptors and neurotransmitter transporters. Several conotoxins have found applications as research tools, with some being used or developed as therapeutics. The primary objective of this study was the large-scale discovery of conotoxin sequences from the venom gland of an Australian cone snail species, Conus victoriae. Using cDNA library normalization, high-throughput 454 sequencing, de novo transcriptome assembly and annotation with BLASTX and profile hidden Markov models, we discovered over 100 unique conotoxin sequences from 20 gene superfamilies, the highest diversity of conotoxins so far reported in a single study. Many of the sequences identified are new members of known conotoxin superfamilies, some help to redefine these superfamilies and others represent altogether new classes of conotoxins. In addition, we have demonstrated an efficient combination of methods to mine an animal venom gland and generate a library of sequences encoding bioactive peptides.

Venomous marine gastropods of the family Conidae are among the most diversified predators in marine realm—in large due to their complex venoms. Besides being a valuable source of bioactive neuropeptides conotoxins, cone-snails venoms are an excellent model for molecular evolution studies, addressing origin of key innovations. However, these studies are handicapped by scarce current knowledge on the tissues involved in venom production, as it is generally assumed the sole prerogative of the venom gland (VG). The role of other secretory glands that are present in all Conus species (salivary gland, SG) or only in some species (accessory salivary gland, ASG) remains poorly understood. Here, for the first time, we carry out a detailed analysis of the VG, SG, and ASG transcriptomes in the vermivorous Conus virgo. We detect multiple transcripts clusters in both the SG and ASG, whose annotations imply venom-related functions. Despite the subsets of transcripts highly-expressed in the VG, SG, and ASG being very distinct, SG expresses an L-, and ASG—Cerm08-, and MEFRR- superfamily conotoxins, all previously considered specific for VG. We corroborate our results with the analysis of published SG and VG transcriptomes from unrelated fish-hunting C. geographus, and C. striatus, possibly fish-hunting C. rolani, and worm-hunting Conus quercinus. In spite of low expression levels of conotoxins, some other specific clusters of putative venom-related peptides are present and may be highly expressed in the SG of these species. Further functional studies are necessary to determine the role that these peptides play in envenomation. In the meantime, our results show importance of routine multi-tissue sampling both for accurate interpretation of tissue-specific venom composition in cone-snails, and for better understanding origin and evolution of venom peptides genes.

A large majority of cone snails (a species in the genus Conus) are vermivorous (worm-hunting), but the diversity and bioactivity of their venom peptides remain largely unexplored. In this study, we report the first venom gland transcriptomes from two species in the Rhizoconus clade, Conus capitaneus and Conus mustelinus, and a new Conus miles transcriptome from a specimen collected in the Philippines. From the set of assembled sequences, a total of 225 C. capitaneus, 121 C. miles, and 168 C. mustelinus putative peptide toxin transcripts were identified, which were assigned to 27 canonical gene superfamilies in C. capitaneus and 24 in C. miles and in C. mustelinus. Most of these venom peptides are novel, and some exhibit new cysteine patterns. Clustering also revealed 12 putative novel gene superfamilies, highlighting the diversity of uncharacterized venom peptides in this group. The O1-, M-, O2-, and con-ikot-ikot superfamilies were the most abundant, while gene superfamilies such as D and G2 were highly expressed. Several hormone-like conopeptides were also identified in this study, revealing the vast diversity of conopeptides from the Rhizoconus species.