Cone snail toxins, conotoxins, are small neurotoxic peptides with disulphide connectivity that target ion-channels or G-protein coupled receptors. Based on the number and pattern of disulphide bonds and biological activities, conotoxins can be classified into several families . Omega, delta and kappa families of conotoxins have a knottin or inhibitor cysteine knot scaffold. The knottin scaffold is a very special disulphide-through-disulphide knot, in which the III-VI disulphide bond crosses the macrocycle formed by two other disulphide bonds (I-IV and II-V) and the interconnecting backbone segments, where I-VI indicates the six cysteine residues starting from the N terminus.The disulphide bonding network, as well as specific amino acids in inter-cysteine loops, provide the specificity of conotoxins . The cysteine arrangements are the same for omega, delta and kappa families, even though omega conotoxins are calcium channel blockers, whereas delta conotoxins delay the inactivation of sodium channels, and kappa conotoxins are potassium channel blockers . Mu conotoxins have two types of cysteine arrangements, but the knottin scaffold is not observed. Mu conotoxins target the voltage-gated sodium channels , and are useful probes for investigating voltage-dependent sodium channels of excitable tissues . Alpha conotoxins have two types of cysteine arrangements , and are competitive nicotinic acetylcholine receptor antagonists.

To expand our capacity to discover venom sequences from the genomes of venomous organisms, we applied targeted sequencing techniques to selectively recover venom gene superfamilies and non-toxin loci from the genomes of 32 cone snail species (family, Conidae), a diverse group of marine gastropods that capture their prey using a cocktail of neurotoxic peptides (conotoxins). We were able to successfully recover conotoxin gene superfamilies across all species with high confidence (> 100X coverage) and used these data to provide new insights into conotoxin evolution. First, we found that conotoxin gene superfamilies are composed of 1-6 exons and are typically short in length (mean = ~85bp). Second, we expanded our understanding of the following genetic features of conotoxin evolution: (a) positive selection, where exons coding the mature toxin region were often three times more divergent than their adjacent noncoding regions, (b) expression regulation, with comparisons to transcriptome d...

epitope description:NPA,antigen name:Alpha-conotoxin GIA,host organism:Capra hircus

The conotoxin market is experiencing robust growth, driven by increasing demand for novel pain therapeutics and advancements in drug discovery technologies. While precise market sizing data is unavailable, considering the high value and specialized nature of conotoxins, a reasonable estimation for the 2025 market size could be in the range of $200-250 million, given the involvement of companies like Bio Component Research and Smartox Biotechnology, which suggests a substantial investment in research and development within this niche. The Compound Annual Growth Rate (CAGR) for the forecast period (2025-2033) is likely to be within the range of 12-15%, fueled by ongoing research into conotoxin's diverse pharmacological properties and the expanding pipeline of preclinical and clinical trials investigating its therapeutic potential. Key growth drivers include the rising prevalence of chronic pain conditions, the limitations of existing treatments, and the potential for conotoxins to offer more targeted and effective pain management solutions. Emerging trends include the exploration of conotoxins for other therapeutic areas beyond pain, such as cancer and neurological disorders, further broadening the market's potential. However, the market faces restraints such as the high cost of research and development, the complex nature of conotoxin extraction and synthesis, and the regulatory hurdles associated with bringing novel biopharmaceuticals to market. Market segmentation will likely include therapeutic applications (pain management, cancer, etc.), delivery methods, and geographical regions. The competitive landscape is characterized by a blend of established pharmaceutical companies and smaller biotech firms focused on conotoxin research and development. Companies like Gene-Biocon and Suzhou Tianma Pharmaceutical, with their established presence in the pharmaceutical industry, bring significant resources and expertise to the field. The competitive dynamics will largely depend on the success of ongoing clinical trials, the development of innovative drug delivery systems, and the speed of regulatory approvals for new conotoxin-based therapies. Further growth is expected as research expands to explore new conotoxin structures and their potential uses in various therapeutic areas, strengthening the market's overall value and potential. The forecast period of 2025-2033 promises significant advancements and expansion within this promising but niche segment of the pharmaceutical industry.

Understanding why some groups of organisms are more diverse than others is a central goal in macroevolution. Evolvability, or the intrinsic capacity of lineages for evolutionary change, is thought to influence disparities in species diversity across taxa. Over macroevolutionary time scales, clades that exhibit high evolvability are expected to have higher speciation rates. Cone snails (family: Conidae, >900 spp.) provide a unique opportunity to test this prediction because their toxin genes can be used to characterize differences in evolvability between clades. Cone snails are carnivorous, use prey-specific venom (conotoxins) to capture prey, and the genes that encode venom are known and diversify through gene duplication. Theory predicts that higher gene diversity confers a greater potential to generate novel phenotypes for specialization and adaptation. Therefore, if conotoxin gene diversity gives rise to varying levels of evolvability, conotoxin gene diversity should be coupled with macroevolutionary speciation rates. We applied exon capture techniques to recover phylogenetic markers and conotoxin loci across 314 species, the largest venom discovery effort in a single study. We paired a reconstructed timetree using 12 fossil calibrations with species-specific estimates of conotoxin gene diversity and used trait-dependent diversification methods to test the impact of evolvability on diversification patterns. Surprisingly, we did not detect any signal for the relationship between conotoxin gene diversity and speciation rates, suggesting that venom evolution may not be the rate-limiting factor controlling diversification dynamics in Conidae. Comparative analyses showed some signal for the impact of diet and larval dispersal strategy on diversification patterns, though detection of a signal depended on the dataset and the method. If our results remain true with increased taxonomic sampling in future studies, they suggest that the rapid evolution of conid venom may cause other factors to become more critical to diversification, such as ecological opportunity or traits that promote isolation among lineages.

Conotoxins are small snail toxins that block ion channels.

Marine cone snail venoms represent a vast library of bioactive peptides with proven potential as research tools, drug leads, and therapeutics. In this study, a transcriptome library of four different organs, namely radular sheath, venom duct, venom gland, and salivary gland, from piscivorous Conus striatus was constructed and sequenced using both Illumina next-generation sequencing (NGS) and PacBio third-generation sequencing (TGS) technologies. A total of 428 conotoxin precursor peptides were retrieved from these transcriptome data, of which 413 conotoxin sequences assigned to 13 gene superfamilies, and 15 conotoxin sequences were classified as unassigned families. It is worth noting that there were significant differences in the diversity of conotoxins identified from the NGS and TGS data: 82 conotoxins were identified from the NGS datasets while 366 conotoxins from the TGS datasets. Interestingly, we found point mutations in the signal peptide sequences of some conotoxins with the same mature sequence. Therefore, TGS broke the traditional view of the conservation of conotoxin signal peptides and the variability of mature peptides obtained by NGS technology. These results shed light on the integrated NGS and TGS technologies to mine diverse conotoxins in Conus species, which will greatly contribute to the discovery of novel conotoxins and the development of new marine drugs.

Conotoxins are a family of highly toxic neurotoxins composed of cysteine-rich peptides produced by marine cone snails. The most lethal cone snail species to humans is Conus geographus, with fatality rates of up to ∼65% from a single sting, which is caused mostly by the activity of α-conotoxins against human nicotinic acetylcholine receptors (nAChRs). While sequence-based machine learning (ML) classifiers have been trained to identify targets of conotoxins binding voltage-gated ion channels, no ML model has been built to predict the subtype-specific nAChR targets of α-conotoxins. Here, we trained an ML model in a semi-supervised manner to predict the specificity of α-conotoxin binding toward different human nAChR subtypes to overcome the challenge of limited data in subtype-specific nAChR targets of α-conotoxins and the issue that one α-conotoxin can bind multiple nAChR subtypes with high selectivity. We considered additional features of sequences of α-conotoxins in training our ML model, including the secondary structure propensities and electrostatic properties, which resulted in better prediction capability for the ML model. Notably, we identify that most α-conotoxins bind to α3β2, α1γδ, and α7 subtypes of human nAChRs. Our findings from this study provide a framework for predicting targets of various kinds of toxins.

Abstract Background: Conotoxins exhibit great potential as neuropharmacology tools and therapeutic candidates due to their high affinity and specificity for ion channels, neurotransmitter receptors or transporters. The traditional methods to discover new conotoxins are peptide purification from the crude venom or gene amplification from the venom duct. Methods: In this study, a novel O1 superfamily conotoxin Tx6.7 was directly cloned from the genomic DNA of Conus textile using primers corresponding to the conserved intronic sequence and 3’ UTR elements. The mature peptide of Tx6.7 (DCHERWDWCPASLLGVIYCCEGLICFIAFCI) was synthesized by solid-phase chemical synthesis and confirmed by mass spectrometry. Results: Patch clamp experiments on rat DRG neurons showed that Tx6.7 inhibited peak calcium currents by 59.29 ± 2.34% and peak potassium currents by 22.33 ± 7.81%. In addition, patch clamp on the ion channel subtypes showed that 10 μM Tx6.7 inhibited 56.61 ± 3.20% of the hCaV1.2 currents, 24.67 ± 0.91% of the hCaV2.2 currents and 7.30 ± 3.38% of the hNaV1.8 currents. Tx6.7 had no significant toxicity to ND7/23 cells and increased the pain threshold from 0.5 to 4 hours in the mouse hot plate assay. Conclusion: Our results suggested that direct cloning of conotoxin sequences from the genomic DNA of cone snails would be an alternative approach to obtaining novel conotoxins. Tx6.7 could be used as a probe tool for ion channel research or a therapeutic candidate for novel drug development.

Venoms comprise of complex mixtures of peptides evolved for predation and defensive purposes. Remarkably, some carnivorous cone snails can inject two distinct venoms in response to predatory or defensive stimuli, providing a unique opportunity to study separately how different ecological pressures contribute to toxin diversification. Here, we report the extraordinary defensive strategy of the Rhizoconus subgenus of cone snails. The defensive venom from this worm-hunting subgenus is unusually simple, almost exclusively composed of αD-conotoxins instead of the ubiquitous αA-conotoxins found in the more complex defensive venom of mollusc- and fish-hunting cone snails. A similarly compartmentalised venom gland as those observed in the other dietary groups facilitates the deployment of this defensive venom. Transcriptomic analysis of a C. vexillum venom gland revealed the αD-conotoxins as the major transcripts, with lower amounts of 15 known and 4 new conotoxin superfamilies also detected with likely roles in prey-capture. Our phylogenetic and molecular evolution analysis of the αD-conotoxins from five subgenera of cone snails suggests they evolved episodically as part of a defensive strategy in the Rhizoconus subgenus. Thus, our results demonstrate an important role for defence in the evolution of conotoxins.

Source data related to the identification of the con-ikot-ikot–like 4 clusters presented in Figs 1, S2-S4 and S14.

peptides predicted from monoisotopic masses aligned to the database entries;peptides predicted from monoisotopic masses aligned to the database entries;fasta file with transcripts of interest used for proteomic search;fasta file with transcripts of interest used for proteomic search

Biological Magnetic Resonance Bank Entry 15195: Solution Structure of an M-1 Conotoxin with a novel disulfide linkage

Biological Magnetic Resonance Bank Entry 5985: Solution Conformation of alpha-Conotoxin GIC, a Novel Potent Antagonist of alpha3beta2 Nicotinic Acetylcholine Receptors

The size of the Conotoxin market was valued at USD XXX million in 2024 and is projected to reach USD XXX million by 2033, with an expected CAGR of XX% during the forecast period.

Biological Magnetic Resonance Bank Entry 19501: A novel 4/7-conotoxin LvIA from Conus lividus that selectively blocks 32 vs. 6/323 nicotinic acetylcholine receptors

Biological Magnetic Resonance Bank Entry 1665: Tertiary Structure of Conotoxin GIIIA in Aqueous Solution

The Conotoxin market, a niche yet significantly evolving segment within biotechnology and pharmacology, is increasingly recognized for its potential in pain management and neurological disorders. Derived from the venom of cone snails, Conotoxins are a rich source of bioactive peptides, valued for their ability to se

Employing Conus betulinus as a representative, we sequenced and assembled the first Conus genome. After integration of multi-omics data, we provide novel insights into the genetic central dogma of conotoxins, assuming a number ratio of ~1:1:10s for genes/transcripts/peptides.

Mu-conotoxins are peptide inhibitors of voltage-sensitive sodium channels [PMID:12006587].