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Toxins
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Conotoxins: Evolution, Classifications and Targets
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Conotoxins: Evolution, Classifications and Targets

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Marine and Freshwater Toxins".

Deadline for manuscript submissions: closed (31 December 2024) | Viewed by 14245

Special Issue Editor

Dr. Manuel B. Aguilar

E-Mail Website
Guest Editor
Laboratory of Marine Neuropharmacology, Department of Cellular and Molecular Neurobiology, National Autonomous University of Mexico, Queretaro 76230, Mexico
Interests: peptides; proteins; toxins; cone snails; conopeptides; conotoxins; receptors; ion channels; nAChR

Special Issue Information

Dear Colleagues,

Cone snails are marine hunters that produce venoms mainly for capturing prey and self-defense. The major components of these venoms are peptidic compounds, named conotoxins or conopeptides. In general, conotoxins bind to their molecular targets (predominantly distinct receptors, and ligand- and voltage-gated ion channels) with high affinity and selectivity. This feature has allowed the application of varied conotoxins as molecular probes for diverse studies of ion channels and receptors, and of ω-conotoxin MVIIA (blocker of N-type calcium channels) as a medicine for chronic pain.

Diverse evidence indicates that less than 10% of the existing conotoxins have been uncovered, and that for less than 1% of them, one or more molecular target has been identified. Fortunately, continuing advances in proteomics and transcriptomics are constantly revealing plethoras of novel sequences, both for toxins and their precursors; however, both their pharmacological targets and their genetic origins are unknown. Therefore, I am pleased to invite you to submit articles to this Special Issue, “Conotoxins: Evolution, Classifications and Targets”.

This Special Issue aims to collect works that provide updates on several current central topics in the field of conotoxin research. Original research articles and reviews are welcome. Research areas may include (but are not limited to) the following: the evolution, pharmacological and genetic classification of conotoxins and their precursors; and the prediction of molecular targets. Reports on omics of cone snail venoms, engineering of conopeptides and evaluation of their activities, identification and characterization of novel conotoxins, and synthesis of mimetics with improved properties are also appreciated.

Dr. Manuel B. Aguilar
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cone snails
  • peptides
  • conopeptides
  • conotoxins
  • precursors
  • disulfide bonds
  • evolution
  • molecular targets
  • gene superfamilies
  • pharmacological families

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Published Papers (8 papers)

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Research

Jump to: Review

18 pages, 3605 KiB  
Article
Proteo-Transcriptomic Analysis of the Venom Gland of the Cone Snail Cylinder canonicus Reveals the Origin of the Predatory-Evoked Venom
by Zahrmina Ratibou, Anicet E. T. Ebou, Claudia Bich, Fabrice Saintmont, Gilles Valette, Guillaume Cazals, Dominique K. Koua, Nicolas Inguimbert and Sébastien Dutertre
Toxins 2025, 17(3), 119; https://doi.org/10.3390/toxins17030119 - 2 Mar 2025
Viewed by 373
Abstract
Cone snails are carnivorous marine predators that prey on mollusks, worms, or fish. They purposefully inject a highly diversified and peptide-rich venom, which can vary according to the predatory or defensive intended use. Previous studies have shown some correlations between the predation- and [...] Read more.
Cone snails are carnivorous marine predators that prey on mollusks, worms, or fish. They purposefully inject a highly diversified and peptide-rich venom, which can vary according to the predatory or defensive intended use. Previous studies have shown some correlations between the predation- and defense-evoked venoms and specific sections of the venom gland. In this study, we focus on the characterization of the venom of Cylinder canonicus, a molluscivorous species collected from Mayotte Island. Integrated proteomics and transcriptomics studies allowed for the identification of 108 conotoxin sequences from 24 gene superfamilies, with the most represented sequences belonging to the O1, O2, M, and conkunitzin superfamilies. A comparison of the predatory injected venom and the distal, central, and proximal sections of the venom duct suggests mostly distal origin. Identified conotoxins will contribute to a better understanding of venom–ecology relationships in cone snails and provide a novel resource for potential drug discovery. Full article
(This article belongs to the Special Issue Conotoxins: Evolution, Classifications and Targets)
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17 pages, 4152 KiB  
Article
ConoGPT: Fine-Tuning a Protein Language Model by Incorporating Disulfide Bond Information for Conotoxin Sequence Generation
by Guohui Zhao, Cheng Ge, Wenzheng Han, Rilei Yu and Hao Liu
Toxins 2025, 17(2), 93; https://doi.org/10.3390/toxins17020093 - 17 Feb 2025
Viewed by 423
Abstract
Conotoxins are a class of peptide toxins secreted by marine mollusks of the Conus genus, characterized by their unique mechanism of action and significant biological activity, making them highly valuable for drug development. However, traditional methods of acquiring conotoxins, such as in vivo [...] Read more.
Conotoxins are a class of peptide toxins secreted by marine mollusks of the Conus genus, characterized by their unique mechanism of action and significant biological activity, making them highly valuable for drug development. However, traditional methods of acquiring conotoxins, such as in vivo extraction or chemical synthesis, face challenges of high costs, long cycles, and limited exploration of sequence diversity. To address these issues, we propose the ConoGPT model, a conotoxin sequence generation model that fine-tunes the ProtGPT2 model by incorporating disulfide bond information. Experimental results demonstrate that sequences generated by ConoGPT exhibit high consistency with authentic conotoxins in physicochemical properties and show considerable potential for generating novel conotoxins. Furthermore, compared to models without disulfide bond information, ConoGPT outperforms in terms of generating sequences with ordered structures. The majority of the filtered sequences were shown to possess significant binding affinities to nicotinic acetylcholine receptor (nAChR) targets based on molecular docking. Molecular dynamics simulations of the selected sequences further confirmed the dynamic stability of the generated sequences in complex with their respective targets. This study not only provides a new technological approach for conotoxin design but also offers a novel strategy for generating functional peptides. Full article
(This article belongs to the Special Issue Conotoxins: Evolution, Classifications and Targets)
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15 pages, 2138 KiB  
Article
Machine Learning Framework for Conotoxin Class and Molecular Target Prediction
by Duc P. Truong, Lyman K. Monroe, Robert F. Williams and Hau B. Nguyen
Toxins 2024, 16(11), 475; https://doi.org/10.3390/toxins16110475 - 3 Nov 2024
Cited by 1 | Viewed by 1376
Abstract
Conotoxins are small and highly potent neurotoxic peptides derived from the venom of marine cone snails which have captured the interest of the scientific community due to their pharmacological potential. These toxins display significant sequence and structure diversity, which results in a wide [...] Read more.
Conotoxins are small and highly potent neurotoxic peptides derived from the venom of marine cone snails which have captured the interest of the scientific community due to their pharmacological potential. These toxins display significant sequence and structure diversity, which results in a wide range of specificities for several different ion channels and receptors. Despite the recognized importance of these compounds, our ability to determine their binding targets and toxicities remains a significant challenge. Predicting the target receptors of conotoxins, based solely on their amino acid sequence, remains a challenge due to the intricate relationships between structure, function, target specificity, and the significant conformational heterogeneity observed in conotoxins with the same primary sequence. We have previously demonstrated that the inclusion of post-translational modifications, collisional cross sections values, and other structural features, when added to the standard primary sequence features, improves the prediction accuracy of conotoxins against non-toxic and other toxic peptides across varied datasets and several different commonly used machine learning classifiers. Here, we present the effects of these features on conotoxin class and molecular target predictions, in particular, predicting conotoxins that bind to nicotinic acetylcholine receptors (nAChRs). We also demonstrate the use of the Synthetic Minority Oversampling Technique (SMOTE)-Tomek in balancing the datasets while simultaneously making the different classes more distinct by reducing the number of ambiguous samples which nearly overlap between the classes. In predicting the alpha, mu, and omega conotoxin classes, the SMOTE-Tomek PCA PLR model, using the combination of the SS and P feature sets establishes the best performance with an overall accuracy (OA) of 95.95%, with an average accuracy (AA) of 93.04%, and an f1 score of 0.959. Using this model, we obtained sensitivities of 98.98%, 89.66%, and 90.48% when predicting alpha, mu, and omega conotoxin classes, respectively. Similarly, in predicting conotoxins that bind to nAChRs, the SMOTE-Tomek PCA SVM model, which used the collisional cross sections (CCSs) and the P feature sets, demonstrated the highest performance with 91.3% OA, 91.32% AA, and an f1 score of 0.9131. The sensitivity when predicting conotoxins that bind to nAChRs is 91.46% with a 91.18% sensitivity when predicting conotoxins that do not bind to nAChRs. Full article
(This article belongs to the Special Issue Conotoxins: Evolution, Classifications and Targets)
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17 pages, 2152 KiB  
Article
Conotoxin Prediction: New Features to Increase Prediction Accuracy
by Lyman K. Monroe, Duc P. Truong, Jacob C. Miner, Samantha H. Adikari, Zachary J. Sasiene, Paul W. Fenimore, Boian Alexandrov, Robert F. Williams and Hau B. Nguyen
Toxins 2023, 15(11), 641; https://doi.org/10.3390/toxins15110641 - 3 Nov 2023
Cited by 5 | Viewed by 3081
Abstract
Conotoxins are toxic, disulfide-bond-rich peptides from cone snail venom that target a wide range of receptors and ion channels with multiple pathophysiological effects. Conotoxins have extraordinary potential for medical therapeutics that include cancer, microbial infections, epilepsy, autoimmune diseases, neurological conditions, and cardiovascular disorders. [...] Read more.
Conotoxins are toxic, disulfide-bond-rich peptides from cone snail venom that target a wide range of receptors and ion channels with multiple pathophysiological effects. Conotoxins have extraordinary potential for medical therapeutics that include cancer, microbial infections, epilepsy, autoimmune diseases, neurological conditions, and cardiovascular disorders. Despite the potential for these compounds in novel therapeutic treatment development, the process of identifying and characterizing the toxicities of conotoxins is difficult, costly, and time-consuming. This challenge requires a series of diverse, complex, and labor-intensive biological, toxicological, and analytical techniques for effective characterization. While recent attempts, using machine learning based solely on primary amino acid sequences to predict biological toxins (e.g., conotoxins and animal venoms), have improved toxin identification, these methods are limited due to peptide conformational flexibility and the high frequency of cysteines present in toxin sequences. This results in an enumerable set of disulfide-bridged foldamers with different conformations of the same primary amino acid sequence that affect function and toxicity levels. Consequently, a given peptide may be toxic when its cysteine residues form a particular disulfide-bond pattern, while alternative bonding patterns (isoforms) or its reduced form (free cysteines with no disulfide bridges) may have little or no toxicological effects. Similarly, the same disulfide-bond pattern may be possible for other peptide sequences and result in different conformations that all exhibit varying toxicities to the same receptor or to different receptors. We present here new features, when combined with primary sequence features to train machine learning algorithms to predict conotoxins, that significantly increase prediction accuracy. Full article
(This article belongs to the Special Issue Conotoxins: Evolution, Classifications and Targets)
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Review

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34 pages, 1404 KiB  
Review
Conotoxins: Classification, Prediction, and Future Directions in Bioinformatics
by Rui Li, Junwen Yu, Dongxin Ye, Shanghua Liu, Hongqi Zhang, Hao Lin, Juan Feng and Kejun Deng
Toxins 2025, 17(2), 78; https://doi.org/10.3390/toxins17020078 - 9 Feb 2025
Viewed by 1096
Abstract
Conotoxins, a diverse family of disulfide-rich peptides derived from the venom of Conus species, have gained prominence in biomedical research due to their highly specific interactions with ion channels, receptors, and neurotransmitter systems. Their pharmacological properties make them valuable molecular tools and promising [...] Read more.
Conotoxins, a diverse family of disulfide-rich peptides derived from the venom of Conus species, have gained prominence in biomedical research due to their highly specific interactions with ion channels, receptors, and neurotransmitter systems. Their pharmacological properties make them valuable molecular tools and promising candidates for therapeutic development. However, traditional conotoxin classification and functional characterization remain labor-intensive, necessitating the increasing adoption of computational approaches. In particular, machine learning (ML) techniques have facilitated advancements in sequence-based classification, functional prediction, and de novo peptide design. This review explores recent progress in applying ML and deep learning (DL) to conotoxin research, comparing key databases, feature extraction techniques, and classification models. Additionally, we discuss future research directions, emphasizing the integration of multimodal data and the refinement of predictive frameworks to enhance therapeutic discovery. Full article
(This article belongs to the Special Issue Conotoxins: Evolution, Classifications and Targets)
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14 pages, 1828 KiB  
Review
Peptide Toxins from Marine Conus Snails with Activity on Potassium Channels and/or Currents
by Luis Martínez-Hernández, Estuardo López-Vera and Manuel B. Aguilar
Toxins 2024, 16(12), 504; https://doi.org/10.3390/toxins16120504 - 22 Nov 2024
Viewed by 988
Abstract
Toxins from Conus snails are peptides characterized by a great structural and functional diversity. They have a high affinity for a wide range of membrane proteins such as ion channels, neurotransmitter transporters, and G protein-coupled receptors. Potassium ion channels are integral proteins of [...] Read more.
Toxins from Conus snails are peptides characterized by a great structural and functional diversity. They have a high affinity for a wide range of membrane proteins such as ion channels, neurotransmitter transporters, and G protein-coupled receptors. Potassium ion channels are integral proteins of cell membranes that play vital roles in physiological processes in muscle and neuron cells, among others, and reports in the literature indicate that perturbation in their function (by mutations or ectopic expression) may result in the development and progression of different ailments in humans. This review aims to gather as much information as possible about Conus toxins (conotoxins) with an effect on potassium channels and/or currents, with a perspective of exploring the possibility of finding or developing a possible drug candidate from these toxins. The research indicates that, among the more than 900 species described for this genus, in only 14 species of the >100 studied to date have such toxins been found (classified according to the most specific evidence for each case), as follows: 17 toxins with activity on two groups of potassium channels (Kv and KCa), 4 toxins with activity on potassium currents, and 5 toxins that are thought to inhibit potassium channels by symptomatology and/or a high sequence similarity. Full article
(This article belongs to the Special Issue Conotoxins: Evolution, Classifications and Targets)
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17 pages, 2798 KiB  
Review
Voltage-Gated Sodium Channel Inhibition by µ-Conotoxins
by Kirsten L. McMahon, Irina Vetter and Christina I. Schroeder
Toxins 2024, 16(1), 55; https://doi.org/10.3390/toxins16010055 - 18 Jan 2024
Cited by 2 | Viewed by 2577
Abstract
µ-Conotoxins are small, potent pore-blocker inhibitors of voltage-gated sodium (NaV) channels, which have been identified as pharmacological probes and putative leads for analgesic development. A limiting factor in their therapeutic development has been their promiscuity for different NaV channel subtypes, [...] Read more.
µ-Conotoxins are small, potent pore-blocker inhibitors of voltage-gated sodium (NaV) channels, which have been identified as pharmacological probes and putative leads for analgesic development. A limiting factor in their therapeutic development has been their promiscuity for different NaV channel subtypes, which can lead to undesirable side-effects. This review will focus on four areas of µ-conotoxin research: (1) mapping the interactions of µ-conotoxins with different NaV channel subtypes, (2) µ-conotoxin structure–activity relationship studies, (3) observed species selectivity of µ-conotoxins and (4) the effects of µ-conotoxin disulfide connectivity on activity. Our aim is to provide a clear overview of the current status of µ-conotoxin research. Full article
(This article belongs to the Special Issue Conotoxins: Evolution, Classifications and Targets)
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14 pages, 4214 KiB  
Review
Diversity and Evolutionary Analysis of Venom Insulin Derived from Cone Snails
by Qiqi Guo, Meiling Huang, Ming Li, Jiao Chen, Shuanghuai Cheng, Linlin Ma and Bingmiao Gao
Toxins 2024, 16(1), 34; https://doi.org/10.3390/toxins16010034 - 9 Jan 2024
Cited by 2 | Viewed by 3208
Abstract
Cone snails possess a diverse array of novel peptide toxins, which selectively target ion channels and receptors in the nervous and cardiovascular systems. These numerous novel peptide toxins are a valuable resource for future marine drug development. In this review, we compared and [...] Read more.
Cone snails possess a diverse array of novel peptide toxins, which selectively target ion channels and receptors in the nervous and cardiovascular systems. These numerous novel peptide toxins are a valuable resource for future marine drug development. In this review, we compared and analyzed the sequence diversity, three-dimensional structural variations, and evolutionary aspects of venom insulin derived from different cone snail species. The comparative analysis reveals that there are significant variations in the sequences and three-dimensional structures of venom insulins from cone snails with different feeding habits. Notably, the venom insulin of some piscivorous cone snails exhibits a greater similarity to humans and zebrafish insulins. It is important to emphasize that these venom insulins play a crucial role in the predatory strategies of these cone snails. Furthermore, a phylogenetic tree was constructed to trace the lineage of venom insulin sequences, shedding light on the evolutionary interconnections among cone snails with diverse diets. Full article
(This article belongs to the Special Issue Conotoxins: Evolution, Classifications and Targets)
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