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Marine Drugs Dec 2014Conotoxins are the peptidic components of the venoms of marine cone snails (genus Conus). They are remarkably diverse in terms of structure and function. Unique potency... (Review)
Review
Conotoxins are the peptidic components of the venoms of marine cone snails (genus Conus). They are remarkably diverse in terms of structure and function. Unique potency and selectivity profiles for a range of neuronal targets have made several conotoxins valuable as research tools, drug leads and even therapeutics, and has resulted in a concerted and increasing drive to identify and characterise new conotoxins. Conotoxins are translated from mRNA as peptide precursors, and cDNA sequencing is now the primary method for identification of new conotoxin sequences. As a result, gene superfamily, a classification based on precursor signal peptide identity, has become the most convenient method of conotoxin classification. Here we review each of the described conotoxin gene superfamilies, with a focus on the structural and functional diversity present in each. This review is intended to serve as a practical guide to conotoxin superfamilies and to facilitate interpretation of the increasing number of conotoxin precursor sequences being identified by targeted-cDNA sequencing and more recently high-throughput transcriptome sequencing.
Topics: Animals; Conotoxins; Conus Snail; DNA, Complementary; Humans; Transcriptome; Venoms
PubMed: 25522317
DOI: 10.3390/md12126058 -
Marine Drugs Mar 2013Conotoxins are small peptides present in the venom of cone snails. The snail uses this venom to paralyze and capture prey. The constituent conopeptides display a high... (Review)
Review
Conotoxins are small peptides present in the venom of cone snails. The snail uses this venom to paralyze and capture prey. The constituent conopeptides display a high level of chemical diversity and are of particular interest for scientists as tools employed in neurological studies and for drug development, because they target with exquisite specificity membrane receptors, transporters, and various ion channels in the nervous system. However, these peptides are known to contain a high frequency and variability of post-translational modifications-including sometimes O-glycosylation-which are of importance for biological activity. The potential application of specific conotoxins as neuropharmalogical agents and chemical probes requires a full characterization of the relevant peptides, including the structure of the carbohydrate part. In this review, the currently existing knowledge of O-glycosylation of conotoxins is described.
Topics: Animals; Conotoxins; Conus Snail; Drug Design; Glycosylation; Humans; Molecular Targeted Therapy; Protein Processing, Post-Translational
PubMed: 23455513
DOI: 10.3390/md11030623 -
Marine Drugs Aug 2022Sea snails of the genus produce toxins that have been the subjects of numerous studies, projects, publications, and patents over the years. Since toxins were... (Review)
Review
Sea snails of the genus produce toxins that have been the subjects of numerous studies, projects, publications, and patents over the years. Since toxins were discovered in the 1960s, their biological activity has been thought to have high pharmaceutical potential that could be explored beyond the limits of academic laboratories. We reviewed 224 patent documents related to conotoxins and conopeptides globally to determine the course that innovation and development has taken over the years, their primary applications, the technological trends over the last six years, and the leaders in the field, since the only previous patent review was performed in 2015 and focused in USA valid patents. In addition, we explored which countries/territories protect their inventions and patents and the most relevant collaborations among assignees. We also evaluated whether academia or pharmaceutical companies are the future of conotoxin research. We concluded that the 224 conotoxin patents reviewed in this study have more academic value than industrial value, which was noted by the number of active patents that have not yet been licensed and the contributions to medical research, especially as tools to study neuropathic pain, inflammation, immunology, drug design, receptor binding sites, cancer, neurotransmission, epilepsy, peptide biosynthesis, and depression. The aim of this review is to provide an overview of the current state of conotoxin patents, their main applications, and success based on the number of licensing and products in the market.
Topics: Animals; Conotoxins; Conus Snail; Humans; Industry; Pharmaceutical Preparations
PubMed: 36005534
DOI: 10.3390/md20080531 -
Toxins Jan 2024µ-Conotoxins are small, potent pore-blocker inhibitors of voltage-gated sodium (Na) channels, which have been identified as pharmacological probes and putative leads... (Review)
Review
µ-Conotoxins are small, potent pore-blocker inhibitors of voltage-gated sodium (Na) 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 Na 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 Na 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.
Topics: Conotoxins; Disulfides; Structure-Activity Relationship; Voltage-Gated Sodium Channels
PubMed: 38251271
DOI: 10.3390/toxins16010055 -
Marine Drugs Oct 2016Nicotinic acetylcholine receptors (nAChRs) are targets for developing new drugs to treat severe pain, nicotine addiction, Alzheimer disease, epilepsy, etc. α-Conotoxins... (Review)
Review
Nicotinic acetylcholine receptors (nAChRs) are targets for developing new drugs to treat severe pain, nicotine addiction, Alzheimer disease, epilepsy, etc. α-Conotoxins are biologically and chemically diverse. With 12-19 residues and two disulfides, they can be specifically selected for different nAChRs. Acetylcholine-binding proteins from (Ac-AChBP) are homologous to the ligand-binding domains of nAChRs and pharmacologically similar. X-ray structures of the α-conotoxin in complex with Ac-AChBP in addition to computer modeling have helped to determine the binding site of the important residues of α-conotoxin and its affinity for nAChR subtypes. Here, we present the various α-conotoxin residues that are selective for Ac-AChBP or nAChRs by comparing the structures of α-conotoxins in complex with Ac-AChBP and by modeling α-conotoxins in complex with nAChRs. The knowledge of these binding sites will assist in the discovery and design of more potent and selective α-conotoxins as drug leads.
Topics: Acetylcholine; Animals; Aplysia; Conotoxins; Crystallography, X-Ray; Oceans and Seas; Protein Binding; Receptors, Nicotinic
PubMed: 27727162
DOI: 10.3390/md14100173 -
Molecules (Basel, Switzerland) Jun 2017Conotoxins are disulfide-rich small peptides, which are invaluable peptides that target ion channel and neuronal receptors. Conotoxins have been demonstrated as potent... (Review)
Review
Conotoxins are disulfide-rich small peptides, which are invaluable peptides that target ion channel and neuronal receptors. Conotoxins have been demonstrated as potent pharmaceuticals in the treatment of a series of diseases, such as Alzheimer's disease, Parkinson's disease, and epilepsy. In addition, conotoxins are also ideal molecular templates for the development of new drug lead compounds and play important roles in neurobiological research as well. Thus, the accurate identification of conotoxin types will provide key clues for the biological research and clinical medicine. Generally, conotoxin types are confirmed when their sequence, structure, and function are experimentally validated. However, it is time-consuming and costly to acquire the structure and function information by using biochemical experiments. Therefore, it is important to develop computational tools for efficiently and effectively recognizing conotoxin types based on sequence information. In this work, we reviewed the current progress in computational identification of conotoxins in the following aspects: (i) construction of benchmark dataset; (ii) strategies for extracting sequence features; (iii) feature selection techniques; (iv) machine learning methods for classifying conotoxins; (v) the results obtained by these methods and the published tools; and (vi) future perspectives on conotoxin classification. The paper provides the basis for in-depth study of conotoxins and drug therapy research.
Topics: Benchmarking; Computational Biology; Conotoxins; Machine Learning
PubMed: 28672838
DOI: 10.3390/molecules22071057 -
Toxins Dec 2017Marine 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... (Review)
Review
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 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 , the big family of cone snails, has become an important genetic resource for conotoxin identification and drug development.
Topics: Animals; Conotoxins; Conus Snail; Drug Discovery; Humans; Protein Binding; Protein Conformation; Proteome; Receptors, Nicotinic; Species Specificity; Transcriptome
PubMed: 29215605
DOI: 10.3390/toxins9120397 -
International Journal of Molecular... Mar 2018Cone snail venoms are considered a treasure trove of bioactive peptides. Despite over 800 species of cone snails being known, each producing over 1000 venom peptides,... (Review)
Review
Cone snail venoms are considered a treasure trove of bioactive peptides. Despite over 800 species of cone snails being known, each producing over 1000 venom peptides, only about 150 unique venom peptides are structurally and functionally characterized. To overcome the limitations of the traditional low-throughput bio-discovery approaches, multi-omics systems approaches have been introduced to accelerate venom peptide discovery and characterisation. This "venomic" approach is starting to unravel the full complexity of cone snail venoms and to provide new insights into their biology and evolution. The main challenge for venomics is the effective integration of transcriptomics, proteomics, and pharmacological data and the efficient analysis of big datasets. Novel database search tools and visualisation techniques are now being introduced that facilitate data exploration, with ongoing advances in related omics fields being expected to further enhance venomics studies. Despite these challenges and future opportunities, cone snail venomics has already exponentially expanded the number of novel venom peptide sequences identified from the species investigated, although most novel conotoxins remain to be pharmacologically characterised. Therefore, efficient high-throughput peptide production systems and/or banks of miniaturized discovery assays are required to overcome this bottleneck and thus enhance cone snail venom bioprospecting and accelerate the identification of novel drug leads.
Topics: Amino Acid Sequence; Animals; Conotoxins; Conus Snail; Databases, Protein; Drug Discovery; Peptides; Proteomics; Transcriptome
PubMed: 29522462
DOI: 10.3390/ijms19030788 -
BMC Bioinformatics May 2011Conotoxin has been proven to be effective in drug design and could be used to treat various disorders such as schizophrenia, neuromuscular disorders and chronic pain....
BACKGROUND
Conotoxin has been proven to be effective in drug design and could be used to treat various disorders such as schizophrenia, neuromuscular disorders and chronic pain. With the rapidly growing interest in conotoxin, accurate conotoxin superfamily classification tools are desirable to systematize the increasing number of newly discovered sequences and structures. However, despite the significance and extensive experimental investigations on conotoxin, those tools have not been intensively explored.
RESULTS
In this paper, we propose to consider suboptimal alignments of words with restricted length. We developed a scoring system based on local alignment partition functions, called free score. The scoring system plays the key role in the feature extraction step of support vector machine classification. In the classification of conotoxin proteins, our method, SVM-Freescore, features an improved sensitivity and specificity by approximately 5.864% and 3.76%, respectively, over previously reported methods. For the generalization purpose, SVM-Freescore was also applied to classify superfamilies from curated and high quality database such as ConoServer. The average computed sensitivity and specificity for the superfamily classification were found to be 0.9742 and 0.9917, respectively.
CONCLUSIONS
The SVM-Freescore method is shown to be a useful sequence-based analysis tool for functional and structural characterization of conotoxin proteins. The datasets and the software are available at http://faculty.uaeu.ac.ae/nzaki/SVM-Freescore.htm.
Topics: Algorithms; Animals; Artificial Intelligence; Conotoxins; Conus Snail; Neuropeptides; Software
PubMed: 21619696
DOI: 10.1186/1471-2105-12-217 -
Marine Drugs Oct 2018Cone snail venoms provide an ideal resource for neuropharmacological tools and drug candidates discovery, which have become a research hotspot in neuroscience and new... (Review)
Review
Cone snail venoms provide an ideal resource for neuropharmacological tools and drug candidates discovery, which have become a research hotspot in neuroscience and new drug development. More than 1,000,000 natural peptides are produced by cone snails, but less than 0.1% of the estimated conotoxins has been characterized to date. Hence, the discovery of novel conotoxins from the huge conotoxin resources with high-throughput and sensitive methods becomes a crucial key for the conotoxin-based drug development. In this review, we introduce the discovery methodology of new conotoxins from various species. It focuses on obtaining full N- to C-terminal sequences, regardless of disulfide bond connectivity through crude venom purification, conotoxin precusor gene cloning, venom duct transcriptomics, venom proteomics and multi-omic methods. The protocols, advantages, disadvantages, and developments of different approaches during the last decade are summarized and the promising prospects are discussed as well.
Topics: Animals; Cloning, Molecular; Conotoxins; Conus Snail; Drug Discovery; High-Throughput Screening Assays; Neurotoxins; Proteomics
PubMed: 30380764
DOI: 10.3390/md16110417