Conotoxins: Structure, Therapeutic Potential and Pharmacological Applications (original) (raw)
Related papers
Scientific reports, 2018
Cone snails are a diverse group of predatory marine invertebrates that deploy remarkably complex venoms to rapidly paralyse worm, mollusc or fish prey. ω-Conotoxins are neurotoxic peptides from cone snail venoms that inhibit Ca2.2 voltage-gated calcium channel, demonstrating potential for pain management via intrathecal (IT) administration. Here, we isolated and characterized two novel ω-conotoxins, MoVIA and MoVIB from Conus moncuri, the first to be identified in vermivorous (worm-hunting) cone snails. MoVIA and MoVIB potently inhibited human Ca2.2 in fluorimetric assays and rat Ca2.2 in patch clamp studies, and both potently displaced radiolabeled ω-conotoxin GVIA (I-GVIA) from human SH-SY5Y cells and fish brain membranes (IC 2-9 pM). Intriguingly, an arginine at position 13 in MoVIA and MoVIB replaced the functionally critical tyrosine found in piscivorous ω-conotoxins. To investigate its role, we synthesized MoVIB-[R13Y] and MVIIA-[Y13R]. Interestingly, MVIIA-[Y13R] completely l...
Discovery of a new subclass of α-conotoxins in the venom of Conus australis
Toxicon : official journal of the International Society on Toxinology, 2014
Cone snails (Conus sp.) are poisonous animals that can be found in all oceans where they developed a venomous strategy to prey or to defend. The venom of these species contains an undeniable source of unique and potent pharmacologically active compounds. Their peptide compounds, called conotoxins, are not only interesting for the development of new pharmaceutical ligands, but they are also useful for studying their broad spectrum of targets. One conotoxin family in particular, the α-conotoxins, acts on nicotinic acetylcholine receptors (nAChRs) which dysfunctions play important roles in pathologies such as epilepsy, myasthenic syndromes, schizophrenia, Parkinson's disease and Alzheimer's disease. Here we define a new subclass of the α-conotoxin family. We purified the venom of a yet unexplored cone snail species, i.e. Conus australis, and we isolated a 16-amino acid peptide named α-conotoxin AusIA. The peptide has the typical α-conotoxin CC-Xm-C-Xn-C framework, but both loop...
Therapeutic Potential of Cone Snail Venom Peptides (Conopeptides)
Current Topics in Medicinal Chemistry, 2012
Cone snails have evolved many 1000s of small, structurally stable venom peptides (conopeptides) for prey capture and defense. Whilst <1% have been pharmacologically characterised, those with known function typically target membrane proteins of therapeutic importance, including ion channels, transporters and GPCRs. Several conopeptides reduce pain in animals models, with one in clinical development ( -conopeptide analogue Xen2174) and one marketed (conotoxin MVIIA or Prialt) for the treatment of severe pain. In addition to their therapeutic potential, conopeptides have been valuable probes for studying the role of a number of key membrane proteins in normal and disease physiology.
I-conotoxins in vermivorous species of the West Atlantic: Peptide sr11a from Conus spurius
Peptides, 2007
Cone snails (superfamily Conoidea, family Conidae, genus Conus) are marine hunters that use their potent venoms mainly to capture prey, but also to defend themselves from predators, and to compete with other hunter species. The main components of Conus venoms are peptides that bind to voltage-gated ion channels (Na + , K + , Ca 2+), ligand-gated ion channels (nAChR, 5-HT 3 R, NMDAR), G-protein-coupled receptors (neurotensin, vasopressin), and neurotransmitter transporters (NE) [21] in the plasma membranes of nerve and muscle cells of organisms with which cones naturally interact, but these peptides also may bind to targets at the surface of mammalian cells [17]. In general, Conus toxins bind their targets with very high affinity and specificity, and some of them are used as molecular tools to study specific subtypes of ion channels and receptors [2,15]. Furthermore, several conotoxins are promising drug leads for to treat several conditions [10,14,25] and one has been approved to relieve chronic pain [23,27].
Structural and Functional Analyses of Cone Snail Toxins
Marine Drugs
Cone snails are marine gastropod mollusks with one of the most powerful venoms in nature. The toxins, named conotoxins, must act quickly on the cone snails´ prey due to the fact that snails are extremely slow, reducing their hunting capability. Therefore, the characteristics of conotoxins have become the object of investigation, and as a result medicines have been developed or are in the trialing process. Conotoxins interact with transmembrane proteins, showing specificity and potency. They target ion channels and ionotropic receptors with greater regularity, and when interaction occurs, there is immediate physiological decompensation. In this review we aimed to evaluate the structural features of conotoxins and the relationship with their target types.
ACS Omega, 2019
Many conotoxins, natural peptides of marine cone snails, have been identified to target neurons. Here, we provide data on pharmacological families of the conotoxins of 11 species of cone snails collected in Bali. The identified definitive pharmacological families possibly targeting neuronal tissues were α (alpha), ι (iota), κ (kappa), and ρ (rho). These classes shall target nicotinic acetylcholine receptors, voltage-gated Na channels, voltage-gated K channels, and α1-adrenoceptors, respectively. The VI/VII-O3 conotoxins might be prospected as an inhibitor of N-methyl-Daspartate. Con-ikot-ikot could be applied as an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor blocker medicine. The definitive pharmacology classes of conotoxins as well as those yet to be elucidated need to be further established and verified.
Diversity of the Neurotoxic Conus Peptides: A Model for Concerted Pharmacological Discovery
Molecular Interventions, 2007
P redatory cone snails (genus Conus) produce a rich array of venoms that collectively contain an estimated 100,000 small, disulfide-rich peptides (i.e., conotoxins, or conopeptides). Over the last few decades, the conopeptides have revealed a remarkable diversity of pharmacological function and utility. An evolutionary rationale for the existence of such a large and pharmacologically diverse set of gene products can be premised on the complexity of intra-and interspecies interactions that define the ecology of Conus snails. Insights into these evolutionary trends, moreover, have been exploited with great neuropharmacological success, so that research into the Conus snails effectively recapitulates a new concerted discovery approach, which we discuss here, for developing unique ligands for both laboratory and therapeutic applications. The Conus peptides thus serve as a model system for reaping the pharmacological potential of biodiverse animal lineages.
Conus regius-Derived Conotoxins: Novel Therapeutic Opportunities from a Marine Organism
Marine Drugs
Conus regius is a marine venomous mollusk of the Conus genus that captures its prey by injecting a rich cocktail of bioactive disulfide bond rich peptides called conotoxins. These peptides selectively target a broad range of ion channels, membrane receptors, transporters, and enzymes, making them valuable pharmacological tools and potential drug leads. C. regius-derived conotoxins are particularly attractive due to their marked potency and selectivity against specific nicotinic acetylcholine receptor subtypes, whose signalling is involved in pain, cognitive disorders, drug addiction, and cancer. However, the species-specific differences in sensitivity and the low stability and bioavailability of these conotoxins limit their clinical development as novel therapeutic agents for these disorders. Here, we give an overview of the main pharmacological features of the C. regius-derived conotoxins described so far, focusing on the molecular mechanisms underlying their potential therapeutic ...
Novel ω-Conotoxins from Conus catus Discriminate among Neuronal Calcium Channel Subtypes
Journal of Biological Chemistry, 2000
Conotoxins selective for N-type calcium channels are useful in the management of severe pain. In an attempt to expand the therapeutic potential of this class, four new-conotoxins (CVIA-D) have been discovered in the venom of the piscivorous cone snail, Conus catus, using assay-guided fractionation and gene cloning. Compared with other-conotoxins, CVID has a novel loop 4 sequence and the highest selectivity for N-type over P/Q-type calcium channels in radioligand binding assays. CVIA؊D also inhibited contractions of electrically stimulated rat vas deferens. In electrophysiological studies,-conotoxins CVID and MVIIA had similar potencies to inhibit current through central (␣ 1B-d) and peripheral (␣ 1B-b) splice variants of the rat N-type calcium channels when coexpressed with rat  3 in Xenopus oocytes. However, the potency of CVID and MVIIA increased when ␣ 1B-d and ␣ 1B-b were expressed in the absence of rat  3 , an effect most pronounced for CVID at ␣ 1B-d (up to 540-fold) and least pronounced for MVIIA at ␣ 1B-d (3-fold). The novel selectivity of CVID may have therapeutic implications. 1 H NMR studies reveal that CVID possesses a combination of unique structural features, including two hydrogen bonds that stabilize loop 2 and place loop 2 proximal to loop 4, creating a globular surface that is rigid and well defined.
Peptides, 2013
Cone snail venoms provide a largely untapped source of novel peptide drug leads. To enhance the discovery phase, a detailed comparative proteomic analysis was undertaken on milked venom from the mollusk-hunting cone snail, Conus textile, from three different geographic locations (Hawai'i, American Samoa and Australia's Great Barrier Reef). A novel milked venom conopeptide rich in post-translational modifications was discovered, characterized and named ␣-conotoxin TxIC. We assign this conopeptide to the 4/7 ␣-conotoxin family based on the peptide's sequence homology and cDNA pre-propeptide alignment. Pharmacologically, ␣-conotoxin TxIC demonstrates minimal activity on human acetylcholine receptor models (100 M, <5% inhibition), compared to its high paralytic potency in invertebrates, PD 50 = 34.2 nMol kg −1 . The non-post-translationally modified form, [Pro] 2,8 [Glu] 16 ␣-conotoxin TxIC, demonstrates differential selectivity for the ␣32 isoform of the nicotinic acetylcholine receptor with maximal inhibition of 96% and an observed IC 50 of 5.4 ± 0.5 M. Interestingly its comparative PD 50 (3.6 Mol kg −1 ) in invertebrates was ∼100 fold more than that of the native peptide. Differentiating ␣-conotoxin TxIC from other ␣-conotoxins is the high degree of post-translational modification (44% of residues). This includes the incorporation of ␥-carboxyglutamic acid, two moieties of 4-trans hydroxyproline, two disulfide bond linkages, and C-terminal amidation. These findings expand upon the known chemical diversity of ␣-conotoxins and illustrate a potential driver of toxin phyla-selectivity within Conus.