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12 pages, 2631 KiB

Open AccessArticle

Structural Characterisation of Predicted Helical Regions in the Chironex fleckeri CfTX-1 Toxin

by Athena Andreosso, Paramjit S. Bansal, Michael J. Smout, David Wilson, Jamie E. Seymour and Norelle L. Daly

Mar. Drugs 2018, 16(6), 201; https://doi.org/10.3390/md16060201 - 07 Jun 2018

Cited by 6 | Viewed by 5183

Abstract

The Australian jellyfish Chironex fleckeri, belongs to a family of cubozoan jellyfish known for their potent venoms. CfTX-1 and -2 are two highly abundant toxins in the venom, but there is no structural data available for these proteins. Structural information on toxins [...] Read more.

The Australian jellyfish Chironex fleckeri, belongs to a family of cubozoan jellyfish known for their potent venoms. CfTX-1 and -2 are two highly abundant toxins in the venom, but there is no structural data available for these proteins. Structural information on toxins is integral to the understanding of the mechanism of these toxins and the development of an effective treatment. Two regions of CfTX-1 have been predicted to have helical structures that are involved with the mechanism of action. Here we have synthesized peptides corresponding to these regions and analyzed their structures using NMR spectroscopy. The peptide corresponding to the predicted N-terminal amphiphilic helix appears unstructured in aqueous solution. This lack of structure concurs with structural disorder predicted for this region of the protein using the Protein DisOrder prediction System PrDOS. Conversely, a peptide corresponding to a predicted transmembrane region is very hydrophobic, insoluble in aqueous solution and predicted to be structured by PrDOS. In the presence of SDS-micelles both peptides have well-defined helical structures showing that a membrane mimicking environment stabilizes the structures of both peptides and supports the prediction of the transmembrane region in CfTX-1. This is the first study to experimentally analyze the structure of regions of a C. fleckeri protein. Full article

(This article belongs to the Special Issue Marine Invertebrate Toxins)

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19 pages, 2357 KiB

Open AccessArticle

Multigene Family of Pore-Forming Toxins from Sea Anemone Heteractis crispa

by Elena Leychenko, Marina Isaeva, Ekaterina Tkacheva, Elena Zelepuga, Aleksandra Kvetkina, Konstantin Guzev, Margarita Monastyrnaya and Emma Kozlovskaya

Mar. Drugs 2018, 16(6), 183; https://doi.org/10.3390/md16060183 - 24 May 2018

Cited by 21 | Viewed by 3985

Abstract

Sea anemones produce pore-forming toxins, actinoporins, which are interesting as tools for cytoplasmic membranes study, as well as being potential therapeutic agents for cancer therapy. This investigation is devoted to structural and functional study of the Heteractis crispa actinoporins diversity. Here, we described [...] Read more.

Sea anemones produce pore-forming toxins, actinoporins, which are interesting as tools for cytoplasmic membranes study, as well as being potential therapeutic agents for cancer therapy. This investigation is devoted to structural and functional study of the Heteractis crispa actinoporins diversity. Here, we described a multigene family consisting of 47 representatives expressed in the sea anemone tentacles as prepropeptide-coding transcripts. The phylogenetic analysis revealed that actinoporin clustering is consistent with the division of sea anemones into superfamilies and families. The transcriptomes of both H. crispa and Heteractis magnifica appear to contain a large repertoire of similar genes representing a rapid expansion of the actinoporin family due to gene duplication and sequence divergence. The presence of the most abundant specific group of actinoporins in H. crispa is the major difference between these species. The functional analysis of six recombinant actinoporins revealed that H. crispa actinoporin grouping was consistent with the different hemolytic activity of their representatives. According to molecular modeling data, we assume that the direction of the N-terminal dipole moment tightly reflects the actinoporins’ ability to possess hemolytic activity. Full article

(This article belongs to the Special Issue Marine Invertebrate Toxins)

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22 pages, 5587 KiB

Open AccessArticle

Toxicological Investigations on the Sea Urchin Tripneustes gratilla (Toxopneustidae, Echinoid) from Anaho Bay (Nuku Hiva, French Polynesia): Evidence for the Presence of Pacific Ciguatoxins

by Hélène Taiana Darius, Mélanie Roué, Manoella Sibat, Jérôme Viallon, Clémence Mahana iti Gatti, Mark W. Vandersea, Patricia A. Tester, R. Wayne Litaker, Zouher Amzil, Philipp Hess and Mireille Chinain

Mar. Drugs 2018, 16(4), 122; https://doi.org/10.3390/md16040122 - 06 Apr 2018

Cited by 45 | Viewed by 6095

Abstract

The sea urchin Tripneustes gratilla (Toxopneustidae, Echinoids) is a source of protein for many islanders in the Indo-West Pacific. It was previously reported to occasionally cause ciguatera-like poisoning; however, the exact nature of the causative agent was not confirmed. In April [...] Read more.

The sea urchin Tripneustes gratilla (Toxopneustidae, Echinoids) is a source of protein for many islanders in the Indo-West Pacific. It was previously reported to occasionally cause ciguatera-like poisoning; however, the exact nature of the causative agent was not confirmed. In April and July 2015, ciguatera poisonings were reported following the consumption of T. gratilla in Anaho Bay (Nuku Hiva Island, Marquesas archipelago, French Polynesia). Patient symptomatology was recorded and sea urchin samples were collected from Anaho Bay in July 2015 and November 2016. Toxicity analysis using the neuroblastoma cell–based assay (CBA-N2a) detected the presence of ciguatoxins (CTXs) in T. gratilla samples. Gambierdiscus species were predominant in the benthic assemblages of Anaho Bay, and G. polynesiensis was highly prevalent in in vitro cultures according to qPCR results. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) analyses revealed that P-CTX-3B was the major ciguatoxin congener in toxic sea urchin samples, followed by 51-OH-P-CTX-3C, P-CTX-3C, P-CTX-4A, and P-CTX-4B. Between July 2015 and November 2016, the toxin content in T. gratilla decreased, but was consistently above the safety limit allowed for human consumption. This study provides evidence of CTX bioaccumulation in T. gratilla as a cause of ciguatera-like poisoning associated with a documented symptomatology. Full article

(This article belongs to the Special Issue Marine Invertebrate Toxins)

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12 pages, 2003 KiB

Open AccessArticle

Cloning, Synthesis and Functional Characterization of a Novel α-Conotoxin Lt1.3

by Jinqin Chen, Li Liang, Huying Ning, Fengtao Cai, Zhuguo Liu, Longxiao Zhang, Liangyi Zhou and Qiuyun Dai

Mar. Drugs 2018, 16(4), 112; https://doi.org/10.3390/md16040112 - 31 Mar 2018

Cited by 16 | Viewed by 4174

Abstract

α-Conotoxins (α-CTxs) are small peptides composed of 11 to 20 amino acid residues with two disulfide bridges. Most of them potently and selectively target nicotinic acetylcholine receptor (nAChR) subtypes, and a few were found to inhibit the GABA_B receptor (GABA_BR)-coupled [...] Read more.

α-Conotoxins (α-CTxs) are small peptides composed of 11 to 20 amino acid residues with two disulfide bridges. Most of them potently and selectively target nicotinic acetylcholine receptor (nAChR) subtypes, and a few were found to inhibit the GABA_B receptor (GABA_BR)-coupled N-type calcium channels (Cav2.2). However, in all of α-CTxs targeting both receptors, the disulfide connectivity arrangement “C¹-C³, C²-C⁴” is present. In this work, a novel α4/7-CTx named Lt1.3 (GCCSHPACSGNNPYFC-NH₂) was cloned from the venom ducts of Conus litteratus (C. litteratus) in the South China Sea. Lt1.3 was then chemically synthesized and two isomers with disulfide bridges “C¹-C³, C²-C⁴” and “C¹-C⁴, C²-C³” were found and functionally characterized. Electrophysiological experiments showed that Lt1.3 containing the common disulfide bridges “C¹-C³, C²-C⁴” potently and selectively inhibited α3β2 nAChRs and not GABA_BR-coupled Cav2.2. Surprisingly, but the isomer with the disulfide bridges “C¹-C⁴, C²-C³” showed exactly the opposite inhibitory activity, inhibiting only GABA_BR-coupled Cav2.2 and not α3β2 nAChRs. These findings expand the knowledge of the targets and selectivity of α-CTxs and provide a new structural motif to inhibit the GABA_BR-coupled Cav2.2. Full article

(This article belongs to the Special Issue Marine Invertebrate Toxins)

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15 pages, 12527 KiB

Open AccessArticle

Makaluvamine G from the Marine Sponge Zyzzia fuliginosa Inhibits Muscle nAChR by Binding at the Orthosteric and Allosteric Sites

by Denis S. Kudryavtsev, Ekaterina N. Spirova, Irina V. Shelukhina, Lina V. Son, Yana V. Makarova, Natalia K. Utkina, Igor E. Kasheverov and Victor I. Tsetlin

Mar. Drugs 2018, 16(4), 109; https://doi.org/10.3390/md16040109 - 28 Mar 2018

Cited by 8 | Viewed by 3992

Abstract

Diverse ligands of the muscle nicotinic acetylcholine receptor (nAChR) are used as muscle relaxants during surgery. Although a plethora of such molecules exists in the market, there is still a need for new drugs with rapid on/off-set, increased selectivity, and so forth. We [...] Read more.

Diverse ligands of the muscle nicotinic acetylcholine receptor (nAChR) are used as muscle relaxants during surgery. Although a plethora of such molecules exists in the market, there is still a need for new drugs with rapid on/off-set, increased selectivity, and so forth. We found that pyrroloiminoquinone alkaloid Makaluvamine G (MG) inhibits several subtypes of nicotinic receptors and ionotropic γ-aminobutiric acid receptors, showing a higher affinity and moderate selectivity toward muscle nAChR. The action of MG on the latter was studied by a combination of electrophysiology, radioligand assay, fluorescent microscopy, and computer modeling. MG reveals a combination of competitive and un-competitive inhibition and caused an increase in the apparent desensitization rate of the murine muscle nAChR. Modeling ion channel kinetics provided evidence for MG binding in both orthosteric and allosteric sites. We also demonstrated that theα1 (G153S) mutant of the receptor, associated with the myasthenic syndrome, is more prone to inhibition by MG. Thus, MG appears to be a perspective hit molecule for the design of allosteric drugs targeting muscle nAChR, especially for treating slow-channel congenital myasthenic syndromes. Full article

(This article belongs to the Special Issue Marine Invertebrate Toxins)

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2821 KiB

Open AccessArticle

APETx4, a Novel Sea Anemone Toxin and a Modulator of the Cancer-Relevant Potassium Channel K_V10.1

by Lien Moreels, Steve Peigneur, Diogo T. Galan, Edwin De Pauw, Lászlo Béress, Etienne Waelkens, Luis A. Pardo, Loïc Quinton and Jan Tytgat

Mar. Drugs 2017, 15(9), 287; https://doi.org/10.3390/md15090287 - 13 Sep 2017

Cited by 32 | Viewed by 5658

Abstract

The human ether-à-go-go channel (hEag1 or K_V10.1) is a cancer-relevant voltage-gated potassium channel that is overexpressed in a majority of human tumors. Peptides that are able to selectively inhibit this channel can be lead compounds in the search for new anticancer [...] Read more.

The human ether-à-go-go channel (hEag1 or K_V10.1) is a cancer-relevant voltage-gated potassium channel that is overexpressed in a majority of human tumors. Peptides that are able to selectively inhibit this channel can be lead compounds in the search for new anticancer drugs. Here, we report the activity-guided purification and electrophysiological characterization of a novel K_V10.1 inhibitor from the sea anemone Anthopleura elegantissima. Purified sea anemone fractions were screened for inhibitory activity on K_V10.1 by measuring whole-cell currents as expressed in Xenopus laevis oocytes using the two-microelectrode voltage clamp technique. Fractions that showed activity on Kv10.1 were further purified by RP-HPLC. The amino acid sequence of the peptide was determined by a combination of MALDI- LIFT-TOF/TOF MS/MS and CID-ESI-FT-ICR MS/MS and showed a high similarity with APETx1 and APETx3 and was therefore named APETx4. Subsequently, the peptide was electrophysiologically characterized on K_V10.1. The selectivity of the toxin was investigated on an array of voltage-gated ion channels, including the cardiac human ether-à-go-go-related gene potassium channel (hERG or Kv11.1). The toxin inhibits K_V10.1 with an IC₅₀ value of 1.1 μM. In the presence of a similar toxin concentration, a shift of the activation curve towards more positive potentials was observed. Similar to the effect of the gating modifier toxin APETx1 on hERG, the inhibition of Kv10.1 by the isolated toxin is reduced at more positive voltages and the peptide seems to keep the channel in a closed state. Although the peptide also induces inhibitory effects on other K_V and Na_V channels, it exhibits no significant effect on hERG. Moreover, APETx4 induces a concentration-dependent cytotoxic and proapoptotic effect in various cancerous and noncancerous cell lines. This newly identified K_V10.1 inhibitor can be used as a tool to further characterize the oncogenic channel K_V10.1 or as a scaffold for the design and synthesis of more potent and safer anticancer drugs. Full article

(This article belongs to the Special Issue Marine Invertebrate Toxins)

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Review

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23 pages, 4372 KiB

Open AccessFeature PaperReview

Neuronal Nicotinic Acetylcholine Receptor Modulators from Cone Snails

by Nikita Abraham and Richard J. Lewis

Mar. Drugs 2018, 16(6), 208; https://doi.org/10.3390/md16060208 - 13 Jun 2018

Cited by 41 | Viewed by 5187

Abstract

Marine cone snails are a large family of gastropods that have evolved highly potent venoms for predation and defense. The cone snail venom has exceptional molecular diversity in neuropharmacologically active compounds, targeting a range of receptors, ion channels, and transporters. These conotoxins have [...] Read more.

Marine cone snails are a large family of gastropods that have evolved highly potent venoms for predation and defense. The cone snail venom has exceptional molecular diversity in neuropharmacologically active compounds, targeting a range of receptors, ion channels, and transporters. These conotoxins have helped to dissect the structure and function of many of these therapeutically significant targets in the central and peripheral nervous systems, as well as unravelling the complex cellular mechanisms modulated by these receptors and ion channels. This review provides an overview of α-conotoxins targeting neuronal nicotinic acetylcholine receptors. The structure and activity of both classical and non-classical α-conotoxins are discussed, along with their contributions towards understanding nicotinic acetylcholine receptor (nAChR) structure and function. Full article

(This article belongs to the Special Issue Marine Invertebrate Toxins)

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26 pages, 362 KiB

Open AccessReview

Phycotoxins in Marine Shellfish: Origin, Occurrence and Effects on Humans

by Federica Farabegoli, Lucía Blanco, Laura P. Rodríguez, Juan Manuel Vieites and Ana García Cabado

Mar. Drugs 2018, 16(6), 188; https://doi.org/10.3390/md16060188 - 29 May 2018

Cited by 105 | Viewed by 9716

Abstract

Massive phytoplankton proliferation, and the consequent release of toxic metabolites, can be responsible for seafood poisoning outbreaks: filter-feeding mollusks, such as shellfish, mussels, oysters or clams, can accumulate these toxins throughout the food chain and present a threat for consumers’ health. Particular environmental [...] Read more.

Massive phytoplankton proliferation, and the consequent release of toxic metabolites, can be responsible for seafood poisoning outbreaks: filter-feeding mollusks, such as shellfish, mussels, oysters or clams, can accumulate these toxins throughout the food chain and present a threat for consumers’ health. Particular environmental and climatic conditions favor this natural phenomenon, called harmful algal blooms (HABs); the phytoplankton species mostly involved in these toxic events are dinoflagellates or diatoms belonging to the genera Alexandrium, Gymnodinium, Dinophysis, and Pseudo-nitzschia. Substantial economic losses ensue after HABs occurrence: the sectors mainly affected include commercial fisheries, tourism, recreational activities, and public health monitoring and management. A wide range of symptoms, from digestive to nervous, are associated to human intoxication by biotoxins, characterizing different and specific syndromes, called paralytic shellfish poisoning, amnesic shellfish poisoning, diarrhetic shellfish poisoning, and neurotoxic shellfish poisoning. This review provides a complete and updated survey of phycotoxins usually found in marine invertebrate organisms and their relevant properties, gathering information about the origin, the species where they were found, as well as their mechanism of action and main effects on humans. Full article

(This article belongs to the Special Issue Marine Invertebrate Toxins)

33 pages, 7060 KiB

Open AccessReview

Ascidian Toxins with Potential for Drug Development

by Dianne J. Watters

Mar. Drugs 2018, 16(5), 162; https://doi.org/10.3390/md16050162 - 13 May 2018

Cited by 45 | Viewed by 7391

Abstract

Ascidians (tunicates) are invertebrate chordates, and prolific producers of a wide variety of biologically active secondary metabolites from cyclic peptides to aromatic alkaloids. Several of these compounds have properties which make them candidates for potential new drugs to treat diseases such as cancer. [...] Read more.

Ascidians (tunicates) are invertebrate chordates, and prolific producers of a wide variety of biologically active secondary metabolites from cyclic peptides to aromatic alkaloids. Several of these compounds have properties which make them candidates for potential new drugs to treat diseases such as cancer. Many of these natural products are not produced by the ascidians themselves, rather by their associated symbionts. This review will focus mainly on the mechanism of action of important classes of cytotoxic molecules isolated from ascidians. These toxins affect DNA transcription, protein translation, drug efflux pumps, signaling pathways and the cytoskeleton. Two ascidian compounds have already found applications in the treatment of cancer and others are being investigated for their potential in cancer, neurodegenerative and other diseases. Full article

(This article belongs to the Special Issue Marine Invertebrate Toxins)

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