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See detailDiscovery and characterization of EIIB, a new α-conotoxin from Conus ermineus venom by nAChRs affinity capture monitored by MALDI-TOF/TOF mass spectrometry
Echterbille, Julien; Gilles, Nicolas; Araoz, Romulo et al

in Toxicon (2017), 130

Animal toxins are peptides that often bind with remarkable affinity and selectivity to membrane receptors such as nicotinic acetylcholine receptors (nAChRs). The latter are, for example, targeted by α ... [more ▼]

Animal toxins are peptides that often bind with remarkable affinity and selectivity to membrane receptors such as nicotinic acetylcholine receptors (nAChRs). The latter are, for example, targeted by α-conotoxins, a family of peptide toxins produced by venomous cone snails. nAChRs are implicated in numerous physiological processes explaining why the design of new pharmacological tools and the discovery of potential innovative drugs targeting these receptor channels appear so important. This work describes a methodology developed to discover new ligands of nAChRs from complex mixtures of peptides. The methodology was set up by the incubation of Torpedo marmorata electrocyte membranes rich in nAChRs with BSA tryptic digests (>100 peptides) doped by small amounts of known nAChRs ligands (α-conotoxins). Peptides that bind to the receptors were purified and analyzed by MALDI-TOF/TOF mass spectrometry which revealed an enrichment of α-conotoxins in membrane-containing fractions. This result exhibits the binding of α-conotoxins to nAChRs. Negative controls were performed to demonstrate the specificity of the binding. The usefulness and the power of the methodology were also investigated for a discovery issue. The workflow was then applied to the screening of Conus ermineus crude venom, aiming at characterizing new nAChRs ligands from this venom, which has not been extensively investigated to date. The methodology validated our experiments by allowing us to bind two α-conotoxins (α-EI and α-EIIA) which have already been described as nAChRs ligands. Moreover, a new conotoxin, never described to date, was also captured, identified and sequenced from this venom. Classical pharmacology tests by radioligand binding using a synthetic homologue of the toxin confirm the activity of the new peptide, called α-EIIB. The Ki value of this peptide for Torpedo nicotinic receptors was measured at 2.2 ± 0.7 nM. [less ▲]

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See detailDiversity in sequences, post-translational modifications and expected pharmacological activities of toxins from four Conus species revealed by the combination of cutting-edge proteomics, transcriptomics and bioinformatics
Degueldre, Michel; Verdenaud, Marion; Garikoitz, Legarda et al

in Toxicon (2017), 130

Venomous animals have developed a huge arsenal of reticulated peptides for defense and predation. Based on various scaffolds, they represent a colossal pharmacological diversity, making them top ... [more ▼]

Venomous animals have developed a huge arsenal of reticulated peptides for defense and predation. Based on various scaffolds, they represent a colossal pharmacological diversity, making them top candidates for the development of innovative drugs. Instead of relying on the classical, low-throughput bioassay-guided approach to identify innovative bioactive peptides, this work exploits a recent paradigm to access to venom diversity. This strategy bypasses the classical approach by combining high-throughput transcriptomics, proteomics and bioinformatics cutting-edge technologies to generate reliable peptide sequences. The strategy employed to generate hundreds of reliable sequences from Conus venoms is deeply described. The study led to the discovery of (i) conotoxins that belong to known pharmacological families targeting various GPCRs or ion-gated channels, and (ii) new families of conotoxins, never described to date. It also focusses on the diversity of genes, sequences, folds, and PTM's provided by such species. [less ▲]

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See detailSecretion and maturation of conotoxins in the venom ducts of Conus textile
Dobson, Rowan ULiege; Collodoro, Mike; Gilles, Nicolas et al

in Toxicon (2012), 60(8), 1370-1379

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See detailG protein-coupled receptors, an unexploited animal toxin targets: Exploration of green mamba venom for novel drug candidates active against adrenoceptors
Maïga, Arhamatoulaye; Mourier, Gilles; Quinton, Loïc ULiege et al

in Toxicon (2012), 59

At a time when pharmaceutical companies are having trouble finding new low MW drugs and when biologics are becoming more common, animal venoms could constitute an underexploited source of novel drug ... [more ▼]

At a time when pharmaceutical companies are having trouble finding new low MW drugs and when biologics are becoming more common, animal venoms could constitute an underexploited source of novel drug candidates. We looked for identifying novel animal toxins active against G protein-coupled receptors (GPCR), the most frequently exploited class of treatment targets, with the aim to develop novel research tools and drug candidates. Screening of green mamba (Dendroaspis angusticeps) venom against adrenoceptors identified two novel venom peptides. r-Da1a shown an affinity of 0.35 nM for the a1a-AR while r-Da1b displayed affinities between 14 and 73 nM for the three a2-ARs. These two venom peptides have sequences similar to those of muscarinic toxins and belong to the three-finger-fold protein family. a1a-AR is the primary target for the treatment of prostate hypertrophy. In vitro and in vivo tests demonstrated that r-Da1a reduced prostatic muscle tone as efficiently as tamsulosin (an antagonist presently used), but with fewer cardiovascular side effects. a2-ARs are the prototype of GPCRs not currently used as treatment targets due to a lack of specific ligands. Blockage of these receptors increases intestinal motility, which may be compromised by abdominal surgery and reduces orthosteric hypotension. In vitro and in vivo tests demonstrated that r-Da1b antagonizes a2-ARs in smooth muscles and increased heart rate and blood catecholamine concentrations. These results highlight possible exploitation of r-Da1a and r-Da1b in important pathologies. [less ▲]

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See detailCharacterization of the neurotoxicity induced by the extract of Magnistipula butayei (Chrysobalanaceae) in rat: Effects of a new natural convulsive agent
Karangwa, Charles; Esters, Virginie ULiege; Tits, Monique ULiege et al

in Toxicon (2007), 49(8), 1109-1119

This study was designed to document convulsant and neurotoxic properties of extracts of a tropical tree, Magnistipula butayei subsp. Montana, and to investigate the involvement of the glutamatergic system ... [more ▼]

This study was designed to document convulsant and neurotoxic properties of extracts of a tropical tree, Magnistipula butayei subsp. Montana, and to investigate the involvement of the glutamatergic system in these effects. Continuous behavioral observations and electroencephalographic (EEG) records were obtained after per os administration of an aqueous extract of Magnistipula (MBMAE) in rats. MBMAE (800 mg/kg) induced behavioral changes resembling motor limbic seizures: staring and head tremor, automatisms, forelimb clonic movements and violent tonic-clonic seizures leading to death in all animals. Concomitantly, important seizure activity that gradually evolved to epileptiform activity was recorded on the EEG. Moreover, c-Fos immunohistochemistry has revealed an increased c-Fos expression in the dentate gyrus and in piriform, peri- and entorhinal cortices 2 and 4h after treatment. This expression pattern suggested that the mechanism of action for the MBMAE is similar to that observed in glutamate-induced models of epilepsy. The MBMAE increased cell death also in hippocampal cell cultures. Furthermore, the build-up of convulsive activity and epileptic discharges induced by MBMAE in rat were abolished by MK-801, an NMDA receptor antagonist. Our study suggests that MBMAE contains a potent toxin, with a powerful neurotoxic activity in rat, and corresponding to a new natural component(s) that act as an NMDA-mediated convulsant molecule. [less ▲]

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See detailFourier transform mass spectrometry: A powerful tool for toxin analysis
Quinton, Loïc ULiege; Le Caër, Jean-Pierre; Vinh, Joëlle et al

in Toxicon (2006), 47(6), 715-726

The crude venom of Conus virgo was analyzed by Fourier transform mass spectrometry (FTMS) using both nano-electrospray ionization and MALDI. The analyses were performed directly on the crude venom ... [more ▼]

The crude venom of Conus virgo was analyzed by Fourier transform mass spectrometry (FTMS) using both nano-electrospray ionization and MALDI. The analyses were performed directly on the crude venom, without chromatographic separation. The mass fingerprinting of the venom yielded 64 distinct molecular masses in the range 500-4500 Da with two major components at 1328.5142 and 1358.5592 Da. To facilitate the de novo sequencing of these compounds, the disulfide bonds of all components were reduced for the whole venom. The mass accuracy, resolution and sensitivity provided by FTMS were necessary to complete the sequencing of the two new peptides named ViVA and ViVB, that turned out to be conotoxins belonging to the T-superfamily, with the disulfide framework V. The peptides shared 80% similarity and as often observed for this class of compound, they were highly post-translationally modified: amidated C-terminus, pyroglutamic acid residue at the N-terminus and two disulfide bonds. Complementary online nano-LC-nano-ESI-FTMS experiments were undertaken. Among the 130 molecular masses found in the coupling experiments, only 45 were common with those obtained in the direct approach, which means that 21 compounds observed by nano-ESI-FTMS were not detected. This clearly shows that some discriminations against some classes of compounds occur when a chromatographic step is used before mass spectrometry. [less ▲]

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See detailAbout the toxicity of some Strychnos species and their alkaloids
Philippe, Geneviève ULiege; Angenot, Luc ULiege; Tits, Monique ULiege et al

in Toxicon (2004), 44(4), 405-416

Poisons are widespread in plants and animals and humankind has often tried to turn them to its own advantage. Owing to their poisonous properties, some species of Strychnos genus have been employed mainly ... [more ▼]

Poisons are widespread in plants and animals and humankind has often tried to turn them to its own advantage. Owing to their poisonous properties, some species of Strychnos genus have been employed mainly in hunting and fishing, as an adjunct to weapons used not only in the search of food and clothes, but also for preventing depredation by wild animals. They have been employed for martial and criminal purposes and also as a means of determining guilt or innocence. By their nature, poisons such as strychnine and curate affect the functioning of the victim's body; this also means that they have been, and are, an important source of pharmacological tools and medicines all over the world. With such potentially dangerous substances, care in medication is essential to avoid complications by overdose. All these points are approached in the present review. (C) 2004 Elsevier Ltd. All rights reserved. [less ▲]

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