Nicolas Gilles

Commissariat à l'Énergie Atomique et aux Énergies Alternatives

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i-10 index

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Loïc Quinton

University of Liège

Edwin De Pauw

University of Liège

Denis Servent

Technologies pour la Santé

Gilles Mourier

Commissariat à l'Énergie Atomique et aux Énergies Alternatives

Grégory Upert

Commissariat à l'Énergie Atomique et aux Énergies Alternatives

Dalia Gordon

Tel Aviv University

Philippe Massonnet

Maastricht University

Justyna Ciolek

Technologies pour la Santé

Julien Echterbille

University of Liège

Michael Gurevitz

Tel Aviv University

Cooperative Institutions

Centre National de la Recherche Scientifique

159

Commissariat à l'Énergie Atomique et aux Énergies Alternatives

123

CEA Paris-Saclay

Inserm

Université Paris-Saclay

Technologies pour la Santé

Institut de Biologie et Technologies

Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement

Frédéric Joliot Institute for Life Sciences

University of Liège

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G protein-coupled receptors, an unexploited animal toxin targets: Exploration of green mamba venom for novel drug candidates active against adrenoceptors

Toxicon (2011)

Arhamatoulaye Maïga Gilles Mourier Loïc Quinton Céline Rouget Céline Galès

10.1016/j.toxicon.2011.03.009

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Citations (35)

A Spider Toxin That Induces a Typical Effect of Scorpion α-Toxins but Competes with β-Toxins on Binding to Insect Sodium Channels

Biochemistry (2005)

Gerardo Corzo Pierre Escoubas Elba Villegas Izhar Karbat Dalia Gordon

δ-Palutoxins from the spider Paracoelotes luctuosus (Araneae: Amaurobiidae) are 36−37 residue long peptides that show preference for insect sodium channels (NaChs) and modulate their function. Although they slow NaCh inactivation in a fashion similar to that of receptor site 3 modifiers, such as scorpion α-toxins, they actually bind with high affinity to the topologically distinct receptor site 4 of scorpion β-toxins. To resolve this riddle, we scanned by Ala mutagenesis the surface of δ-PaluIT2, a δ-palutoxin variant with the highest affinity for insect NaChs, and compared it to the bioactive surface of a scorpion β-toxin. We found three regions on the surface of δ-PaluIT2 important for activity: the first consists of Tyr-22 and Tyr-30 (aromatic), Ser-24 and Met-28 (polar), and Arg-8, Arg-26, Arg-32, and Arg-34 (basic) residues; the second is made of Trp-12; and the third is made of Asp-19, whose substitution by Ala uncoupled the binding from toxicity to lepidopteran larvae. Although spider δ-palutoxins and scorpion β-toxins have developed from different ancestors, they show some commonality in their bioactive surfaces, which may explain their ability to compete for an identical receptor (site 4) on voltage-gated NaChs. Yet, their different mode of channel modulation provides a novel perspective about the structural relatedness of receptor sites 3 and 4, which until now have been considered topologically distinct.

Spider toxin

Scorpion toxin

Scorpion Venoms

10.1021/bi048434k

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Citations (38)

Mass spectrometric sequencing of peptidic toxins : an overview

Loïc Quinton Julien Echterbille Pierre Escoubas Nicolas Gilles Edwin De Pauw

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Ion mobility mass spectrometry as a tool to perform structural characterization of peptides bearing disulfide bond(s)

Philippe Massonnet Grégory Upert Jean Haler Michel Degueldre Denis Morsa

Characterization

Ion-mobility spectrometry

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Distinct primary structures of the major peptide toxins from the venom of the spider Macrothele gigas that bind to sites 3 and 4 in the sodium channel¹

FEBS Letters (2003)

Gerardo Corzo Nicolas Gilles Honoo Satake Elba Villegas Li Dai

Six peptide toxins (Magi 1–6) were isolated from the Hexathelidae spider Macrothele gigas . The amino acid sequences of Magi 1, 2, 5 and 6 have low similarities to the amino acid sequences of known spider toxins. The primary structure of Magi 3 is similar to the structure of the palmitoylated peptide named PlTx‐II from the North American spider Plectreurys tristis (Plectreuridae). Moreover, the amino acid sequence of Magi 4, which was revealed by cloning of its cDNA, displays similarities to the Na + channel modifier δ‐atracotoxin from the Australian spider Atrax robustus (Hexathelidae). Competitive binding assays using several 125 I‐labelled peptide toxins clearly demonstrated the specific binding affinity of Magi 1–5 to site 3 of the insect sodium channel and also that of Magi 5 to site 4 of the rat sodium channel. Only Magi 6 did not compete with the scorpion toxin LqhαIT in binding to site 3 despite high toxicity on lepidoptera larvae of 3.1 nmol/g. The K i s of other toxins were between 50 pM for Magi 4 and 1747 nM for Magi 1. In addition, only Magi 5 binds to both site 3 in insects ( K i =267 nM) and site 4 in rat brain synaptosomes ( K i =1.2 nM), whereas it showed no affinities for either mammal binding site 3 or insect binding site 4. Magi 5 is the first spider toxin with binding affinity to site 4 of a mammalian sodium channel.

Spider toxin

10.1016/s0014-5793(03)00666-5

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Citations (102)

Evaluation of the Spider (Phlogiellus genus) Phlotoxin 1 and Synthetic Variants as Antinociceptive Drug Candidates

Toxins (2019)

Tânia C. Gonçalves Pierre Lesport Sarah Kuylle E.A. Stura Justyna Ciolek

Over the two last decades, venom toxins have been explored as alternatives to opioids to treat chronic debilitating pain. At present, approximately 20 potential analgesic toxins, mainly from spider venoms, are known to inhibit with high affinity the NaV1.7 subtype of voltage-gated sodium (NaV) channels, the most promising genetically validated antinociceptive target identified so far. The present study aimed to consolidate the development of phlotoxin 1 (PhlTx1), a 34-amino acid and 3-disulfide bridge peptide of a Phlogiellus genus spider, as an antinociceptive agent by improving its affinity and selectivity for the human (h) NaV1.7 subtype. The synthetic homologue of PhlTx1 was generated and equilibrated between two conformers on reverse-phase liquid chromatography and exhibited potent analgesic effects in a mouse model of NaV1.7-mediated pain. The effects of PhlTx1 and 8 successfully synthetized alanine-substituted variants were studied (by automated whole-cell patch-clamp electrophysiology) on cell lines stably overexpressing hNaV subtypes, as well as two cardiac targets, the hCaV1.2 and hKV11.1 subtypes of voltage-gated calcium (CaV) and potassium (KV) channels, respectively. PhlTx1 and D7A-PhlTx1 were shown to inhibit hNaV1.1–1.3 and 1.5–1.7 subtypes at hundred nanomolar concentrations, while their affinities for hNaV1.4 and 1.8, hCaV1.2 and hKV11.1 subtypes were over micromolar concentrations. Despite similar analgesic effects in the mouse model of NaV1.7-mediated pain and selectivity profiles, the affinity of D7A-PhlTx1 for the NaV1.7 subtype was at least five times higher than that of the wild-type peptide. Computational modelling was performed to deduce the 3D-structure of PhlTx1 and to suggest the amino acids involved in the efficiency of the molecule. In conclusion, the present structure–activity relationship study of PhlTx1 results in a low improved affinity of the molecule for the NaV1.7 subtype, but without any marked change in the molecule selectivity against the other studied ion channel subtypes. Further experiments are therefore necessary before considering the development of PhlTx1 or synthetic variants as antinociceptive drug candidates.

Spider toxin

10.3390/toxins11090484

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Citations (13)

δ-Conopeptide EVIA isolated from Conus ermineus is a new pharmacological tool for discriminating sodium channel subtypes

Journal of Physiology-Paris (2006)

Julien Barbier Hung Lamthanh Frédéric Le Gall Philippe Favreau Évelyne Benoit

Conus

10.1016/j.jphysparis.2005.12.020

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Citations (0)

Secretion and maturation of conotoxins in the venom ducts of Conus textile

Toxicon (2012)

Rowan Dobson Mike Collodoro Nicolas Gilles Andrei Turtoï Edwin De Pauw

Conotoxin

Conus

10.1016/j.toxicon.2012.09.013

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Citations (18)

Specific mutations in the cholesterol-binding site of APP alter its processing and favor the production of shorter, less toxic Aβ peptides.

Research Square (Research Square) (2022)

Linda Hanbouch Béatrice Schaack Amal Kasri Gaëlle Fontaine Eleni Gkanatsiou

Abstract Excess brain cholesterol is strongly implicated in the pathogenesis of Alzheimer disease (AD). Here we evaluated how the presence of a cholesterol-binding site (CBS) in the transmembrane and juxtamembrane regions of the amyloid precursor protein (APP) regulates its processing.We generated nine point mutations in the APP gene, changing the charge and/or hydrophobicity of the amino-acids which were previously shown as part of the CBS. Most mutations triggered a reduction of amyloid-β peptides Aβ40 and Aβ42 secretion from transfected HEK293T cells. Only the K to A mutation at position 28 of Aβ in the APP sequence (APP K28A ) resulted in a concomitant increase in the production of shorter Aβ peptides. Mass Spectrometry (MS) confirmed the predominance of Aβx-33 and Aβx-34. The enzymatic activity of α-, β- and g-secretases remained unchanged in cells expressing the APP K28A and all other mutants. Similarly, subcellular localization of the mutants in early endosomes did not differ from the APP WT protein. A transient increase of plasma membrane cholesterol enhanced the production of Aβ40 and Aβ42 by APP WT , an effect absent in APP K28A mutant. Finally, WT but not CBS mutant Aβ derived peptides bound to cholesterol-rich exosomes. Collectively, the present data revealed a major role of juxtamembrane amino acids of the APP CBS in modulating the production of toxic Aβ species. More generally, they underpin the role of cholesterol in the pathophysiology of AD.

HEK 293 cells

10.21203/rs.3.rs-1574121/v1

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Citations (0)

Pharmacological characterization of zinc and copper interaction with the human alpha1A-adrenoceptor

European Journal of Pharmacology (2011)

Justyna Ciolek Arhamatoulaye Maïga Elodie Marcon Denis Servent Nicolas Gilles

Affinities

10.1016/j.ejphar.2010.12.042

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Citations (18)