Exploration des caractéristiques tridimensionnelles des amas protéiques hydrophobes issus du formalisme "Hydrophobic Cluster Analysis" (HCA) (modélisation de formes oligomériques solubles du peptide Ab impliqué dans la maladie d'Alzheimer, et identification d'un 'point chaud" commun à différentes protéines amyloïdes)

Nous avons d abord exploré les caractéristiques 3D des amas d acides aminés hydrophobes issus de la méthode "Hydrophobic Cluster Analysis" (HCA), au travers d une représentation originale en tesselation de Voronoï. Chaque amas peut être ainsi caractérisé dans ses conformations ou et ses affinités préférentielles pour d autres amas peuvent être décrites. Le repliement protéique peut alors être décrit comme l assemblage de ces amas HCA 3D. Nous avons ensuite construit, en utilisant des outils d alignement tels que HCA, des modèles 3D des formes oligomériques solubles du peptide A . Ce peptide, impliqués dans la maladie d Alzheimer, serait neurotoxique sous cette forme soluble. Ce travail nous a permis de proposer une hypothèse expliquant le comportement différencié de p3, sans la région N-terminale d A . Enfin, nous avons pu mettre en évidence la présence d un ou plusieurs "points chauds" communs aux protéines amyloïdes, pouvant être à l origine de leur propriété à former des fibres.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Sequence-Based Modeling of Ab42 Soluble Oligomers

International audienceAb fibrils, which are central to the pathology of Alzheimer's disease, form a cross-b-structure that contains likely parallel b-sheets with a salt bridge between residues Asp23 and Lys28. Recent studies suggest that soluble oligomers of amyloid peptides have neurotoxic effects in cell cultures, raising the interest in studying the structures of these intermediate forms. Here, we present three models of possible soluble Ab forms based on the sequences similarities, assumed to support local structural similarities, of the Ab peptide with fragments of three proteins (adhesin, Semliki Forest virus capsid protein, and transthyretin). These three models share a similar structure in the C-terminal region composed of two b-strands connected by a loop, which contain the Asp23-Lys28 salt bridge. This segment is also structurally well conserved in Ab fibril forms. Differences between the three monomeric models occur in the N- terminal region and in the C-terminal tail. These three models might sample some of the most stable conformers of the soluble Ab peptide within oligomeric assemblies, which were modeled here in the form of dimers, trimers, tetramers, and hexamers. The consistency of these models is discussed with respect to available experimental and theorical data

p3 peptide, a truncated form of Aβ\beta devoid of synaptotoxic effect, does not assemble into soluble oligomers

International audienceIn previously proposed models of A$\beta$ soluble oligomers, the N-terminal domain A$\beta_{1-16}$ which is missing in p3 peptides, protects the hydrophobic core of the oligomers from the solvent. Without this N-terminal part, oligomers of p3 peptides would likely expose hydrophobic residues to water and would consequently be less stable. We thus suggest, based on theoretical and experimental results, that p3 peptides would have a low propensity to assemble into stable oligomers, evolving then directly to fibrillar aggregates. These properties may explain why p3 would be devoid of any impact on synaptic function and moreover, strengthen the hypothesis that A$\beta$ oligomers are the principal synaptotoxic forms of A$\beta$ peptides in Alzheimer disease

In silico chemical library screening and experimental validation of novel compounds with potential varroacide activities

The mite Varroa destructor is an ectoparasite and has been identified as a major cause of worldwide honey bee colony losses. The use of yearly treatments for the control of varroosis is the most common answer to prevent collapses of honey bee colonies due to the mite. However, the number of effective acaricides is small and the mite tends to become resistant to these few active molecules. In this study, we have been looking for a new original varroacide treatment inhibiting selectively Varroa destructor AChE (vdAChE) with respect to Apis mellifera AChE (amAChE). To do this an original drug design methodology was used applying virtual screening of the CERMN chemolibrary, starting from a vdAChE homology sequence model. By combining the in silico screening with in vitro experiments, two promising compounds were found. In vitro tests of AChE inhibition for both species have confirmed good selectivity toward the mite vdAChE. Moreover, an in vivo protocol was performed and highlighted a varroacide activity without acute consequences on honey bee survival. The two compounds discovered have the potential to become new drug leads for the development of new treatments against the mite varroa. The method described here clearly shows the potential of a drug-design approach to develop new solutions to safeguard honey bee health

Protecting honey bees: identification of a new varroacide by in silico, in vitro, and in vivo studies.

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Corrigendum to “Interpretation of honeybees contact toxicity associated to acetylcholinesterase inhibitors” [Ecotoxicol. Environ. Saf. 79 (2012) 13–21]

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Interpretation of honeybees contact toxicity associated to acetylcholinesterase inhibitors

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Dual Histamine H3R/Serotonin 5-HT4R Ligands with Antiamnesic Properties: Pharmacophore-Based Virtual Screening and Polypharmacology.

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Protective effects of caffeic acid against hypothalamic neuropeptides alterations induced by malathion in rat

International audienceExposure to pesticides is suspected to cause human health problems. Our study aimed to evaluate preventive effects of caffeic acid (3,4-dihydroxycinnamic acid) in the hypothalamus against malathion-induced neuropeptides gene expression alterations. Malathion at 100 mg/kg was administered intragastrically to rats alone or in combination with caffeic acid at 100 mg/kg during 4 weeks. A molecular expression of hypothalamic neuropeptides and plasmatic cholinesterase activity was investigated. Furthermore, we used in silico analysis, known as computational docking, to highlight the nature of acetylcholinesterase-malathion/caffeic acid interactions. Our findings showed differences in the responses and indicate that caffeic acid reversed malathion-induced decrease in corticotropin-releasing hormone mRNA but not brain-derived neurotrophic factor which presented an increased tendency. We suggest that caffeic acid can interact with acetylcholinesterase as the primary target of organophosphorus compounds. Results predict that caffeic acid can block partly the acetylcholinesterase gorge entrance via π-π stacking interaction with Tyr 124 and Trp 286 residues of the peripheral site leading to its stricture. Under this condition, we suggested that acetylcholine trafficking toward the catalytic site is ameliorated compared to malaoxon according to their size