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H:\Impression\Couverture 1 Sami BRUMENT Mémoire présenté en vue de l’obtention du grade de Docteur de l'Université de Nantes sous le sceau de l’Université Bretagne Loire École doctorale : ED3MPL Discipline : Chimie organique Spécialité : Glycochimie Unité de recherche : CEISAM UMR 6230 Soutenue le 03 Novembre 2016 Ligands multivalents pour l'interaction par effet chélate avec les récepteurs nicotiniques et les lectines AFL et DC-SIGN JURY Président du jury : Olivier RENAUDET, Professeur des Universités, Département de chimie moléculaire de Grenoble Rapporteur : Boris VAUZEILLES, Directeur de Recherche au CNRS, ICMMO - SM2B - Université Paris-Sud Examinateur : Gwladys POURCEAU, Maitre de conférences, LG2A - Université de Picardie Jules Verne Invité(s) : Franck HALARY, Chargé de recherche au CNRS, INSERM/CRTI-Nantes Directeur de Thèse : Sébastien Gouin, Chargé de recherche au CNRS, CEISAM Nantes Co-directeur de Thèse : Patrice LE PAPE, Professeur d'université, Université de Nantes « Sience sans conscience n’est que ruine de l’âme. » Rabelais Remerciements : Je tiens tout d’abord à remercier le Docteur Bruneau Bujoli pour m’avoir accueilli au sein du laboratoire CEISAM (Chimie et Interdisciplinarité : Synthèse, Analyse et Modélisation). Je remercie tout particulièrement les Docteurs Olivier Renaudet, Boris Vauzeilles pour avoir accepté de juger ces travaux de thèse en tant que rapporteurs ainsi que Gwladys Pourceau pour avoir accepté d’être examinatrice. J’adresse mes plus sincères remerciements au Docteur Sébastien Gouin, mon directeur de thèse, ainsi que le Professeur David Deniaud, qui m’ont été d’un grand soutien pendant ces trois années, qui m’ont conseillé et aiguillé pour parvenir au bout de ces travaux de recherche. Merci également pour tous les bons moments passés ensemble, pour cette disponibilité même en dehors du cadre du laboratoire qui permettait de décompresser. Merci à tous les membres du laboratoire, particulièrement au personnel technique, vous avez été vraiment présents quand j’avais besoin de vous, même pour me donner toutes les explications que je vous demandais avec une grande patience. Merci encore à tous les doctorants pour les bons moments passés ensembles que ce soit dans le laboratoire ou en dehors. Merci aussi à tous les membres de l’équipe CORAIL, permanents, doctorants, post-docs ou stagiaires avec qui cela a toujours été agréable de travailler et d’échanger. Merci à Martin, Dimitri, Tibo. Si ces trois années ont été si agréables c’est en bonne partie grâce à vous, et pourvu que ça ne s’arrête pas là, on n’arrête pas un train CORAIL si facilement. Les moments passés ensemble que ce soit à la rituelle pause-café ou au Michelet du vendredi étaient obligatoires pour venir à bout de ces trois années. Les soirées jeux accompagnées de rhum au piment me manqueront, même s’il nous reste encore quelques occasions de le finir quand même ce rhum ! Merci à Lucie, même si tu n’es restée que quelques mois, tu t’étais fait ta place et on en a bien profité pendant tes stages. Merci beaucoup pour le travail que tu as abattu, pourvu que tes souvenirs du laboratoire ne soient pas trop marqués par mon amour pour la vaisselle. Merci à ma famille, pour le soutien pendant toutes mes études et surtout pendant la thèse. Même si cette thèse n’aboutira sur rien de concret pour moi dans l’avenir, elle a au moins permis de vous montrer de quoi j’étais capable et de vous en mettre plein les yeux ! Merci surtout à Anaïs qui m’a toujours soutenu et aidé durant ces trois ans, si j’avais besoin de me relever tu as toujours été là, à me donner de la force pour surmonter les mauvais moments, tu as vraiment su me donner le courage d’aller au bout. Abréviations : 9-BBN : 9-Borabicyclo[3.3.1]nonane ABPA : Aspergillose broncho-pulmonaire allergique AFL : Aspergillus Fumigatus Lectin AFM : Atomic-force microscopy (Microscope à force atomique) AI : Aspergillose invasive AIBN : Azobisisobutyronitrile APC : Allophycocyanin Asn : Asparagine BSA : Bovine serum albumine (albumine de sérum bovin) CD : Cyclodextrine CFU : Colony-Forming Unit (unité formant colonie) cGMP : Cyclic guanosine monophosphate (guanosine monophosphate cyclique) CLR : C-type lectin receptor (récepteur lectine de type C) CMH : Complexe majeur d’histocompatibilité CMV : Cytomégalovirus CNG : Cyclic nucleotide–gated ConA : Concavaline A CRD : Carbohydrate recognition domain (domaine de reconnaissance des sucres) CuAAC : Copper(I)-catalyzed alkyne-azide cycloaddition (cycloaddition alcyne-azoture cupro-catalysée) CYP34A : Cytochrome P450 3A4 DAPI : 4',6-diamidino-2-phénylindole DCM : Dichlorométhane DCs : Dendritic cells (cellules dendritiques) DEAD : Diéthyl azodicarboxylate DIAD : Diisopropyl azodicarboxylate DLS : Dynamic light scattering (diffusion dynamique de la lumière) DMAP : 4-Diméthylaminopyridine DME : Diméthoxyéthane DMF : N,N-Diméthylformamide DMJ : désoxymannojirimycine DNJ : désoxynojirimycine DPPA : Diphenylphosphoryl azide (azoture de diphosphoryle) EC50 : (half maximal) Effective concentration (concentration efficace médiane) ELISA : Enzyme-linked immunosorbent assay (dosage d'immunoabsorption par enzyme liée) gB : Glycoprotéine B GFP : Green fluorescent protein (Protéine fluorescente verte) Glc : Glucose Glu : Glutamate GM1 : Monosialotetrahexosylganglioside HAART : Highly active antiretroviral therapy (traitement antirétroviral hautement actif) HATU : 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HBA : Hydrogen bond acceptor (accepteur de liaison hydrogène) HM : Heptylmannoside HOBT : Hydroxybenzotriazole IC50 : (half maximal) Inhibitory concentration (Concentration inhibitrice médiane) IL : Interleukine ITC : Isothermal titration calorimetry (titration calorimétrique isotherme) JbMan : mannosidase de Jack Bean Kd : Constante de dissociation Ki : Constant d’inhibition LiHMDS : Bis(triméthylsilyl)amidure de lithium LT : Lymphocytes T Man : Mannose MBP : Mannose binding protein (protéine se liant au mannose) MOI : Multiplicity Of Infection (multiplicité d'infection cellulaire) nAChR : Nicotinic acetylcholine receptor (récepteur nicotinique à acetylcholine) NK : Natural Killer (tueur naturel) OEG : Oligoéthylène glycol PA : Potentiel d’action PPSE : Potentiel post-synaptique excitateur PRR : Pattern recognition receptor (récepteurs de reconnaissance de motifs moléculaires) RMN : Résonance magnétique nucléaire ROMP : Ring-opening metathesis polymerization (polymérisation par ouverture de cycle) SIDA : Syndrome d'immunodéficience acquise SNC : Système nerveux central TCR : T cells receptors (récepteurs des Lymphocytes T) TEBAC : triéthylbenzylammonium TES : Triethylsilane THF : Tetrahydrofurane VIH : Virus de l'immunodéficience humaine Sommaire Ligands Multivalents : Principes et applications .................. 1 I. Effets de multivalence .................................................................................. 2 1) Définition et principes généraux ................................................................................2 2) Effets multivalents ..................................................................................................... 3 3) Structuration d’un composé multivalent ................................................................. 12 II. Champs d’application de la multivalence .................................................... 24 1) Inhibition de l’interaction hôte-pathogène............................................................. 24 2) Inhibition de protéines fonctionnelles .................................................................... 28 III. Objectifs ..................................................................................................... 32 1) Inhibiteurs multivalents d’adhésion du cytomégalovirus ....................................... 32 2) Inhibiteurs multivalents d’adhésion d’Aspergillus fumigatus .................................. 32 3) Ligands multivalents de récepteurs nicotiniques ................................................... 33 Aspergillus fumigatus ................................................................. 34 I. Introduction ............................................................................................... 35 1) Découverte/partie historique .................................................................................. 35 2) Risque infectieux ...................................................................................................... 36 3) Aspergilloses ............................................................................................................. 36 4) Traitements ............................................................................................................... 39 5) Adhésion fongique - Aspergillus fumigatus lectin .................................................... 41 6) Stratégie antiadhésive appliquée à AFL - structures envisagées ........................... 44 II. Synthèse .................................................................................................... 46 1) Synthèse des charpentes ......................................................................................... 46 2) Synthèse des ligands ................................................................................................. 52 3) Insertion des ligands sur la charpente .................................................................... 55 4) Synthèse du ligand monovalent de référence ........................................................ 58 III. Evaluations biologiques .............................................................................
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