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Synthesis of (Cyclo)Maltooligosaccharide-Based Glycosaminoglycan Mimetics and Their Interaction with Heparin Binding Growth Factors Rubal Ravinder

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Synthesis of (Cyclo)Maltooligosaccharide-Based Glycosaminoglycan Mimetics and Their Interaction with Heparin Binding Growth Factors Rubal Ravinder Synthesis of (cyclo)maltooligosaccharide-based glycosaminoglycan mimetics and their interaction with heparin binding growth factors Rubal Ravinder To cite this version: Rubal Ravinder. Synthesis of (cyclo)maltooligosaccharide-based glycosaminoglycan mimetics and their interaction with heparin binding growth factors. Organic chemistry. Université Grenoble Alpes [2020- ..], 2020. English. NNT : 2020GRALV034. tel-03192820 HAL Id: tel-03192820 https://tel.archives-ouvertes.fr/tel-03192820 Submitted on 8 Apr 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE Pour obtenir le grade de DOCTEUR DE L’UNIVERSITE GRENOBLE ALPES Spécialité : Chimie organique Arrêté ministériel : 25 mai 2016 Présentée par Rubal RAVINDER Thèse dirigée par Sami HALILA, Chargé de Recherche, CNRS, et codirigée par Romain VIVÈS, Directeur de Recherche, CNRS préparée au sein du Centre de Recherche sur les Macromolécules Végétales (CERMAV) et de l’Institut de Biologie Structurale (IBS) dans l'École Doctorale Chimie et Sciences du Vivant Synthèse de mimes de glycosaminoglycanes sulfatés à base de (cyclo)maltooligosaccharides et leur interaction avec des facteurs de croissance liant l’héparine Synthesis of (cyclo)maltooligosaccharide- based sulfated glycosaminoglycan mimetics and their interaction with heparin binding growth factors Thèse soutenue publiquement le 7 décembre 2020 devant le jury composé de : Madame Angela RUSSELL Professeure, St John’s College, University of Oxford, Rapportrice Monsieur José KOVENSKY Professeur des Universités, Université de Picardie, Rapporteur Madame Chrystel LOPIN-BON Professeure des Universités, Université d’Orléans, Examinatrice Madame Sandrine PY Directrice de Recherche, CNRS, Examinatrice, Présidente du jury Monsieur Romain VIVÈS Directeur de Recherche, CNRS, Co-directeur de thèse Monsieur Sami HALILA Chargé de Recherche, CNRS, Directeur de thèse Remerciements Ce manuscrit est l’aboutissement de trois années de recherche, en qualité de doctorante principalement au sein du Centre de Recherche sur les Macromolécules Végétales (équipe Auto-assemblage de Glycopolymères, Grenoble) mais aussi au sein de l’Institut de Biologie Structurale (groupe Structure et Activité des GlycosAminoGlycanes, Grenoble). Je tiens tout d’abord à remercier mon directeur de thèse Monsieur Sami HALILA pour m’avoir accueilli au sein du CERMAV. Je le remercie pour son accompagnement, ses idées judicieuses, sa disponibilité et son soutien au cours de ces trois années malgré toutes les difficultés que j’ai pu rencontrer durant ce projet ambitieux et pluridisciplinaire. J’ai énormément appris en glycochimie, et ma passion pour ce domaine n’en a été que renforcée. Sa bonne humeur et son « humour » m’ont aidé à avancer autant sur le plan personnel que professionnel. Je tiens également à remercier mon co-directeur de thèse Monsieur Romain VIVÈS pour m’avoir accueilli au sein de son équipe à l’IBS. Je le remercie pour sa disponibilité, sa bonne humeur et son accompagnement, et j’espère avoir l’opportunité de faire quelques essaies à l’IBS pour renforcer mes compétences. Je le remercie d’avoir pris du temps pour m’expliquer la complexité des glycosaminoglycanes tout au long du projet, mais aussi de m’avoir aidé à comprendre et interpréter les résultats en biologie lors de la rédaction. J’aimerais ensuite remercier Madame Angela RUSSELL et Monsieur José KOVENSKY, rapporteurs de mon jury, pour avoir accepté de juger ce travail avec bienveillance et pour la discussion qui a suivie la soutenance. Je remercie également Madame Chrystel LOPIN-BON pour avoir examiné ce travail et Madame Sandrine PY, pour avoir en plus présider le jury et pour l’aide pour les réactions d’hydrogénolyse effectuées au sein du laboratoire DCM (Grenoble). Je souhaite remercier Mesdames Patricia ALBANESE et Carine-Manuela BORGES au laboratoire Gly- CRRET, Croissance, Réparation et Régénération Tissulaires, pour avoir effectué les tests biologiques, pour nos discussions enrichissantes et pour le précieux temps qu’elles m’ont accordé pour m’expliquer les tests et les résultats obtenus. Mes remerciements s’adressent également à tous les permanents du laboratoire, qui ont créé une atmosphère de travail agréable. J’ai passé de très agréables moments, leurs conseils et leur bienveillance m’ont énormément aidé. Un très grand merci à tous les non-permanents (anciens et nouveaux) de l’équipe et plus particulièrement à Marie CARRIERE, Charlène EFFLIGENIR, Sophie RENAUD, Justine SOLIER, Cornélia LUNTADILA (les PCG gurlz !), mais aussi à Robin BRAHMI, Shun YAO, Hong LI, Ahlem MNASRI et Julie PERRIN pour cette aventure et ces moments riches en émotions ! Vous avez énormément contribué à l’ambiance de l’équipe, vous m’avez beaucoup aidé, et fait apprécier mon séjour à Grenoble. Merci également à tous les non-permanents que j’ai rencontré au laboratoire (et je m’excuse d’avance pour ceux que j’ai pu oublier) : Dania, Claire, Simon, Raphael, Vanina, Marie-Carole, Paul C., Fabien, Maeva, Rafael, Robin, Pierre, Antoine, Paul R., Axel, Laurent, Emeline, Céline, Julien, etc. J’ai adoré discuter avec vous tous, votre gentillesse m’émue et j’espère qu’on aura l’occasion de fêter mon diplôme tous ensemble ! Je souhaite exprimer mes profonds remerciements à tous mes amis (dont Emilie, Sylvie, Pauline, Samuel, Merrick et Ghada). Votre présence me fait oublier mes soucis et m’aide à avancer dans ma vie. 4 Je remercie ma famille, et plus particulièrement mon petit frère, Ravneet, le soleil de ma vie. Ils m’ont appris à toujours me battre, et c’est grâce à eux que j’ai entrepris cette thèse. Aussi un grand merci à la famille de mon conjoint pour m’avoir si chaleureusement accueilli et supporté. Vous êtes des personnes en or. Enfin, je voudrais remercier mon conjoint, Olivier : merci d’exister. 5 Résumé en français Chapitre 1 : Contexte L’arthrose est une maladie commune affectant les articulations de l’organisme. Dans un organisme sain, l’articulation se compose de deux extrémités d’os protégées par du tissu cartilagineux. Celui-ci est principalement formé d’une matrice extra-cellulaire riche en fibre de collagène, en protéoglycanes (PGs) et en glycosaminoglycanes (GAGs). Un seul type de cellule est présent dans ce tissu avasculaire, les chondrocytes, en charge de la production et la dégradation des composés matriciels et donc de l’intégrité du tissu. C’est lorsque l’équilibre établi par les chondrocytes est rompu que l’arthrose a lieu avec pour principal effet la dégradation du tissu cartilagineux et notamment des protéoglycanes et glycosaminoglycanes. Lors de stades avancés, la dégradation du cartilage outrepasse la production d’éléments matriciels. Les chondrocytes produisent alors des composés matriciels structurellement altérés incapables de posséder des fonctions physiologiques ce qui contribue à l’inflammation du tissu et à des douleurs au niveau des articulations. L’arthrose est actuellement la maladie rhumatismale la plus commune dans le monde et est reconnue comme un fardeau pour la santé publique mondiale. Le nombre de patients atteint d’arthrose augmente tous les jours dû au vieillissement de la population et à l’augmentation de la prévalence de l’obésité. Malheureusement, seuls des traitements symptomatiques sont prescrits aux patients car aucun traitement curatif n’a été mis au point à ce jour. Les thérapies actuelles en développement se basent sur l’ingénierie tissulaire avec la mise en place de réseaux de protéoglycanes et glycosaminoglycanes artificiels ou mimés dans lesquelles des cellules souches mésenchymateuses seraient introduites afin qu’elles puissent se différencier en chondrocytes produisant des éléments matriciels « sains » dans un environnement non-inflammatoire. Cette stratégie a donc été explorée dans le cadre de notre projet. Les GAGs sont de longues chaines linéaires de polysaccharides naturels composées de la répétition d’un motif disaccharidique où chaque monosaccharide de la chaine peut être acétylé, épimérisé ou sulfaté à différentes positions du sucre. La nature du disaccharide, le type de modification ainsi que la position des groupements sulfates sur chaque monomère de sucre sont la source de l’extrême diversité structurale des glycosaminoglycanes. Ces biomolécules hautement chargées négativement sont ubiquitaires dans l’organisme et possèdent une multitude de fonctions structurales et fonctionnelles telles que la croissance, la différentiation et la signalisation cellulaire ou encore la régulation de la bioactivité d’une multitude de protéines dont les facteurs de croissance. 6 Les GAGs sont communément retrouvés attachés à un corps protéique formant ainsi des PGs. Cette structure leur confère de la multivalence, propriété indispensable pour exercer leurs activités. Le rôle des PGs dans l’organisme est principalement lié aux chaines de GAGs qu’ils portent. De par leur implication dans une large gamme de processus physio- et patho-logiques, les GAGs et les PGs sont connus pour être de bonnes cibles thérapeutiques et ont d’ailleurs été étudiés dans le cadre de la croissance des cellules
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