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Régulation De L'activité Protéolytique Des Cathepsines À Cystéine S Et K

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Régulation De L'activité Protéolytique Des Cathepsines À Cystéine S Et K UNIVERSITÉ DE TOURS ÉCOLE DOCTORALE SSBCV Centre d’Etude des Pathologies Respiratoires (CEPR) INSERM UMR 1100 THÈSE présentée par : Mylène WARTENBERG soutenue le : 13 décembre 2018 pour obtenir le grade de : Docteur de l’université de Tours Discipline/ Spécialité : Sciences de la Vie et de la Santé / Biochimie Régulation de l’activité protéolytique des cathepsines à cystéine S et K par des inactivateurs/inhibiteurs chimiques et pseudopeptidiques THÈSE dirigée par : M LALMANACH Gilles Professeur, Université de Tours, Tours RAPPORTEURS : Mme LANONE Sophie Directeur de Recherche, INSERM, Créteil M RODRIGUES-LIMA Fernando Professeur, Université Paris Diderot (Paris VII), Paris JURY : M LALMANACH Gilles Professeur, Université de Tours, Tours Mme LANONE Sophie Directeur de Recherche, INSERM, Créteil M MARCHAND-ADAM Sylvain PU-PH, Université de Tours, Tours M RODRIGUES-LIMA Fernando Professeur, Université Paris Diderot (Paris VII), Paris M SAPI Janos Professeur, Université de Reims Champagne-Ardenne, Reims M VOURC’H Patrick PU-PH, Université de Tours, Tours Remerciements Ce travail de thèse a été effectué à l’INSERM U1100 (Centre d’Étude des Pathologies Respiratoires, CEPR, Tours) dirigée par le Dr Mustapha Si-Tahar, au sein de l'équipe 2 "Mécanismes protéolytiques dans l'inflammation" (Responsable: Pr Gilles Lalmanach). Ce projet a bénéficié d'un contrat doctoral financé par la Région Centre-Val de Loire. Je tiens à exprimer mes remerciements à : Monsieur Gilles Lalmanach, Professeur de l’Université de Tours, pour m’avoir accordée sa confiance et m’avoir donnée la chance de pouvoir travailler à ses côtés durant ces trois dernières années. Merci pour votre enthousiasme à toute épreuve et votre bienveillance. Merci de m’avoir suivie au quotidien tout en me laissant suffisamment de liberté dans mon travail. Grâce à vous, j’ai appris (entre autre) à être « pragmatique » et à arrêter l’« auto-flagellation ». Madame Sophie Lanone, Directeur de Recherche, INSERM, Créteil, et Monsieur Fernando Rodrigues-Lima, Professeur de l’Université Paris Diderot, pour m’avoir fait l’honneur d’être les rapporteurs de ce travail. Monsieur Sylvain Marchand-Adam, PU-PH de l’Université de Tours, Monsieur Janos Sapi, Professeur de l’Université de Reims Champagne-Ardenne et Monsieur Patrick Vourc’h, PU- PH de l’Université de Tours d’avoir accepté d’être les examinateurs de cette thèse. Monsieur Mustapha Si-Tahar, Directeur de Recherche de l’INSERM UMR 1100 - Centre d’Étude des Pathologies Respiratoires, pour m’avoir accueillie au sein de son unité. Et je tiens également à remercier : Monsieur Fabien Lecaille, Maître de Conférences à l’Université de Tours, pour sa bonne humeur et ses conseils. Ahlame Saïdi, ma binôme de galère, pour notre soutien mutuel pendant les heures sombres au LUMINA et au confocal… Merci pour ton aide et pour m’avoir initiée à la culture cellulaire. 1 Pierre-Marie Andrault, « maître », pour m’avoir accompagnée dans mes premiers pas au labo et d’avoir répondue à mes innombrables questions. Mariana Kasabova, pour sa bonne humeur, sa gentillesse et son aide dans mes débuts. Alix Joulin-Giet, Sylvie Mavel et Lydie Nadal-Desbarats, pour leur gentillesse et leur participation à ce travail. Les membres du Centre de Biophysique Moléculaire, CNRS, UPR 4301 (Orléans) et de l’ICOA, CNRS UMR 7311 (Orléans) pour la synthèse des inhibiteurs et leur participation à ces travaux. Julien Burlaud-Gaillard, nos rendez-vous trimestriels en microscopie confocale vont me manquer… Même si je sais qu’il ne faudra pas attendre longtemps pour se retrouver au bota! Merci pour ta patience et ton aide précieuse. David Ducluzeau et Paul Bigot, les étudiants que j’ai eu le plaisir d’encadrer durant leur stage dans l’unité. Frédéric Esnard, Sylvie Attucci, Thomas Baranek, Sandrine Dallet-Choisy, Thierry Moreau, Florence Velge-Roussel, Marilou Zani, Marilou Fauquet et Fabien Barbarin, membres du département de Biochimie, pour m’avoir accueillie et accompagnée lors de mes trois années d’enseignement. Aurélie Henriques et Catherine Douteau, pour leur aide au quotidien pour toutes les procédures administratives, leur gentillesse et leur patience. Yves Courty et Agnès Petit, pour nos discussions sur les sujets les plus divers. Un merci particulier pour les membres du bureau des « étudiants »: Seda Seren, Justine Renault, Delphine Fouquenet, Lise Vanderlynden, Woodys Lenga (Ouidiz’) et Thibault Chazeirat, qui m’ont supporté pendant ces trois années (N’oubliez pas de continuer la collection de marabout et d’approvisionner la cagnotte!). Ainsi que nos chers stagiaires de M2 partis vers d’autres horizons : Fanny Lisée, Adélaïde Chesnay, Damien Sizaret, Ghania Kara-Ali et Victor Tiroille. 2 Un immense merci à « la masse informe » (Christelle, David et Mélia), je pourrais écrire une thèse entière sur les fous rires et les délires que nous avons eu pendant ces trois années : la reproduction des coccinelles, la bataille des ciseaux contre les licornes, le grand chelem au bota, les lettres du corbeau et notre credo : « Brule tout ! »… Merci pour tout, ces années n’auraient pas été pareilles sans vous ! Je tiens également à remercier l’ensemble des personnes que j’ai côtoyé au cours de ces années pour leur accueil et leur gentillesse: Ribal Al-Mawla, Elsa Bodier-Montagutelli, Chloé Boisseau, Déborah Bréa, Maria Cabrera, Florent Creusat, Emilie Dalloneau, Aurélie Domene, Marion Ferreira, Yveline Hamon, Virginie Hervé, Natalie Heuzé- Vourc’h, Sophie Iochmann, Youenn Jouan, Baris Korkmaz, Anne-Sophie Lamort, Déborah Le Pennec, Alexie Mayor, Eric Morello, Christophe Paget, Jeoffrey Pardessus, Pascale Reverdiau, Thomas Secher, Alexandre Valayer, Virginie Vasseur. Je remercie mes amis de Tours et d’ailleurs : Mes gonzesses (Mathilde, Sara, Didi et Chacha) et leur moitié Antoine, Nico et Pierrot. Les Chesnoys & co : Macké, Céline, Seb, Maïlys, Joe, Mino, Lamith, Elo, Yohann, Mimi, Flo, Clém, Joubis, Alex … pour leur soutien durant ces trois années et leur amitié. Merci de m’avoir permis de m’évader loin de la thèse au moins le temps d’une soirée ou d’un weekend. Enfin, je remercie ma famille pour leur amour : Mes parents : tout cela est un peu grâce à vous. Même si je me suis un peu éloignée du pommier, jouer avec des molécules chimiques en plastique quand j’étais petite a porté ses fruits. Merci de m’avoir soutenue et d’avoir cru en moi toutes ces années. Ma sœur (c’est bon tu as enfin le mot « Cathé-pss-in ») et mon beauf pour m’avoir aidée à décompresser quand j’en avais besoin. Mon frère et Nadia (sa femme) pour avoir partagé leur expérience et m’avoir aidée à relativiser (« Plus c’est dur et plus on est heureux quand ça se termine… »). Anna et Zoé, pour avoir fait de moi une tata comblée. Mes grands parents, oncles, tantes, cousins et cousines pour leurs encouragements et leur soutien. Mickaël, mon cœur, je sais que ces derniers mois ont été durs pour toi aussi, qui as dû supporter mon stress et mes sautes d’humeur. Merci infiniment pour tout ce que tu fais pour moi chaque jour. 3 4 Résumé La cathepsine (Cat) S est une protéase ciblée pour le développement de médicaments utilisés dans les maladies auto-immunes ou la douleur neuropathique. Elle joue également un rôle clé durant l’emphysème compte tenu de ses propriétés élastinolytiques. La Cat K, qui est une collagénase impliquée dans la résorption osseuse, représente une cible pertinente dans le traitement de l’ostéoporose et des métastases osseuses. De plus ces deux protéases sont des protagonistes majeurs du remodelage matriciel et l’homéostasie pulmonaire. Lors de la BPCO, la dégradation tissulaire bronchique est associée à une réaction inflammatoire qui s’accompagne d’un stress oxydatif et d’un déséquilibre de la balance protéases/antiprotéases. L'exposition à la fumée de cigarette constitue le principal facteur de risque dans la BPCO. Malgré la présence d'une cystéine nucléophile (Cys25) dans son site actif, nous avons constaté que la Cat S conserve partiellement son activité enzymatique après exposition à la fumée de cigarette. Ainsi, nous avons exploré les mécanismes soutenant la stabilité de la Cat S, en présence d’oxydants majeurs de la fumée de cigarette : peroxyde d’hydrogène, formaldéhyde, acroléine et peroxynitrite. Par ailleurs, dans le but de réguler l'activité des cathepsines à cystéine K et S, nous avons développé des inhibiteurs pseudopeptidiques de nouvelle génération dérivés de séquences substrats des cathepsines S et K ainsi que des dérivés triazines. Mots clés: BPCO, cathepsine K, cathepsine S, dérivés triazines, fumée de cigarette, inhibiteurs pseudopeptidiques, oxydation. 5 6 Résumé en anglais Cathepsin (Cat) S is an attractive target for drugs in autoimmune diseases or neuropathic pain. Moreover Cat S plays a key role during emphysema according to its potent elastinolytic activity. Cat K is a critical bone-resorbing collagenase and is a relevant target for the treatment of osteoporosis and bone metastasis. Both enzymes play a key role in matrix remodeling and pulmonary homeostasis. During COPD, the degradation of pulmonary parenchyma depends on inflammatory reactions associated with oxidative stress and proteases/antiproteases imbalance. Exposure to cigarette smoke, a major source of oxidants, is the main risk factor for COPD. Despite the presence of a nucleophilic cysteine (Cys25) within its active site, we found that CatS preserved partially its proteolytic activity after exposure to cigarette smoke extract (CSE). Thus, we have explored molecular mechanisms supporting this stability in the presence of
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