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Development of a Binding Assay Between the HIV-1 Envelope

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Development of a Binding Assay Between the HIV-1 Envelope Development of a binding assay between the HIV-1 envelope protein (gp120) and coreceptors CCR5/CXCR4 by Surface Plasmon Resonance : Screening and optimization of viral entry inhibitors Bridgette Janine Connell To cite this version: Bridgette Janine Connell. Development of a binding assay between the HIV-1 envelope protein (gp120) and coreceptors CCR5/CXCR4 by Surface Plasmon Resonance : Screening and optimiza- tion of viral entry inhibitors. Agricultural sciences. Université de Grenoble, 2012. English. NNT : 2012GRENV013. tel-00721774 HAL Id: tel-00721774 https://tel.archives-ouvertes.fr/tel-00721774 Submitted on 30 Jul 2012 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’UNIVERSITÉ DE GRENOBLE Spécialité : CHIMIE ET SCIENCES DU VIVANT (218) Arrêté ministériel : 7 août 2006 Présentée par Bridgette Janine CONNELL Thèse dirigée par Hugues LORTAT-JACOB préparée au sein du Laboratoire Structure and Activity of GlycosAminoGlycans (SAGAG), Institut de Biologie Structurale (IBS) dans l'École Doctorale Chimie et Sciences du Vivant Développement d’un test d’interaction entre la protéine d’enveloppe du VIH-1 (gp120) et les corécepteurs CCR5/CXCR4 par résonance plasmonique de surface: Criblage et optimisation d’inhibiteurs de l’entrée virale Thèse soutenue publiquement le 16 Mars 2012, devant le jury composé de : Dr. Hugues LORTAT-JACOB DR, CNRS, Directeur de thèse, Examinateur Dr. Fernando ARENZANA-SEISDEDOS DR, INSERM, Institut Pasteur, Rapporteur Dr. Marc PARMENTIER Proff, Université Libre de Bruxelles, Rapporteur Dr. Winfried WEISSENHORN Proff, Unit for Virus Host-Cell Interactions (UVHCI), UJF, Examinateur Dr. Anne IMBERTY DR, CNRS, Invité Je remercie Prof. David Bonnaffé pour son jolie image de mCD4-HS12 sur la couverture ☺ II THÈSE Pour obtenir le grade de DOCTEUR DE L’UNIVERSITÉ DE GRENOBLE Spécialité : CHIMIE ET SCIENCES DU VIVANT (218) Arrêté ministériel : 7 août 2006 Présentée par Bridgette Janine CONNELL Thèse dirigée par Hugues LORTAT-JACOB préparée au sein du Laboratoire Structure and Activity of GlycosAminoGlycans (SAGAG), Institut de Biologie Structurale (IBS) dans l'École Doctorale Chimie et Sciences du Vivant Development of a binding assay between the HIV-1 envelope protein (gp120) and coreceptors CCR5/CXCR4 by Surface Plasmon Resonance: Screening and optimization of viral entry inhibitors Thèse soutenue publiquement le 16 Mars 2012, devant le jury composé de : Dr. Hugues LORTAT-JACOB DR, CNRS, Directeur de thèse, Examinateur Dr. Fernando ARENZANA-SEISDEDOS DR, INSERM, Institut Pasteur, Rapporteur Dr. Marc PARMENTIER Proff, Université Libre de Bruxelles, Rapporteur Dr. Winfried WEISSENHORN Proff, Unit for Virus Host-Cell Interactions (UVHCI), UJF, Examinateur Dr. Anne IMBERTY DR, CNRS, Invité Je remercie Prof. David Bonnaffé pour son jolie image de mCD4-HS12 sur la couverture ☺ IV This work is dedicated to John Anthony CONNELL and George THEMISTOCLEOUS V “The tipping point is that moment when an idea, trend, or social behavior crosses a threshold, tips, and spreads like wildfire.” ― Malcolm Gladwell, The Tipping Point: How Little Things Can Make a Big Difference VI ABSTRACT Cell-associated Heparan Sulphate (HS) binds the V3 loop of gp120 of HIV-1 thus aiding in viral infectivity. However, a soluble polyanion (HS12) has anti-viral properties once conjugated to CD4 (mCD4-HS12), and showed nM activity against HIV-1 in vitro. Due to the structural complexity of HS, screening differently sulphated-oligosaccharides to improve the molecule’s activity would be too cumbersome, thus in order to obtain a more specific, higher affinity and easier to produce moiety, collaborators synthesized HS mimetic peptides. We aimed to screen these peptides and other anionic molecules for their capacity to inhibit HIV-1 entry. Thus we set-up a platform whereby solubilised CCR5 and CXCR4 were immobilized on biosensors (biacore) and used to screen for molecules that inhibited gp120-CD4 binding to the coreceptors. To control the solubilization process, CXCL12, the natural ligand of CXCR4, was injected over the immobilized CXCR4. The affinities of CXCL12 isoforms (α and γ) for CXCR4 were calculated within the ranges of previously described values with different techniques thus proving the functionality of our system. We show for the first time that HS differently regulates the binding mechanisms of these two isoforms and we propose a novel mode of action for the unusually basic C-terminal of CXCL12 γ with CXCR4. The system was subsequently used to screen the inhibitory capacity of the HS mimetic peptides. Each peptide, [S(XDXS)n], contained amino acids that mimic the hydroxyl, carboxyl and sulphate groups on HS chains. The peptide containing sulphotyrosine residues, when conjugated to mCD4 (mCD4-P3YSO3), displayed nM IC50 for simultaneously inhibiting gp120 binding to HS, CD4, antibody, coreceptors and HIV-1 infection in vitro. This is the first bivalent entry inhibitor that targets both R5 and X4 viruses and the concept of a HS-mimetic peptide lends itself to structural-functional analysis of HS chains binding to proteins, a novel technique in this field. La gp120 du VIH-1 se fixe aux héparane sulfate (HS) cellulaires, par le biais de la boucle V3 ce qui favorise l'infectivité virale. Cependant, une polyanion solubles (HS12), conjugués à CD4 (mCD4-HS12) a des propriétés antivirales et a montré in vitro une activité contre le VIH- 1 à de concentrations nM. En raison de la complexité structurale des HS, le criblage d’oligosaccharides différenciellement sulfatés pour améliorer l'activité de la molécule serait trop difficile. En vue d'obtenir une molécule plus spécifique, de plus haute affinité et plus facile à produire, des peptides mimant les HS ont été synthétisés par nos collaborateurs. Notre but était de cribler ces peptides pour leur capacité à inhiber l'entrée de VIH-1. Nous avons mis en place une plateforme permettant d’immobiliser CCR5 et CXCR4 solubilisés sur des biocapteurs pour cribler des molécules qui inhibent la liaison de gp120-CD4 aux corécepteurs. Pour contrôler le processus de solubilisation, CXCL12, le ligand naturel de CXCR4, a été injecté sur CXCR4 immobilisé. Les affinités des isoformes CXCL12 (α et γ) pour CXCR4 ont été calculées dans les fourchettes de valeurs précédemment décrites avec des techniques différentes prouvant la fonctionnalité de notre système. Nous montrons pour la première fois que les HS régulent différemment les mécanismes de liaison de ces deux isoformes et nous proposons un nouveau mode d'action pour le domaine C-terminal particulièrement basique de CXCL12 γ vis-à-vis de CXCR4. Le système a ensuite été utilisé pour cribler la capacité d'inhibition des peptides mimétiques du HS. Chaque peptide, [S(XDXS)n] contient des acides aminés qui imitent les groupes hydroxyles, carboxyles et sulfates des HS. Le peptide contenant des résidus sulphotyrosines, une fois conjugué à mCD4 (mCD4-P3YSO3), montre un IC50 de l’ordre du nM, pour l’inhibition simultanée de la liaison de gp120 aux HS, à CD4, aux anticorps, aux corécepteurs ainsi que l’infection par VIH-1 in cellulo. Il constitue le premier inhibiteur bivalent de l’entrée qui cible à la fois les virus R5 et X4 et le concept d'un peptide mimétique des HS se prête à une analyse structurale et fonctionnelle de la liaison des chaînes HS aux protéines, une nouvelle technique dans ce domaine. VII VIII ACKNOWLEDGEMENTS Tout d'abord, je tiens à te remercier, Hugues. Merci de m'avoir acceptée dans ton équipe, de m’avoir donné cette opportunité de faire une thèse sur le VIH, l’un de mes rêves - et d’avoir eu une telle confiance en moi. Merci d’avoir toujours eu une porte ouverte pour mes questions et les sujets scientifiques dont je voulais discuter. Tu as toujours été disponible pour débattre de l'orientation scientifique de mon projet, donner ton avis sur mes expériences au laboratoire et parfois, des conseils pour mon anglais! Lorsque mes expériences ne fonctionnaient toujours pas et que la situation était désespérée, tu m’as laissée persister jusqu'à atteindre la perfection / d’or (ou platine?)! Ces expériences ont été difficiles et ont nécessité une grande quantité de consommables, donc je te remercie de m’avoir permis, malgré le coût financier, de continuer à travailler jusqu'à ce qu’elles fonctionnent. Tes idées, ta manière pédagogique de penser et d'écrire sont des compétences que je vais essayer de garder avec moi. Je pense qu’ensemble, nous avons fait une bonne équipe dans la lutte contre le SIDA! Je tenais à remercier sincèrement les membres de mon jury. Merci Fernando Arenzana-Seisdedos et Marc Parmentier d’avoir accepté d'examiner mon manuscrit. Merci également à Winfried Weissenhorn et Anne Imberty pour votre participation à ce jury. C'est un honneur pour moi de vous compter parmi les membres de mon jury et que vous ayez examiné mon travail. Veuillez trouver ici mes sincères remerciements pour la qualité de jugement que vous portez à ce travail et soyez assurés de ma profonde reconnaissance. Grazie mille a Carlo Petosa per aver partecipato alla mia “thesis advisory commitee” per i primi due anni del mio dottorato di ricerca. Merci beaucoup à Sidaction. Sans votre soutien, mon rêve de réaliser une thèse au cœur de la recherche sur le VIH n'aurait pas été possible. Grâce à votre action de recherche sur le VIH en France, nous avons avancé sur le développement d'un inhibiteur d’entrée du VIH-1 et j'ai noué de précieux liens dans ce domaine.
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