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Nouvelles Molécules Antivirales Ciblant La Protéine De La UNIVERSITÉ DE STRASBOURG ÉCOLE DOCTORALE __ED414__ Ecole Doctorale des Sciences de la Vie et de la Santé Université de Strasbourg THÈSE présentée par : Beata BASTA soutenue le : 26 Septembre 2012 pour obtenir le grade de : Docteur de l’université de Strasbourg Discipline/ Spécialité : Biophysique ouvelles molécules antivirales ciblant la protéine de la nucléocapside du virus VIH-1. THÈSE dirigée par : MELY Yves prof. Université de Strasbourg RAPPORTEURS : Olivier MAUFRET dr, ENS de Cachan May MORRIS dr, CNRS Montpelier AUTRES MEMBRES DU JURY : Jan MISIEWICZ prof, Wroclaw University of Technology Marc RUFF dr, IGBMC, Strasbourg Beata BASTA ouvelles molécules antivirales ciblant la protéine de la nucléocapside du virus VIH-1. Résumé Etant donnée la séquence hautement conservée de la NC et son rôle crucial dans le cycle viral de VIH-1, les molécules inhibant la NC sont susceptibles d’agir comme complément aux thérapies anti-rétrovirales à haute activité (HAART) basées sur des médicaments ciblant les enzymes virales. Des médicaments anti-NC sont ainsi susceptibles d’entraîner un maintien de l’inhibition de la réplication d’un large panel d’isolats VIH-1 incluant des lignées virales résistantes aux médicaments ciblant les enzymes virales. Récemment, dans le cadre du consortium Européen TRIoH, de nouvelles stratégies visant à cibler spécifiquement les propriétés chaperonnes de la NC sur les acides nucléiques ont été développées. Selon une stratégie protégée par un brevet soumis, une série de peptides a été conçue afin d’agir comme compétiteurs de la NC et pouvant ainsi inhiber la réplication du virus. Au sein de cette série, plusieurs peptides ont montré une inhibition efficace des propriétés de déstabilisation des acides nucléiques par la NC. Quatre de ces peptides ont été testés en milieu cellulaire et trois d’entre eux ont montré qu’ils pouvaient inhiber efficacement la réplication du HIV-1 dans les lymphocytes. Dans ce contexte, un premier objectif de cette thèse fût de caractériser avec précision les propriétés de ces peptides. En outre, un objectif supplémentaire fût de caractériser le mécanisme moléculaire vis-à-vis de la NC de petites molécules anti-virales développées par les groupes de D. Daelemans (Leuven) et M. Botta (Sienne). Résumé en anglais Due to the highly conserved sequence of NC and its crucial function during HIV-1 life cycle, molecules directed against NC are believed to be able to complement the highly active anti-retroviral therapies (HAART) based on drugs targeting the viral enzymes. Anti-NC drugs are thought to provide a sustained replication inhibition of a large panel of HIV-1 isolates including virus strains resistant to drugs targeting viral enzymes. Recently, within the European consortium TRIoH, new strategies to specifically target the nucleic acid chaperone properties of NC were developed. According to a strategy protected by a submitted patent, a series of peptides have been designed to act as competitors for NC and thus, inhibit virus replication. Among this series, several peptides were found to efficiently inhibit the nucleic acid destabilization properties of NC. Four of them have been tested in the cellular context and three out of them were found to efficiently inhibit the replication of HIV-1 in lymphocytes. In this context, the objective of the thesis was to characterize in depth the properties of these peptides. Moreover, an additional objective was to characterize the molecular mechanism in respect to NC of small antiviral drugs developed by the group of D. Daelemans (Leuven) and M. Botta (Siena). Acknowledgement This work was conducted in cooperation between Wroclaw University of Technology (Wroclaw, Poland) and University of Strasbourg (Alsace, France). I also would like to express my gratitude to the French National Agency for Research on AIDS and Viral Hepatitis and the Regional Parliament of Lower Silesia Province for financial support. I would like to express my heartfelt gratitude to Director of my thesis Prof. Yves MELY for his supervision, inspiration and encouragement during my research. He has been generous with his time and knowledge. It has been a privilege for me, to be a student of him. I would like to express my deepest gratitude and sincere appreciation to my co-Director Prof. Jan Misiewicz for help and guidance for monitoring my research. I would like to extend my gratitude to Prof. Jean-Luc Darlix for his discussion and fruitful comments. I am greatly honored by the kind acceptance of Dr. May MORRIS, Dr. Marc RUFF and Dr. Olivier MAUFFRET as members of jury for my thesis and would like to thanks them for serving as my advisory committee. Special thanks to Dr. Guy DUPORTAIL for his help and support, and Dr. Hughes de ROCQUIGNY for his help with the HPLC and peptide synthesis. I would like to extend my gratitude to Dr. Eleonore REAL for valuable discussion and help in antiviral activity assays, Dr. Andrey KLIMCHENKO for his discussion, Dr. Ludovic RICHERT and Dr. Pascal DIDIER for their help in fluorescence correlation spectroscopy experiments. I would like to thank group of Dr. Daelemans (Leuven, Belgium) and Prof. Botta (Siena, Italy) for fruitful collaboration. I would like to give special thanks to my friend, Armelle JOUONANG for all the help and support. I would like to thank all my friends from the lab Victoria PUSTUPALENKO, Kamal kant SHARMA, Zeinab DARWICH, Hussein FTOUNI, Avisek GHOSH, Vanille GRENIER, Noemy KEMPF, Julien GODET and Frederic PRZYBILLA for their constant help and our great discussions. On the personal note, I would like to thank my beloved husband, for all the support during my graduate studies. Table of contents Abbreviations 7 General Introduction 10 Bibliographic review I. Retroviruses I.1. Definition 12 I.2. Discovery 13 I.3. Classification 14 II. HIV1 virus II.1. Origin of HIV1 19 II.2. Epidemiology 22 II.3. Classification 23 II.4.Structure of HIV1 virus particles 24 III. Genome of HIV1 III.1.Genome organization 25 III.1.1 The Ψ domain 28 III.1.2. Other non coded regions in the viral genome 29 III.1.3. Coding regions 30 IV. Viral proteins IV.1. Envelop proteins 30 IV.2. Structural proteins IV.2.1. Matrix protein (MA) 33 IV.2.2. Capsid protein (CA) 35 IV.2.3.ucleocapsid protein (C) 36 IV.2.4. p6 36 V. Viral enzymes V.1.Protease(PR) 37 V.2. Reverse transcriptase(RT) 38 V.3. Integrase(I) 41 VI. Regulatory proteins VI.1. Tat (TransActivator of Transcription) 43 VI.2. Rev (Regulatory of virion expression) 45 VI.3. Vpr (Viral protein R) 46 VI.4. Vif (Viral infectivity factor) 46 3 Table of contents VI.5. ef (egative regulatory factor) 47 VI.6.Vpu (Viral protein U) 47 VII. Life cycle of virus HIV1 VII.1.Early phase VII.1.1. Virus entry 50 VII.1.2. Uncoating 52 VII.1.3.Reverse transcription 53 VII.1.4. uclear import and integration 55 VII.2. Late phase VII.2.1. Gene expression 58 VII.2.2. Virus particle production 58 VII.2.3. RA encapsidation 59 VII.2.4. Assembly and release 62 VII.2.5. Maturation 63 VIII. ucleocapsid protein VIII.1. Structure and properties of HIV-1 C 65 VIII.1.1. ucleic acid binding 68 VIII.2. Chaperone properties of C 69 VIII.2.1. ucleic acid destabilization activity of C 71 VIII.2.2. ucleic acid annealing activity of C 73 VIII.3. Role of C during the viral lifecycle VIII.3.1. C role during the early phase of the viral lifecycle 77 VIII.3.2. C role during the late steps of virus lifecycle 80 IX. Protective host responses towards HIV1 infection 81 X. Development in antiretroviral therapy 86 X.1.1 ucleoside/nucleotide reverse transcriptase inhibitors (TRIs) 88 X.1.2. onnucleoside reverse transcriptase inhibitors (TRIs) 89 X.1.3.HIV protease inhibitors 91 X.1.4. Integrase inhibitors 95 X.1.5. Fusion inhibitors (FIs) 96 X.1.6. Chemokine receptors antagonists 97 4 Table of contents X.2. ovel antiviral treatment X.2.1. Maturation inhibitors 98 X.2.2. Peptide inhibitors of HIV1 Egress 99 X.2.3. Anti-C molecules X.2.3.1. Zinc ejectors 100 X.2.3.2. onzinc ejecting C binders 102 X.2.3.3. ucleic acid intercalators and aptamers 103 X.2.3.4. Peptides 105 X.3. HIV1 vaccines 106 X.4.Recent developments in HIV1 vaccines 110 Research Aim 113 Materials and Methods 1.Materials 1.1. Peptide synthesis 117 1.2. Preparation of peptide/protein solutions 118 1.3.ucleic acid sequences 119 1.4. Chemical compounds inhibiting C 122 1.5. Lentiviral vectors 124 2.Methods 2.1. Fluorescence correlation spectroscopy (FCS) 2.1.1. Principle of FCS 126 2.1.2.Processing and analyzing of FCS data 126 2.1.3. Experimental 129 2.2. Flow cytometry 2.2.1. Principle 129 2.2.2. Processing and analyzing data 129 2.2.3. Experimental 130 2.3. Confocal microscopy 2.3.1.Principle 133 2.3.2. Processing and analyzing data 133 2.3.3. Experimental 134 2.4. Steady state fluorescence spectroscopy 2.4.1. Tryptophan fluorescence 135 5 Table of contents 2.4.2. Experimental 136 2.4.3. Fluorescence Resonance Energy Transfer ( FRET) 140 Results and Discussions Characterization of ,’bis (1,2,3thiadiazol5yl) benzene1,2diamine chelating zinc ions from the retroviral nucleocapsid zinc fingers 143 (Publication 1) 147 Characterization of a phenylthiadiazolylidene-amine derivative chelating zinc ions from retroviral nucleocapsid zinc fingers 156 (Publication 2 ) 160 Zinc ejection from HIV-1 nucleocapsid affects virion associated genomic RA stability 208 (Publication 3) 211 Use of virtual screening for discovering antiretroviral compounds interacting with HIV1 nucleocapsid protein 215 (Publication 4) 218 Antiviral Peptides: physicochemical properties 229 Antiviral peptide: intracellular pathway
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