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Characterization of Plasmodium Falciparum Membrane Transporters As Potential Antimalarial Targets

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Characterization of Plasmodium Falciparum Membrane Transporters As Potential Antimalarial Targets UNIVERSITÉ PARIS-SUD ÉCOLE DOCTORALE 419 : BIOSIGNE Laboratoire : UMR 8221 - Laboratoire des Protéines Membranaires (CEA Saclay) THÈSE SCIENCES DE LA VIE ET DE LA SANTÉ par Stéphanie CORREIA DE MATOS DAVID BOSNE Characterization of Plasmodium falciparum membrane transporters as potential antimalarial targets Date de soutenance : 10/10/2014 Composition du jury : Directeur de thèse : Christine JAXEL Chercheur CNRS, UMR 8221 CNRS, CEA SACLAY Co-directeur de thèse : Marc le MAIRE Professeur, Université Paris-Sud Président du jury : Oliver NÜSSE Professeur, Université Paris-Sud Rapporteurs : Bruno MIROUX Directeur de Recherches INSERM, IBPC, Paris Martin PICARD Chercheur CNRS, CNRS UMR 8015, Paris Examinateurs : Isabelle FLORENT Professeur MNHN, MNHN Paris Philippe LOISEAU Professeur, Université Paris-Sud 1 2 Merci à tous ceux qui ont rendu cette thèse possible, rien n’aurait été réalisable sans vous ! A minha Mãe, à Alexandre, Pour avoir été présent dans les meilleurs et les pires moments, merci ! 3 4 Index Table of Contents Index ........................................................................................................................................................ 5 Table of Contents .................................................................................................................................... 5 Table of Figures ..................................................................................................................................... 10 Table of Tables....................................................................................................................................... 13 Introduction ........................................................................................................................................... 15 I – Malaria .............................................................................................................................................. 17 I.1 – Historical and Sociological Context of Malaria .......................................................................... 17 I.1.1 – The socio-economic burden of malaria .............................................................................. 17 I.1.2 – A long story made short ..................................................................................................... 17 I.2 - Plasmodium ................................................................................................................................ 20 I.2.1 – Plasmodium parasites ......................................................................................................... 20 I.2.2 – Plasmodium falciparum life cycle ....................................................................................... 21 I.3 – The Disease: Prevention and Treatments .................................................................................. 23 I.3.1 – The Symptoms .................................................................................................................... 23 1.3.2 – Diagnosis ............................................................................................................................ 23 I.3.3 – Prevention .......................................................................................................................... 24 I.3.4- The vaccine ........................................................................................................................... 27 I.3.5 - Antimalarial drugs ............................................................................................................... 31 I.3.7 - Antimalarial resistance ........................................................................................................ 35 1.3.8 - Finding antimalarials mode of action ................................................................................. 35 I.4 - New Antimalarial Research......................................................................................................... 37 I.4.1 – Strategies for new antimalarial discovery .......................................................................... 37 I.4.2- New targets explored ........................................................................................................... 39 I.4.3 - Biological target validation .................................................................................................. 41 I.4.4- Compound screening ........................................................................................................... 41 5 I.4.5 – New antimalarials discovered ............................................................................................ 44 I.5 – Artemisinins ............................................................................................................................... 45 I.5.1 – Artemisinin antimalarial class ............................................................................................. 45 I.5.2 – Artemisinin mode of action ................................................................................................ 47 I.5.3 - Artemisinin resistance ......................................................................................................... 51 I.5.4 -Molecular markers of artemisinin resistance ...................................................................... 52 II – Plasmodium Membrane Transporters as Potential Antimalarial Targets ....................................... 57 II.1 - Malaria Membrane Transport Proteins ..................................................................................... 57 II.2 - Transporters as Potential Drug Targets ..................................................................................... 58 II.3 – Heterologous Expression Systems for Plasmodium Transporters ............................................ 63 II.4 – Generalities on P- ATPases ....................................................................................................... 65 II.5 - Generalities on Calcium ATPases ............................................................................................... 67 II.6 – SERCA Pumps ............................................................................................................................ 69 II.6.1 – Calcium transport .............................................................................................................. 69 II.6.2 – SERCA pumps and disease ................................................................................................. 73 II.7 - PfATP6 and Calcium signaling in Plasmodium parasites ........................................................... 73 II.7.1– Calcium signaling in Plasmodium ....................................................................................... 73 II.7.2– PfATP6 ................................................................................................................................ 73 II.7.3– PfATP6 as the proposed target of artemisinins .................................................................. 75 II.7.4 – Mutations in PfATP6, responsible for artemisinin resistance ........................................... 78 II.7.5 – PfATP6, is not the direct target of artemisinins ................................................................ 80 II.7.6 – PfATP6 polymorphisms ...................................................................................................... 83 II.8 - PfATP4 ........................................................................................................................................ 84 II.8.1 – PfATP4 as a proposed Ca2+-ATPase.................................................................................... 84 II.8.2 – PfATP4 as the target of Spiroindolones ............................................................................. 85 II.8.3 – PfATP4 is a Na+/H+ - ATPase ............................................................................................... 86 II.9 – PfAdT ......................................................................................................................................... 88 II.9.1 – The ATP/ADP carrier family ............................................................................................... 88 II.9.2 – The ATP/ADP carrier in Plasmodium ................................................................................. 89 II.9.3 – PfAdT as a potential antimalarial target ............................................................................ 90 III – The project ...................................................................................................................................... 92 Results and Discussion .......................................................................................................................... 95 6 Chapter I ................................................................................................................................................ 97 Large Scale production of PfATP6 in view of screening of potential antimalarial compounds ............ 97 I.1 – Preamble .................................................................................................................................... 97 I.2 - Article - Antimalarial screening via large-scale purification of Plasmodium falciparum Ca2+- ATPase 6 and in vitro studies ............................................................................................................. 98 I.3 - Cytotoxicity of the Molecules
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