Parasitological evaluation of SC81458 and SC83288, a novel class of drugs against Plasmodium falciparum [Elektronische Ressource] / presented by Yulin Wang

Wangyulin

Sujets

• Biologie

Informations

• Publié par: ruprecht-karls-universitat_heidelberg
• Publié le: 01 janvier 2010
• Nombre de lectures: 15
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

Dissertation
Submitted to the
Combined Faculties for the Natural Sciences and for Mathematics
of the Ruperto-Carola University of Heidelberg, Germany
for the degree of
Doctor of Natural Sciences










Presented by
Yulin Wang
born in Fuxin, China

Oral examination:…………………






Parasitological Evaluation of SC81458
and SC83288, a Novel Class of Drugs
against Plasmodium Falciparum











Referees : Prof. Dr. Michael Lanzer
Prof. Dr. Luise Krauth-Siegel
Ich erkläre hiermit, dass ich die vorgelegte Dissertation selbst verfasst und mich dabei keiner
anderen als der von mir ausdrücklich bezeichneten Quellen und Hilfen bedient habe.

Ich erkläre hiermit, dass ich an keiner anderen Stelle ein Prüfungsverfahren beantragt bzw. die
Dissertation in dieser oder anderer Form bereits anderweitig als Prüfungsarbeit verwendet oder
einer anderen Fakultät als Dissertation vorgelegt habe.

Die vorgelegte Arbeit wurde am Hygieneinstitut, Abteilung Parasitlogie der Universität
Heidelberg in der Zeit März 2006 bis Oktober 2009 unter der Leitung von Prof. Dr. Michael
Lanzer durchgeführt.



















Acknowledgements

Acknowledgements
First of all, I would like to thank Prof. Dr. Lanzer, for giving me the opportunity to join his lab
and for his constant trust and support throughout the course of my PhD. I would also like to
thank Prof. Stein, for his excellent guidance on drug resistance research. Furthermore, I am
very thankful to Dr. Stefano, my nice cooperator from 4SC, for his excellent contributions to
our project.
I would like to thank all the members past and present of the Lanzer lab for their consistently
good help.
Finally, I would like to thank my family for their love and support throughout this time.


IAbbreviations

ABBREVIATIONS
3D 3 Dimensional
ACT Artemisinin-based combination therapy
ADMET absorption, distribution, metabolism, excretion and toxicity
AG Aktiengesellschaft
ATP Adenosine triphosphate
cm centimeter
CQR Chloroquine resistance
CRT Chloroquine transporter
DHFR Dihydrofolate reductase
DHPS Dihydropteroate synthase
DMSO Dimethylsulfoxide
DNA Desoxyribonucleic acid
E Glutamic acid
Fig. Figure
GmbH Gesellschaft mit beschränkter Haftung
hrs hour
H O Water 2
IC half maximal inhibitory concentration 50
IC 90% of maximal inhibitory concentration 90
IC 99% of maxima99
L Leucine
m Milli
M Molar or Methionine
m Meter
MDR Multi-drug resistance
min Minute
MMV Medicines for Malaria Venture
n Nano
ND Not determined
NMR Nuclear magnetic resonance
NPP New Permeation Pathway
O Oxygen 2
IIAbbreviations

oC Celcium degrees
P. Plasmodium
PCT Parasite clearance time
Pf Plasmodium falciparum
pH Potential hydrogenii
PK Pharmacokinetics
PMR Parasite multiplication rate
PPM Parasite Plasma Membrane
PV Parasitophorous Vacuole
PVM Parasitophorous Vacuolar Membrane
QSAR Quantitative structure-activity relationship
RPMI Rosewell Park Memorial Institute
RT Room Temperature or Reverse Transcriptase
SAR Structure-activity relationship
SBDD Structure based drug design
sec Second
2+SERCA Sarco/Endoplasmic Reticulum Ca -ATPase
v/v volume to volume
vol Volume
w/w weight to volume
WHO World Health Organization
X-ray Roentgen ray
μ Micro



IIITable of contents

TABLE OF CONTENTS
Acknowledgements……………………………………………………………………………Ⅰ
Abbreviations………………………………………………………………………………….Ⅱ
Table of contents………………………………………………………………………………Ⅳ
Summary………………………………………………………………………………………...1
Zusammenfassung……………………………………………………………………………….2
1 Introduction……………………………………………………………………………...…3
1.1 Malaria…………………………………………………………………………………3
1.1.1 Life cycle…………………………………………………………………………..4
1.1.2 Clinical manifestations…………………………………………………………….6
1.2 Anti-malarial drugs…………………….………………………………………………7
1.2.1 Anti-malarial drugs in clinical use…………………...……………………………7
1.2.1.1 Arylaminoalcohols………….…………………………………………………7
1.2.1.1.1 Quinine……………………………………………………………………7
1.2.1.1.2 Mefloquine……………………...…………………………………………8
1.2.1.1.3 Halofantrine………………….……………………………………………8
1.2.1.1.4 Lumefantrine…………………...…………………………………………9
1.2.1.2. Aminoquinolines……………….………….…………………………………9
1.2.1.2.1 Chloroquine……………………………….………………………………9
1.2.1.2.2 Amodiaquine………………………………………………………………10
1.2.1.3 8-Aminoquinolines…………………………………………..………………11
1.2.1.3.1 Primaquine………………………………………………….……………11
1.2.1.4 Artemisinines…………………………………...……………………………12
1.2.1.5 Antifolates……………………………………………………………………13
1.2.1.5.1 Chloroguanide (Proguanil)………………………………………………13
1.2.1.5.2 Dapsone……………………………………………………...…………..13
1.2.1.5.3 Pyrimethamine and Sulphadoxine……………………………………….13
1.2.1.6 Antibiotics……………………………………………………………………14
1.2.1.6.1 Tetracyclines……………………………………………………......……14
1.2.1.7 Inhibitors of the respiratory chain…………………………………...……….14
1.2.1.7.1 Atovaquone…………………………………………………………...….14
IVTable of contents

1.2.2 Anti-malarial drugs combination in clinical use…………………………………15
1.2.2.1 Artemisinin-based combination therapies (ACTs)…………………………..15
1.2.2.1.1 Artemether-Lumefantrine (CoartemTM)……………………………..…16
1.2.2.1.2 Artesunate-mefloquine…………………………………………………..16
1.2.2.1.3 Artesunate-Amodiaquine…………………………………………….…..16
1.2.2.1.4 Dihydroartemisinin–piperaquine (Artekin™)……………………...……16
1.2.2.2 Atovaquone-Proguanil (MalaroneTM)………………………………………17
1.2.2.3 Pyrimethamine-Sulphadoxine (FansidarTM)………….…………………….17
1.2.3 Drugs in clinical studies for future chemotherapy……………………………….19
1.2.3.1 Tafenoquine…………………………………………………………….……19
1.2.3.2 AQ-13………………………………………………………………………..19
1.2.3.3 Ferroquine…………………………………………………………...……….19
1.2.3.4 T3………………………………………………………………...…………..19
1.2.3.5 Fosmidomycin………………………………………………………………..20
1.2.3.6 Isoquine…………………………………………………………..…………..20
1.2.4 Anti-malarial drugs combination in clinical studies……………………………..20
1.2.4.1 Chlorproguanil-dapsone-artesunate (Lapdap™)………………………….….20
1.2.4.2 Fosmidomycin-clindamycin……………………………………………...….21
1.2.4.3 Pyronaridine-artesunate (PANDA)…………………………………….…….21
1.3 The reason for the widespread of malaria………………………………………..…..21
1.3.1 No effective vaccine available against malaria…………………………………..21
1.3.2 Drug resistance………………………………………………………………...…22
1.3.2.1Parasite originated drug resistance elements: transporter and enzyme…………..23
1.3.2.1.1 Drug resistance related Plasmodium transporter…………………...……23
1.3.2.1.1.1 PfCRT………………………………………………………………..23
1.3.2.1.1.2 PfMDR1……………………………………………………………..24
1.3.2.1.1.3 Plasmodium falciparum CG2………………………………………..24
1.3.2.1.2 Drug resistance related enzymes………………………………………...24
1.3.2.1.2.1 dihydrofolate reductase (PfDHFR)………..24
1.3.2.1.2.2 Plasmodium falciparum dihydropteroate synthase (PfDHPS)………25
1.3.2.1.2.3 Plasmodium falciparum ATP6(PfATP6)……………………………25
1.3.2.2 Drug originated drug resistance elements……………………………………26
1.3.2.2.1 In vivo elimination half-life……………………………………………...26
1.3.2.2.2 The gene stability of drug target…………………………………………27
VTable of contents

1.4 The targets used for the development of novel anti-malarial drugs………………….27
1.4.1 The drug targets of Plasmodium Falciparum in biochemical pathways…………27
1.4.1.1 The Plasmodium Falciparum specific biochemical pathways in the apicoplast…..27
1.4.1.2 The Plasmodium Falciparum specific metabolic pathways in the mitochondrial ..28
1.4.1.3 Choline biosynthesis pathway………………………………………………..29
1.4.1.4 Plasmodium Falciparum special proteases…………………………………..29
1.4.1.5 Carbonic Anhydrase (CA) inhibitors……………..30
1.4.1.6 Targeting the shikimate pathway…………………………………………….30
1.4.1.7 Microtubule inhibitors……………………………………………………….30
1.4.1.8 Targeting the redox system…………..………………………………………30
1.4.1.9 Targeting the methionine cycle, methylation, and polyamines……………...31
1.4.1.10 Targeting nucleic acid metabolism…………………………………………31
1.4.1.11 Targeting folate metabolism………………………………………………..32
1.4.1.12 Targeting Hematin or the Hemozoin Crystal……………………………….32
1.4.1.13 emamozoin Crystal……………………………….33
1.4.2 Other drug targets of Plasmodium Falciparum………………………………..…33
1.4.2.1 New permeability pathways (NPPs)…………………………………………33
1.4.2.2 Parasite transporters………………………………………………………….34
1.5 Aim of this study…………………..…………………………………………………34
2 Material and method……………………………………………………………………...35
2.1 Materials……………………………………………………………………………...35
2.1.1 Equipment………………………………………………………………………..35
2.1.2 Disposables………………