COMPREHENSIVE ANALYSIS OF PARASITE BIOLOGY: FROM METABOLISM TO DRUG DISCOVERY

Part One Identification and Validation of New Drugs and Targets 1
1 Discovery of theMechanism of Action of Novel Compounds That Target Unicellular Eukaryotic Parasites 3
2 Antiparasitics fromAlgae 41
3 Contribution of Natural Products to Drug Discovery in Tropical Diseases 75
4 Isoxazolines: A Novel Chemotype Highly Effective on Ectoparasites 105
5 Trypanosomal Cysteine Peptidases: Target Validation and Drug Design Strategies 121
6 Potential of Pyrimidine Metabolism for Antitrypanosomal Drug Discovery 147
7 Phosphatidylcholine and Phosphatidylethanolamine Biosynthesis Pathways in Plasmodium 171
8 Immunophilins as Possible Drug Targets in Apicomplexan Parasites 193
9 Targeting the Atg8 Conjugation Pathway for Novel Anti-Apicomplexan Drug Discovery 213
10 Turnover of Glycosomes in Trypanosomes – Perspectives for Drug Discovery 231
11 Glideosome of Apicomplexans as a Drug Target 255
12 N-Myristoyltransferase as a Target for Drug Discovery in Malaria 275

Part Two Metabolomics in Drug and Target Discovery 295
13 Methods to InvestigateMetabolic Systems in Trypanosoma 297
14 The Role of Metabolomics in Antiparasitic Drug Discovery 321
15 The Importance of Targeting Lipid Metabolism in Parasites for Drug Discovery 343
16 CarbonMetabolism of Plasmodium falciparum 371

Part Three Gene Expression and Its Regulation – A Promising Research Area for Drug Discovery 399
17 Epigenetic Gene Regulation: Key to Development and Survival of Malaria Parasites 401
18 Mechanisms Regulating Transcription in Plasmodium falciparum as Targets for Novel Antimalarial Drugs 421
19 Aminoacyl t-RNA Synthetases as Antimalarial Drug Targets 441

Part Four Mathematical Approaches to Drug and Target Discovery 455
20 MathematicalModeling and Omic Data Integration to Understand Dynamic Adaptation of Apicomplexan Parasites and Identify Pharmaceutical Targets 457
21 Understanding Protozoan Parasite Metabolism and Identifying Drug Targets through Constraint-Based Modeling 487
22 Attacking Blood-Borne Parasites with Mathematics 513

Index 543

Written and edited by experts in the field, this book brings together the current state of the art in phenotypic and rational, target-based approaches to drug discovery against pathogenic protozoa. The chapters focus particularly on virtual compounds and high throughput screening, natural products, computer-assisted drug design, structure-based drug design, mechanism of action identification, and pathway modelling. Furthermore, state-of the art "omics" technologies are described and currently studied enzymatic drug targets are discussed. Mathematical, systems biology-based approaches are introduced as new methodologies for dissecting complex aspects of pathogen survival mechanisms and for target identification. In addition, recently developed anti-parasitic agents targeting particular pathways, which serve as lead compounds for further drug development, are presented.

Authors
• Prof. Sylke Muller received her PhD in 1991 from the University of Hamburg. In 1992 she worked at the London School of Hygiene and Tropical Medicine, before returning to the Bernhard Nocht Institute for Tropical Medicine in Hamburg in 1994. In 1999 she was awarded the Habilitation and the venia legendi. From 2001 to 2012 she was funded by a Wellcome Trust Senior Fellowship at Dundee University (until 2004) and the University of Glasgow (2004 to 2012). In 2006 she was awarded a Personal Chair in Molecular and Biochemical Parasitology at the University of Glasgow.
• Prof. Rachel Cerdan received her PhD from the University of Paris XI in 1997. She spent three years at the Laboratory of Molecular Biology (Medical Research Council) in Cambridge, UK as a Marie Curie post-doctoral fellow. She then moved to the Centre of Structural Biochemistry in Montpellier, France. In 2003, she joined the laboratory of Dynamics of Membrane Interactions in Normal and Pathological Cells in Montpellier. Currently, she is professor in biochemistry and structural biology at the University of Montpellier, France. Her current projects focus on the biochemical and structural characterization of pharmacological targets to develop new classes of antimalarials.
• Prof. Ovidiu Radulescu studied physics and mathematics in Bucharest and Paris and obtained his PhD in 1994 from the University of Paris XI, France. Immediately after his PhD, he worked in theoretical condensed matter physics, first in the Institute of Theoretical Physics in Nijmegen, the Netherlands, and then in the Physics Department of the University of Leeds, UK. In 1999 he joined as a lecturer the Department of Mathematics of the University of Rennes 1, France. At that time, he was also associate member of the French Institute for Research in Computer Science and Automation, INRIA.
Since 2009, he is Professor in Systems Biology and team leader at the University of Montpellier, France. His team is part of the laboratory DIMNP UMR5235, whose main focuses are in parasitology and immunology.