Trypanosomatid Diseases: Molecular Routes to Drug Discovery

This is the first resource to provide researchers in academia and industry with an urgently needed update on drug intervention against trypanosomatides. As such, it covers every aspect of the topic from basic research findings, via current treatments to translational approaches in drug development and includes both human and livestock diseases. The outstanding editor and contributor team reads like a Who’s Who of the field, thus guaranteeing the outstanding quality of this ready reference.

Foreword IX Acknowledgment XV Preface XVII List of Contributors XIX Part One Disease Burden, Current Treatments, Medical Needs, and Strategic Approaches 1 1 Visceral Leishmaniasis – Current Treatments and Needs 3 Poonam Salotra, Ruchi Singh, and Karin Seifert 2 Chemotherapy of Leishmaniasis: A Veterinary Perspective 17 María Jesus Corral–Caridad and Jose María Alunda 3 Pharmacological Metabolomics in Trypanosomes 37 Darren J. Creek, Isabel M. Vincent, and Michael P. Barrett 4 Drug Design and Screening by In Silico Approaches 57 Mattia Mori and Maurizio Botta 5 Computational Approaches and Collaborative Drug Discovery for Trypanosomal Diseases 81 Sean Ekins and Barry A. Bunin Part Two Metabolic Peculiarities in the Trypanosomatid Family Guiding Drug Discovery 103 6 Interaction of Leishmania Parasites with Host Cells and its Functional Consequences 105 Uta Schurigt, Anita Masic, and Heidrun Moll 7 Function of Glycosomes in the Metabolism of Trypanosomatid Parasites and the Promise of Glycosomal Proteins as Drug Targets 121 Melisa Gualdron–Lopez, Paul A.M. Michels, Wilfredo Qui∼nones, Ana J. Caceres, Luisana Avilan, and Juan–Luis Concepcion 8 Glyoxalase Enzymes in Trypanosomatids 153 Marta Sousa Silva, Antonio E.N. Ferreira, Ricardo Gomes, Ana M. Tomas, Ana Ponces Freire, and Carlos Cordeiro 9 Trypanothione–Based Redox Metabolism of Trypanosomatids 167 Marcelo A. Comini and Leopold Flohe 10 Thiol Peroxidases of Trypanosomatids 201 Helena Castro and Ana M. Tomas 11 Peroxynitrite as a Cytotoxic Effector Against Trypanosoma cruzi: Oxidative Killing and Antioxidant Resistance Mechanisms 215 Madia Trujillo, María Noel Alvarez, Lucía Piacenza, Martín Hugo, Gonzalo Peluffo, and Rafael Radi 12 Selenoproteome of Kinetoplastids 237 Alexei V. Lobanov and Vadim N. Gladyshev 13 Replication Machinery of Kinetoplast DNA 243 Rachel Bezalel–Buch, Nurit Yaffe, and Joseph Shlomai 14 Life and Death of Trypanosoma brucei: New Perspectives for DrugDevelopment 261 Torsten Barth, Jasmin Stein, Stefan Mogk, Caroline Sch€onfeld, Bruno K. Kubata, and Michael Duszenko Part Three Validation and Selection of Drug Targets in Kinetoplasts 279 15 Rational Selection of Anti–Microbial Drug Targets: Unique or Conserved? 281 Boris Rodenko and Harry P. de Koning 16 Drug Targets in Trypanosomal and Leishmanial Pentose Phosphate Pathway 297 Marcelo A. Comini, Cecilia Ortíz, and Juan Jose Cazzulo 17 GDP–Mannose: A Key Point for Target Identification and Drug Design in Kinetoplastids 315 Sebastien Pomel and Philippe M. Loiseau 18 Transporters in Anti–Parasitic Drug Development and Resistance 335 Vincent Delespaux and Harry P. de Koning 19 Peptidases in Autophagy are Therapeutic Targets for Leishmaniasis 351 Roderick A.M. Williams 20 Proteases of Trypanosoma brucei 365 Dietmar Steverding Part Four Examples of Target–Based Approaches and Compounds Under Consideration 383 21 Screening Approaches Towards Trypanothione Reductase 385 Mathias Beig, Frank Oellien, R. Luise Krauth–Siegel, and Paul M. Selzer 22 Redox–Active Agents in Reactions Involving the Trypanothione/Trypanothione Reductase–based System to Fight Kinetoplastidal Parasites 405 Thibault Gendron, Don Antoine Lanfranchi, and Elisabeth Davioud–Charvet 23 Inhibition of Trypanothione Synthetase as a Therapeutic Concept 429 Oliver Koch, Timo J€ager, Leopold Flohe, and Paul M. Selzer 24 Targeting the Trypanosomatidic Enzymes Pteridine Reductase and Dihydrofolate Reductase 445 Stefania Ferrari, Valeria Losasso, Puneet Saxena, and Maria Paola Costi 25 Contribution to New Therapies for Chagas Disease 473 Patricia S. Doyle and Juan C. Engel 26 Ergosterol Biosynthesis for the Specific Treatment of Chagas Disease: From Basic Science to Clinical Trials 489 Julio A. Urbina 27 New Developments in the Treatment of Late–Stage Human African Trypanosomiasis 515 Cyrus J. Bacchi, Robert T. Jacobs, and Nigel Yarlett Index 531

Volume Editors: Timo Jäger studied biology at the Technical University of Braunschweig, Germany, where he also received his PhD. He worked as a Postdoc at the German Research Centre for Biotechnology, Braunschweig, and served as Head of Biological Research and Development for MOLISA GmbH in Magdeburg, Germany. His research centered on the redox metabolism of pathogens, function and catalytic mechanism of peroxiredoxins, target evaluation, characterization, and drug development against infectious diseases, especially tuberculosis and trypanosomiasis. He is currently Managing Director of the Coordination Office of the German Centre for Infection Research DZIF in Braunschweig. Oliver Koch studied pharmacy and computer science at the Philipps–University of Marburg, Germany, where he also received his PhD in the field of computer–aided drug design. During his post–doctoral studies, he worked as a scientific software engineer at the Cambridge Crystallographic Data Centre (CCDC) in Cambridge, UK, before joining the drug discovery department at MSD Animal Health Innovation GmbH, Germany. Currently, he is junior research group leader at the faculty of chemistry, TU Dortmund, Germany. His research interests focus on the development and application of computational methods in drug discovery and molecular design. Leopold Flohé studied philosophy, medicine and biochemistry and obtained his MD and the venia legendi for Biochemistry from the University of Tübingen, Germany. He served as Scientific Director for Grünenthal GmbH in Aachen, the German Biotechnology Centre (HZI) in Braunschweig and Molisa GmbH in Magdeburg, Germany, while simultaneously teaching at the local universities. His contributions to science were acknowledged with Honorary Degrees from the Universities of Buenos Aires and Montevideo, the Claudius–Galenus–Preis, the Klaus Schwarz Commemorative Medal, the Science and Humanity Price (OCC) and the Trevor Frank Slater Award and Gold Medal (SFRRI). Paul M. Selzer studied biology, parasitology, and biochemistry at the University of Tübingen, Germany, where he also received his PhD in biochemistry. He spent three years at the Molecular Design Institute and the Parasitology and Tropical Disease Research Laboratory at the University of California, San Francisco. During his career he has worked as a researcher and scientific manager for several pharmaceutical companies, and is currently Director, Molecular Discovery Sciences at MSD Animal Health Innovation GmbH, Germany. He is also a visiting professor and teacher at the Biochemistry Institute of the University of Tübingen, and an honorary professor of the Department of Infection, Immunity, and Inflammation at the University of Glasgow, UK.