Trypanosomatid Diseases: Molecular Routes to Drug Discovery -- Contents -- Foreword -- Acknowledgment -- Preface -- List of Contributors -- Part One Disease Burden, Current Treatments, Medical Needs, and Strategic Approaches -- 1 Visceral Leishmaniasis - Current Treatments and Needs -- Introduction -- Current Anti-Leishmanial Drugs and Treatment Options for Visceral Leishmaniasis -- Available Drugs -- New Treatment Regimes -- Regional Differences in Clinical Drug Efficacy -- PKDL -- Pathology and Immunopathology of PKDL -- Current Treatment Options for PKDL -- Open Questions and Needs -- References -- 2 Chemotherapy of Leishmaniasis: A Veterinary Perspective -- Introduction -- Status of the Chemotherapy of Leishmaniasis -- Chemotherapy of Canine Leishmaniasis -- Canine Leishmaniasis by L. infantum (=L. chagasi) -- Chemotherapy of Canine Leishmaniasis -- Pentavalent Antimonials -- Allopurinol -- Alkylphosphocholine (Miltefosine) -- Amphotericin B -- Use of Drug Delivery Systems for Amphotericin B -- Aminosidine (Paromomycin), Pentamidine, and Other Compounds -- Exploration of New Anti-Leishmanial Drugs -- Concluding Remarks -- Acknowledgments -- References -- 3 Pharmacological Metabolomics in Trypanosomes -- Introduction -- Metabolomics - New Technologies Applied to Trypanosomes -- Sample Preparation -- NMR-Based Metabolomics -- MS-Based Metabolomics -- Data Analysis -- Metabolic Affects of Trypanocidal Drugs -- Pentamidine -- Suramin -- Melarsoprol -- Eflornithine -- NECT -- Conclusion -- Acknowledgments -- References -- 4 Drug Design and Screening by In Silico Approaches -- Introduction -- Computer-Aided Drug Design: General Remarks -- Supercomputers and Other Technical Resources -- Molecular Modeling and Anti-Kinetoplastida Drug Design -- Ligand-Based Approaches Against Trypanosoma Parasites -- Structure-Based Drug Design and Screening.

Virtual Screening Approaches against Trypanosome Proteins -- In Silico Prediction of Protein Druggability -- References -- 5 Computational Approaches and Collaborative Drug Discovery for Trypanosomal Diseases -- Introduction -- CDD Database -- Using HTS Data for Machine Learning Models -- Discussion -- Acknowledgments -- References -- Part Two Metabolic Peculiarities in the Trypanosomatid Family Guiding Drug Discovery -- 6 Interaction of Leishmania Parasites with Host Cells and its Functional Consequences -- Life Cycle of Leishmania -- Host Cells of Leishmania -- Neutrophils -- Macrophages -- DCs -- Conclusion -- References -- 7 Function of Glycosomes in the Metabolism of Trypanosomatid Parasites and the Promise of Glycosomal Proteins as Drug Targets -- Introduction -- Glycosomes of T. brucei -- Glycosomes of T. cruzi -- Glycosomes of Leishmania spp. -- Essentiality of Controlled Communication Across the Glycosomal Membrane -- Essentiality of Correct Integration of Glycosomal Metabolism in the Overall Metabolism - Relation to Life Cycle Differentiation -- What Has Been Achieved So Far in Target Characterization? -- What Has Been Achieved So Far in the Development of Inhibitors of Glycosomal Enzymes or Processes -- Discussion and Conclusions -- Acknowledgments -- References -- 8 Glyoxalase Enzymes in Trypanosomatids -- Glyoxalase Pathway -- Glyoxalase I -- Glyoxalase II -- Glyoxalase Pathway Regulation -- Glyoxalase Pathway as a Therapeutic Target -- Conclusion -- References -- 9 Trypanothione-Based Redox Metabolism of Trypanosomatids -- Thiol RedoxMetabolism of Trypanosomatids:ABrief Historical Overview -- Trypanothione Biosynthesis -- Glutathione Synthesis -- Polyamine Synthesis, Salvage, and Uptake -- Trypanothione Synthesis -- Trypanothione Recycling -- Trypanothione Utilization -- Redoxin-Independent Functions of Trypanothione.

Trypanothione-Dependent Ligation of Iron-NO Complexes and ISCs -- Trypanothione-Dependent Detoxification Reactions and Drug Resistance -- Redoxin-Dependent Functions of Trypanothione -- Hydroperoxide Metabolism -- Redoxin and DNA Synthesis -- New Putative Functions for TXN and Peroxidases -- Redoxins and Peroxidases as Drug Targets? -- Conclusions -- Acknowledgments -- References -- 10 Thiol Peroxidases of Trypanosomatids -- Thiol-Dependent Peroxidases in Trypanosomatids -- Mechanism of Reaction of Thiol Peroxidases -- Trypanosomatid PRXs -- Trypanosomatid GPXs -- Function of Thiol Peroxidases in Trypanosomatids -- Conclusions -- References -- 11 Peroxynitrite as a Cytotoxic Effector Against Trypanosoma cruzi: Oxidative Killing and Antioxidant Resistance Mechanisms -- Introduction -- PeroxynitriteFormationDuringT. cruzi-MammalianHostCellInteraction -- Peroxynitrite Diffusion and Reactivity with T. cruzi Targets -- Peroxynitrite Detoxification Systems -- T. cruzi Antioxidant Enzymes as Virulence Mediators -- Conclusions -- Acknowledgments -- References -- 12 Selenoproteome of Kinetoplastids -- Introduction -- Kinetoplastid Selenoproteome -- Selenoproteome is Dispensable -- Selenoproteome is Relevant for Long-Term Protection -- Conclusions -- References -- 13 Replication Machinery of Kinetoplast DNA -- Introduction: kDNA Network and its Monomeric Subunits -- Replication of kDNA Minicircles, Maxicircles, and Networks -- Components of the kDNA Replication Machinery: Replication Proteins and Complexes -- Recognition of the Replication Origin: UMS-Binding Protein (UMSBP) and p38 -- Priming of DNA Synthesis: DNA Primases -- kDNA Chain Elongation: DNA Polymerases -- Unwinding of Duplex kDNA Circles and More: Kinetoplast DNA Helicases -- kDNA Repair Enzymes: Mitochondrial DNA Ligases -- Topological Reactions During kDNA Replication: DNA Topoisomerases.

Regulation of kDNA Replication -- Replication Initiation: Redox Regulation of UMSBP Binding to the Replication Origin -- Periodic Expression of kDNA Replication Genes -- Role of a Mitochondrial HslVU Protease in the Regulation of kDNA Replication -- Conclusion: kDNA Replication Machinery as an Anti-Trypanosomal Drug Target -- Acknowledgments -- References -- 14 Life and Death of Trypanosoma brucei: New Perspectives for Drug Development -- Necrosis -- Autophagic Cell Death -- Apoptosis in Protozoan Parasites -- Outlook -- References -- Part Three Validation and Selection of Drug Targets in Kinetoplasts -- 15 Rational Selection of Anti-Microbial Drug Targets: Unique or Conserved? -- Introduction -- Phosphodiesterases -- Ergosterol Synthesis -- N-Myristoyl Transferase -- Proteases -- Kinases -- Concluding Remarks -- References -- 16 Drug Targets in Trypanosomal and Leishmanial Pentose Phosphate Pathway -- Pentose Phosphate Pathway in Trypanosomatids: General Considerations and Biological Relevance -- Biochemical and Structural Hallmarks of Trypanosomatids PPP Enzymes -- Inhibitor Discovery Against PPP Enzymes -- Conclusions -- Acknowledgments -- References -- 17 GDP-Mannose: A Key Point for Target Identification and Drug Design in Kinetoplastids -- Introduction -- Comparison of Mannosylation Pathways between Mammals and Kinetoplastids -- Enzymes and Transporters Involved in Mannosylation in Mammals and Kinetoplastids -- Hexose Transporter -- Hexokinase -- Phosphoglucose Isomerase (PGI) -- Phosphomannose Isomerase (PMI) -- Phosphomannomutase (PMM) -- Guanosine-Diphospho-D-mannose Pyrophosphorylase (GDP-MP) -- Dolichol-Phosphate Mannose Synthase (DPMS) -- GDP-Mannose-Dependent Mannosyltransferases -- GDP-Mannose Transporter (LPG2) -- Mannosyl Phosphate Transferases (MPTs) -- Conclusion -- References.

18 Transporters in Anti-Parasitic Drug Development and Resistance -- Introduction -- "Rule of Five" -- Diffusion -- Selective Uptake by Protozoan Transporters -- Role of Efflux Transporters -- Diagnosing Drug Resistance Through Screening of Transporter Mutations: T. congolense as an Example -- Concept -- Evaluation -- Sensitivity and Implementation -- Concluding Remarks -- References -- 19 Peptidases in Autophagy are Therapeutic Targets for Leishmaniasis -- Introduction -- Molecular Machinery for Autophagosome Biogenesis -- ATG4 Regulates the Autophagic Pathway of Leishmania spp. -- Leishmania's Cathepsins Regulates Autophagy and Virulence -- Other Possible Peptidase Targets -- Cysteine Peptidase Inhibitors: Opportunities and Challenges -- Conclusions and Future Directions -- Acknowledgments -- References -- 20 Proteases of Trypanosoma brucei -- Introduction -- Classes of Proteases -- Cysteine Peptidases -- Serine Peptidases -- Metalloproteases -- Threonine Proteases -- Cellular Functions -- TbCATB and TbCATL -- TbCALPs -- TbMCAs -- TbGPI8 -- TbOPB and TbPOP -- TbMSP-B -- Proteasome -- Proteases as Drug Targets -- TbCATB and TbCATL -- TbCALPs -- TbMCAs -- TbGPI8 -- TbOPB and TbPOP -- TbMSP-B -- Proteasome -- Conclusion -- References -- Part Four Examples of Target-Based Approaches and Compounds Under Consideration -- 21 Screening Approaches Towards Trypanothione Reductase -- Introduction -- Parasitic Diseases Caused by Trypanosomatids -- Present Chemotherapy of Trypanosomiasis and Leishmaniasis -- Unique Thiol Redox Metabolism of Trypanosomatids as a Target Area for Future Drug Development -- TR is a Validated Drug Target -- Structural Comparison of TR and Human GR -- Screening Approaches Towards TR -- Current State of the Art -- Combined In Vitro/In Silico Screening Campaign -- TR Assay Adaptation -- In Vitro Screening -- In Silico Screening.

Second In Vitro Screen.