Table of Contents
Cover
Title Page
Copyright
List of Contributors
Foreword
Preface
Part One: Identification and Validation of New Drugs and Targets
Chapter 1: Discovery of the Mechanism of Action of Novel Compounds That Target Unicellular Eukaryotic Parasites
Introduction
Principles
Initial Investigations
Biochemical Methods and Candidate Genes
Classical Genetics and Genomics
Changes in mRNA Levels
Reverse Genetic Screens
Proteins and Proteomes
Metabolomics
Validation
Conclusions
References
Chapter 2: Antiparasitics from Algae
Introduction
Plasmodium falciparum
Kinetoplastida –
Trypanosoma brucei sp.
,
Trypanosoma cruzi
, and
Leishmania
sp
Anaerobic Protozoan Parasites –
Entamoeba histolytica, Giardia lamblia, and Trichomonas vaginalis
Helminths
Microalgae
Conclusion
References
Chapter 3: Contribution of Natural Products to Drug Discovery in Tropical Diseases
Introduction
Antiparasitic Natural Product Compound Classes
Discussion
Conclusion and Future Perspectives
References
Chapter 4: Isoxazolines: A Novel Chemotype Highly Effective on Ectoparasites
Arthropod Ectoparasites: Burden to the Agricultural and Veterinary Sectors
Ligand-Gated Chloride Channels as Suitable Targets for Ectoparasiticides
Mode of Action
Isoxazolines: Novel Ectoparasiticides Acting on GABACls and GluCls
Structure and Active Sites of Chloride Channels
Isoxazoline Mode of Action and Binding Site
Selectivity and Safety Profile
Isoxazoline Derivatives: Continuous Exploration of the Novel Chemotype
Conclusions
Acknowledgments
References
Chapter 5: Trypanosomal Cysteine Peptidases: Target Validation and Drug Design Strategies
Cysteine Peptidases from
Trypanosoma cruzi
Cysteine Peptidases from
Trypanosoma brucei
Development of Antitrypanosomal Cysteine Peptidase Inhibitors
Peptidic Derivatives
Nonpeptidic Derivatives
Conclusion
Acknowledgments
References
Chapter 6: Potential of Pyrimidine Metabolism for Antitrypanosomal Drug Discovery
Introduction
De novo
Biosynthesis of Pyrimidines
Pyrimidine Salvage
UMP Downstream Enzymes
Final Remarks
References
Chapter 7: Phosphatidylcholine and Phosphatidylethanolamine Biosynthesis Pathways in Plasmodium
Introduction
Kinases
Cytidylyltransferases
Phosphotransferase
Transversal Pathways
Conclusion
Acknowledgments
References
Chapter 8: Immunophilins as Possible Drug Targets in Apicomplexan Parasites
Immunophilins
Immunophilins in Apicomplexa
Immunophilins as Drug Targets
Conclusions
References
Chapter 9: Targeting the Atg8 Conjugation Pathway for Novel Anti-Apicomplexan Drug Discovery
Autophagy: An Overview
Phylum, Apicomplexa
Conservation of Autophagy in Apicomplexa
Functions of Apicomplexan Autophagy Proteins
Targeting the Plasmodial (and Apicomplexan) Atg8-Conjugation Pathway
Concluding Remarks
References
Chapter 10: Turnover of Glycosomes in Trypanosomes – Perspectives for Drug Discovery
Glycosomes of Trypanosomatid Parasites Are Unique, Peroxisome-Related Organelles
Glycosomes are Essential Organelles
Glycosomal Metabolism Changes during the Life Cycle of the Parasites
Biogenesis of Glycosomes
Autophagy and Pexophagy of Glycosomes
Proteins Involved in Glycosome Biogenesis and Degradation are Potential Drug Targets
Discussion and Conclusions
Acknowledgments
References
Chapter 11: Glideosome of Apicomplexans as a Drug Target
Economic and Public Health Burden of Apicomplexans
Phylogenetic Relation of Human and Livestock Apicomplexan Pathogens
Burden of Malaria
Life Cycle of the Parasite
Invasion Machinery (Glideosome)
Conservation of the Glideosome in Apicomplexans
Components of the Glideosome: Function and Potential as Drug Targets
Exploring the Essentiality of the Adhesins and Glideosome Components
Concluding Remarks
References
Chapter 12: N-Myristoyltransferase as a Target for Drug Discovery in Malaria
Introduction: Malaria and the Need for New Drugs
Phenotypic Screening and Inhibitors Directed toward PI4K and eEF2
Protein
N-
Myristoylation in
Plasmodium
Structure, Specificity, and Mechanism of NMT
NMT as a Drug Target
Discovery of Inhibitors of
Plasmodium
NMT – “Piggyback” Approaches
Discovery of Inhibitors of
Plasmodium
NMT – High-Throughput Approaches
Using NMT Inhibitors to Validate NMT as a Drug Target in Malaria
Essential Function of NMT in Plasmodium Parasites
Conclusion
Acknowledgments
References
Part Two: Metabolomics in Drug and Target Discovery
Chapter 13: Methods to Investigate Metabolic Systems in Trypanosoma
Trypanosomes, Unconventional Organisms
Metabolomics
Application of Metabolomics to
T. brucei
– Selected Illustrations
Concluding Remarks
References
Chapter 14: The Role of Metabolomics in Antiparasitic Drug Discovery
Introduction
Principles of Metabolomics
Metabolomics in Drug Discovery
Metabolomics Methodology
Metabolomics for Drug Discovery in Kinetoplastid Parasites
Metabolomics for Drug Discovery in Apicomplexan Parasites
Summary
References
Chapter 15: The Importance of Targeting Lipid Metabolism in Parasites for Drug Discovery
Introduction
Parasites Nutrient Requirements from the Host for Lipid Metabolism
Drugs Affecting Phospholipid Metabolism in Protozoan Parasites
Drugs Affecting Sterol Metabolism in Protozoan Parasites
Drug Resistances and Its Association with Altered Lipid Composition
Modern Technological Methods to Phenotype Changes in Lipid Content
Perspectives
Acknowledgments
References
Chapter 16: Carbon Metabolism of Plasmodium falciparum
Introduction
Cytosolic Glucose Metabolism
Mitochondrial Metabolism
Apicoplast Metabolism
Conclusions
Acknowledgments
References
Part Three: Gene Expression and Its Regulation – A Promising Research Area for Drug Discovery
Chapter 17: Epigenetic Gene Regulation: Key to Development and Survival of Malaria Parasites
Introduction
Epigenetics – An Overview
The Unique Genome and Chromatin Landscape of
Plasmodium falciparum
Epigenetic Regulation of Gene Expression in
P. falciparum
Concluding Remarks and Perspective
References
Chapter 18: Mechanisms Regulating Transcription in Plasmodium falciparum as Targets for Novel Antimalarial Drugs
Transcription in
Plasmodium falciparum
Nucleosome Landscape
Chromatin Remodeling Enzymes
Histone Posttranslational Modifications
Histone-Modifying Enzymes
Nuclear Architecture
Proteins Involved in Nuclear Organization
Long Noncoding RNAs
Posttranscriptional Control of Gene Expression
Conclusions
References
Chapter 19: Aminoacyl t-RNA Synthetases as Antimalarial Drug Targets
Introduction
Alanyl-tRNA Synthetase (AlaRS)
Isoleucyl-tRNA Synthetase (IleRS)
Threonyl-tRNA Synthetase (ThrRS)
Methionyl-tRNA Synthetase (MetRS)
Lysyl-tRNA Synthetase (LysRS)
Prolyl-tRNA Synthetase (ProRS)
Conclusions
References
Part Four: Mathematical Approaches to Drug and Target Discovery
Chapter 20: Mathematical Modeling and Omic Data Integration to Understand Dynamic Adaptation of Apicomplexan Parasites and Identify Pharmaceutical Targets
Introduction
Omics-Based Approaches
Mathematical Modeling
Role of Kinetic Models to Elucidate Mechanism of Effectors and Identify Putative Drug Target
Conclusion and Future Perspectives
References
Chapter 21: Understanding Protozoan Parasite Metabolism and Identifying Drug Targets through Constraint-Based Modeling
Introduction
Genome-Scale Reconstruction
Metabolic Model Simulation
Applications of Flux Balance Analysis in Identifying Potential Drug Targets
Conclusion
References
Chapter 22: Attacking Blood-Borne Parasites with Mathematics
The Importance of Flexible Metabolism for the Parasites
Trypanosoma brucei
and
Plasmodium falciparum
Metabolism as a Drug Target
Computer Models Can Aid Our Understanding of Metabolism
Construction and Validation of Detailed Kinetic Models of Glycolysis of BSF
T. brucei
and of the Trophozoite Stage of
P. falciparum
Metabolic Control Analysis Ranks Enzymes for Drug Target Potential
Work in Progress: Future Extensions and Use of the Kinetic Models of
T. brucei
and
P. falciparum
Do It Yourself: Databases and Tools to Do Your Own Simulations with the Detailed Kinetic Models
Concluding Remarks
Acknowledgments
References
Index
End User License Agreement
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Guide
Cover
Table of Contents
Foreword
Preface
Part One: Identification and Validation of New Drugs and Targets
Begin Reading