Parasitic Helminths: Targets, Screens, Drugs and Vaccines -- Foreword to Parasitic Helminths: Targets, Screens, Drugs and Vaccines -- Contents -- Preface -- List of Contributors -- Part One: Targets -- 1 Ligand-Gated Ion Channels as Targets for Anthelmintic Drugs: Past, Current, and Future Perspectives -- Introduction -- Established LGIC Anthelmintic Drug Targets -- GluCls - Targets for Ivermectin -- L-Type nAChRs -Targets for Levamisole, Pyrantel, Morantel, and Tribendimidine -- nAChRs (DEG-3 Group) - Targets for AADs -- GABA-Gated Chloride Channels - Targets for Piperazine -- Evaluating Possible Anthelmintic Targets for the Future -- N-Type nAChRs -- Nematode-Specific nAChRs and Orphan nAChR-Like Subunits -- GABA Receptor Cation Channels -- 5-HT Channels -- ACh Chloride Channels -- GGR-1 Group -- GGR-3 Group -- LGC-45 Group -- Ungrouped Subunits -- Cys-Loop LGIC Superfamilies of Other Nematodes -- Genomics -- Chemistry-to-Gene Screens to Identify New Targets -- First Crystal Structure of a Cys-Loop LGIC Complexed with a Commercial Animal Health Drug -- Conclusions and Future Lines of Research -- References -- 2 How Relevant is Caenorhabditis elegans as a Model for the Analysis of Parasitic Nematode Biology? -- Introduction -- Comparative Genome Analysis for the Phylum Nematoda -- Functional Characterization of Parasite Genes by Heterologous Expression in C. elegans -- Comparative Pharmacology of C. elegans and Parasitic Nematode Neurotransmitter Receptors -- C. elegans as a Tool to Understand the Mode of Action of Novel Anthelmintics -- C. elegans as a Platform for Target Discovery -- Conclusions -- References -- 3 Integrating and Mining Helminth Genomes to Discover and Prioritize Novel Therapeutic Targets -- Introduction -- Availability of Genome Sequence Information for Parasitic Helminths.

Overview of Genome Annotation Datasets that Aid Target Identification -- Orthology-Based Annotations and Comparative Genomics -- Predictions of Essentiality -- Orthology-Based RNAi Phenotype Data Mapping Between C. elegans and Parasitic Helminths -- The TDR Targets Database -- Target Prioritization in B. malayi and S. mansoni Using the TDR Targets Database -- Currently Unavailable Genomic Datasets that will Improve Target Prioritization for Parasitic Helminths -- Conclusions -- Acknowledgments -- References -- 4 Recent Progress in Transcriptomics of Key Gastrointestinal Nematodes of Animals - Fundamental Research Toward New Intervention Strategies -- Introduction -- Recent Developments in the Bioinformatic Tools and Pipelines for the Analysis of Expressed Sequence Tag Data -- Characterizing the Transcriptomes of Strongylid Nematodes -- Conclusions and Prospects -- Acknowledgments -- References -- 5 Harnessing Genomic Technologies to Explore the Molecular Biology of Liver Flukes-Major Implications for Fundamental and Applied Research -- Introduction -- Transcriptomic Studies of Liver Flukes Utilizing an Integrated High- Throughput Sequencing and Bioinformatic Platform -- Exciting Prospects for "Omics" Research of Liver Flukes -- Conclusions -- Acknowledgments -- References -- 6 RNA Interference: A Potential Discovery Tool for Therapeutic Targets of Parasitic Nematodes -- Introduction -- From Sequence Data to Target Discovery -- Functional Genomics Using Caenorhabditis elegans -- Drug Target Identification Using C. elegans -- RNAi in Parasitic Nematodes - Story so Far -- In Vivo RNAi -- Improving RNAi in Parasitic Nematodes -- Conclusions -- References -- 7 RNA Interference as a Tool for Drug Discovery in Parasitic Flatworms -- Platyhelminth Parasites -- RNAi - Background -- RNAi in Platyhelminths -- RNAi in Schistosomes -- RNAi Pathway in Schistosomes.

RNAi as a Discovery Tool -- RNAi-Induced Phenotypes and Identifying Essential Genes -- RNAi-Based Drugs -- RNAi in Other Parasitic Platyhelminths -- Conclusions -- Acknowledgments -- References -- Part Two: Screens -- 8 Mechanism-Based Screening Strategies for Anthelmintic Discovery -- Introduction -- Mechanism-Based Screens for Anthelmintics: Examples -- Screens for Enzyme Inhibitors -- Neuromuscular Targets in HTS -- Challenges and Prospects for Anthelmintic HTS -- References -- 9 Identification and Profiling of Nematicidal Compounds in Veterinary Parasitology -- Introduction -- Drug Discovery Approaches for New Anthelmintics -- Physiology-Based Nematode Assays in Veterinary Parasitology -- EHT -- LDT -- Physiology-Based Assays on L3 and Adult Helminths -- Physiology-Based Screening Assays Using Parasitic Nematode Stages -- Compound Screening for Novel Anthelmintics -- Biological Activity and Phenotype Correlation -- Lead Optimization Towards a Drug Candidate -- Conclusions -- Acknowledgments -- References -- 10 Quantitative High-Content Screening-Based Drug Discovery against Helmintic Diseases -- Introduction -- Basic Concepts of Biological Image Analysis for Quantitative Phenotyping -- Image Segmentation: A Closer Look -- Segmentation and Automated Phenotype Analysis: A Brief Review -- Automated Phenotype Analysis for Drug Screening Against Schistosomiasis and Filariasis -- Algorithms for Schistosome Segmentation -- Segmentation of Filarial Parasites for HTS -- Tracking, Phenotype Quantification, and Phenotype Classification -- Conclusions -- Acknowledgments -- References -- 11 Use of Rodent Models in the Discovery of Novel Anthelmintics -- Introduction -- Translational Science -- Nematode Infection Models -- Nematode Infections in Livestock -- Trichostrongylus Rodent Models -- Haemonchus Rodent Models -- Other Nematode Species.

Gastrointestinal Nematode Parasites of Humans -- Disease and Impact -- Hookworm Infection and Rodent Models -- Strongyloides Stercoralis -- Rodent Models -- Rodent Models of Other STH Infections -- Filarial Parasite Models -- Filarial Parasites of Humans -- Lymphatic Filariasis -- Rodent Models of Lymphatic Filarial Infection -- Onchoceriasis -- Rodent Models of Onchocerciasis -- Trematode and Cestode Infection Models -- Trematode Infections in Humans and Livestock -- Schistosomiasis -- Rodent Models -- Fascioliasis -- Cestode Infection in Humans and Livestock -- Conclusions -- References -- 12 To Kill a Mocking Worm: Strategies to Improve Caenorhabditis elegans as a Model System for use in Anthelmintic Discovery -- Introduction -- C. elegans as a Platform for Anthelmintic Characterization -- C. elegans as a Platform for Anthelmintic Drug Discovery -- Xenobiotic Resistance of C. elegans -- Circumventing Xenobiotic Resistance -- Modifying the Screening Paradigm -- Modifying the Chemistry -- Modifying C. elegans -- Conclusions -- Acknowledgments -- References -- Part Three: Drugs -- 13 Anthelmintic Drugs: Tools and Shortcuts for the Long Road from Discovery to Product -- Introduction -- Target Product Profile: First Know Where You Want to Go -- Drug Development Stages -- Discovery -- Preclinical Studies -- Chemistry, Manufacturing, and Controls -- Clinical Trials -- Regulatory Considerations -- Getting the Job Done -- PDPs -- Government Resources and Incentives -- Conclusions -- Acknowledgments -- References -- 14 Antinematodal Drugs - Modes of Action and Resistance: And Worms Will Not Come to Thee (Shakespeare: Cymbeline: IV, ii) -- Introduction -- Modes of Action of Anthelmintics -- Cholinergic Agonists -- AADs (Monepantel) -- Cholinergic Antagonists (Derquantel and Phenothiazine) -- Derquantel -- Phenothiazine.

Glutamate-gated chloride ion channels (GluCls) and γ-Aminobutyric Acid (GABA) Allosteric Modulators -- Avermectins (Ivermectin, Doramectin, Eprinomectin, and Abamectin) and Milbemycins (Moxidectin and Milbemycin) -- GABA Agonist -- Piperazine -- SLO-1 Potassium Channel Activator -- Emodepside -- β-Tubulin Ligands -- Thiabendazole, Mebendazole, Flubendazole, Oxibendazole, and Albendazole -- Chitinase Inhibitor/Ionophore -- Closantel -- Innate Immune Response Inhibitor -- Diethylcarbamazine -- SH Ligand -- Melarsamine -- Pyruvate: Ferredoxin Oxidoreductase Inhibitor -- Nitazoxanide -- Isothiocyanate-ATP Inhibition -- Nitroscanate, Amoscanate, and Sulfoscanate -- Resistance -- Cholinergic Agonists -- Levamisole and Pyrantel Resistance -- Monepantel Resistance (AADs) -- GluCl Modulators (Changed Receptor Subunit SNPs, and Increased Expression of P-Glycoproteins and Multidrug Resistance Proteins) -- β-Tubulin Ligands - Benzimidazole Resistance -- Acknowledgments -- References -- 15 Drugs and Targets to Perturb the Symbiosis of Wolbachia and Filarial Nematodes -- Introduction -- Anti-Wolbachia Treatment as an Effective Antifilarial Therapy -- Indications for Doxycycline as an Antifilarial Treatment -- Search for Second-Generation Anti-Wolbachia Drugs -- A· WOL Drug Regimen Refinement -- A· WOL Assay Development and Screening Strategy -- A· WOL Library Screening -- Registered Drug Library Screening -- Focused Anti-Infective Library Screening -- Diversity-Based Library Screening -- A· WOL Target Discovery -- Conclusions -- Acknowledgments -- References -- 16 Promise of Bacillus thuringiensis Crystal Proteins as Anthelmintics -- Introduction -- Safety of B. thuringiensis Cry Proteins -- Mechanism of Action -- Cry Proteins Have a Broad-Spectrum of Activity Against Free-Living and Parasitic Roundworms Ex Vivo.

Cry Proteins Intoxicate a Wide Range of Free-Living Roundworms.