Parasitic Helminths E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Serie: Drug Discovery in Infectious Diseases
• Sprache: Englisch

Seitenzahl: 1089

Veröffentlichungsjahr: 2012

Beschreibung

This third volume in the successful 'Drug Discovery in Infectious Diseases' series is the first to deal with drug discovery in helminthic infections in human and animals. The result is a broad overview of different drug target evaluation methods, including specific examples of successful drug development against helminthes, and with a whole section devoted to vaccine development.
With its well-balanced mix of high-profile contributors from academia and industry, this handbook and reference will appeal to a wide audience, including parasitologists, pharmaceutical industry, epidemiologists, and veterinary scientists.

Leseprobe

Contents

Cover

Titles of the Series “Drug Discovery in Infectious Diseases”

Title Page

Copyright

Foreword to Parasitic Helminths: Targets, Screens, Drugs and Vaccines

Preface

List of Contributors

Part I: Targets

Chapter 1: Ligand-Gated Ion Channels as Targets for Anthelmintic Drugs: Past, Current, and Future Perspectives

Introduction

Established LGIC Anthelmintic Drug Targets

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

Chapter 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

Chapter 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

Chapter 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

Chapter 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

Chapter 6: RNA Interference: A Potential Discovery Tool for Therapeutic Targets of Parasitic Nematodes

Introduction

From Sequence Data to Target Discovery

RNAi in Parasitic Nematodes – Story so Far

Improving RNAi in Parasitic Nematodes

Conclusions

References

Chapter 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 II: Screens

Chapter 8: Mechanism-Based Screening Strategies for Anthelmintic Discovery

Introduction

Mechanism-Based Screens for Anthelmintics: Examples

Challenges and Prospects for Anthelmintic HTS

References

Chapter 9: Identification and Profiling of Nematicidal Compounds in Veterinary Parasitology

Introduction

Drug Discovery Approaches for New Anthelmintics

Physiology-Based Nematode Assays in Veterinary Parasitology

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

Chapter 10: Quantitative High-Content Screening-Based Drug Discovery against Helmintic Diseases

Introduction

Basic Concepts of Biological Image Analysis for Quantitative Phenotyping

Segmentation and Automated Phenotype Analysis: A Brief Review

Automated Phenotype Analysis for Drug Screening Against Schistosomiasis and Filariasis

Tracking, Phenotype Quantification, and Phenotype Classification

Conclusions

Acknowledgments

References

Chapter 11: Use of Rodent Models in the Discovery of Novel Anthelmintics

Introduction

Translational Science

Nematode Infection Models

Filarial Parasite Models

Trematode and Cestode Infection Models

Conclusions

References

Chapter 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

Conclusions

Acknowledgments

References

Part III: Drugs

Chapter 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

Getting the Job Done

Conclusions

Acknowledgments

References

Chapter 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

Resistance

Acknowledgments

References

Chapter 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

A·WOL Target Discovery

Conclusions

Acknowledgments

References

Chapter 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

Therapeutic Activity of Cry Proteins (Cry5B and Cry21A) Against Two Mammalian Intestinal Roundworm Parasites In Vitro and In Vivo

Powerful Combinatorial Antiroundworm Activity Between Cry Proteins and nAChR Agonists

Conclusions

Acknowledgments

References

Chapter 17: Monepantel: From Discovery to Mode of Action

Discovery of the Amino-Acetonitrile Derivatives

Selection of AAD-1566 (Monepantel)

Tolerability of the AADs

Investigation of the Mode of Action of Monepantel

Elucidating the Molecular Mode of Action of Monepantel

Developing a Model for the Mode of Action of Monepantel

Conclusions

References

Chapter 18: Discovery, Mode of Action, and Commercialization of Derquantel

Introduction

Discovery and Characterization of PNU-141962 (2-Deoxy-paraherquamide)

Mode of Action of Derquantel: B-Subtype Nicotinic Acetylcholine Receptor Antagonist

Development of Startect®: A Novel Combination of Derquantel and Abamectin

Safety Studies

Commercialization

Conclusions

References

Chapter 19: Praziquantel: Too Good to be Replaced?

Praziquantel: A Success Story

Limitations

Resistance

Mechanism of Action

Not Only Schistosomiasis

Search for a Better PZQ

Conclusions

References

Chapter 20: Drug Discovery for Trematodiases: Challenges and Progress

Trematodiases

Current Therapy

Challenges Confronting Drug Discovery for Trematodiases

New Infrastructures to Reinvigorate Trematode Drug Discovery

Repurposing Drugs and New Drug Leads

Phenotypic Screens: Assay Development and Automation

Improving Genomics and Functional Genomics Tools

Target Validation Through Reverse Genetics: RNAi

Recent Advances with Metabolic Profiling

Conclusions

Acknowledgments

References

Part IV: Vaccines

Chapter 21: Barefoot thru' the Valley of Darkness: Preclinical Development of a Human Hookworm Vaccine

Introduction

Potency Testing Program

A Cautionary Tale for NTD Vaccines: Hookworm Disease

Potency Testing for NTD Vaccines

Potency Assays for NTDs: Setting Specifications with Few Assumptions

Conclusions

References

Chapter 22: Vaccines Linked to Chemotherapy: A New Approach to Control Helminth Infections

Introduction

Current Progress in Helminth Vaccine Development

Product Development Strategies that Involve Manufacturing Partners in Disease-Endemic Countries

Conclusions

Acknowledgment

References

Chapter 23: Antifilarial Vaccine Development: Present and Future Approaches

General Aspects of Human Filarial Infection and Disease

Natural Host–Parasite Systems for Onchocerciasis and Lymphatic Filariasis

Vaccinology

Current Status of Filarial Vaccine Development

Multivalent Vaccines

Discovery of New Vaccine Candidates

Conclusions

References

Chapter 24: Proteases as Vaccines Against Gastrointestinal Nematode Parasites of Sheep and Cattle

Introduction

Proteases of Gastrointestinal Nematodes of Livestock – Overview

Desirable Vaccine Efficacy

Gut-Expressed Proteases as Vaccine Antigens

O. ostertagi Cysteine Proteases

Confirmation of the Efficacy of Vaccine Targets and Approaches to Antigen Production and Delivery

Conclusions

Acknowledgments

References

Chapter 25: Schistosomiasis Vaccines – New Approaches to Antigen Discovery and Promising New Candidates

Introduction

Schistosomes

Schistosome Genomics and Transcriptomics

Schistosome Proteomics

Schistosome Postgenomics

Schistosome Immunomics

Case for a Schistosomiasis Vaccine

Sm-TSP-2 Schistosomiasis Vaccine

Conclusions

References

Chapter 26: Sm14 Schistosoma mansoni Fatty Acid-Binding Protein: Molecular Basis for an Antihelminth Vaccine

Schistosomiasis and Fascioliasis

Discovery of the Sm14 Vaccine Antigen

Function of Parasite FABPs

Development of Sm14: A FABP-Based Vaccine Against Helminths

Sm14 Protein Stability

Scaling-Up the Sm14 Production Process

Clinical Trials

Conclusions

References

Chapter 27: Mechanisms of Immune Modulation by Fasciola hepatica: Importance for Vaccine Development and for Novel Immunotherapeutics

Introduction

Conclusions

References

Chapter 28: Prospects for Immunoprophylaxis Against Fasciola hepatica (Liver Fluke)

Introduction

Secreted Cysteine Proteases as Vaccines

LAP Vaccine

Antioxidant Vaccines

Way Forward: Combination Vaccines

Recent Advances in Understanding Immunity to Liver Fluke Infection

Surface Tegument Proteins as Proposed New Candidate Vaccines

Criteria Needed for Development of a Commercial Liver Fluke Vaccine

Prospects for a Human Vaccine

Conclusions

References

Chapter 29: Vaccines Against Cestode Parasites

Introduction

Vaccine Development in Definitive Hosts

Vaccines Against Cestode Infections in Intermediate Hosts

Prospects for Practical Application of Anticestode Vaccines

Unique Combination of Vaccination and Chemotherapy

Conclusions

Acknowledgments

References

Index

Titles of the Series “Drug Discovery in Infectious Diseases”

Selzer, P. M. (ed.)

Antiparasitic and Antibacterial Drug Discovery

From Molecular Targets to Drug Candidates

2009

ISBN: 978-3-527-32327-2

Becker, K. (ed.)

Apicomplexan Parasites

Molecular Approaches toward Targeted Drug Development

2011

ISBN: 978-3-527-32731-7

Forthcoming Topics of the Series

Drug Discovery for Trypanosomatid DiseasesProtein Phosphorylation in Parasites: Novel Targets for Antiparasitic Intervention

Related Titles

Gunn, A., Pitt, S. J.

Parasitology

An Integrated Approach

2012

ISBN: 978-0-470-68424-5

Scott, I., Sutherland, I.

Gastrointestinal Nematodes of Sheep and Cattle

Biology and Control

2009

ISBN: 978-1-4051-8582-0

Schwartz, E.

Tropical Diseases in Travelers

2009

ISBN: 978-1-4051-8441-0

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty can be created or extended by sales representatives or written sales materials. The Advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

Library of Congress Card No.: applied for

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library.

Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at http://dnb.d-nb.de.

© 2012 Wiley-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

Wiley-Blackwell is an imprint of John Wiley & Sons, formed by the merger of Wiley's global Scientific, Technical, and Medical business with Blackwell Publishing

All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

Composition Thomson Digital, Noida, India

Cover Design Adam Design, Weinheim

Print ISBN: 978-3-527-33059-1

ePDF ISBN: 978-3-527-65293-8

oBook ISBN: 978-3-527-65296-9

epub ISBN: 978-3-527-65294-5

Foreword to Parasitic Helminths: Targets, Screens, Drugs and Vaccines

Peter Hotez

The last decade has witnessed a renewed interest in neglected diseases caused by parasitic helminths, especially for the high prevalence gastrointestinal nematode infections, filarial infections, schistosomiasis, food-borne trematodiases and larval cestode infections. A number of factors have contributed to this resurgent interest in helminthic infections as global health threats:

1. There is new information suggesting that parasitic helminthiases are the most common causes of infection among the “bottom billion”, i.e., the 1.4 billion world's poorest people who live below the World Bank poverty level in developing countries of Asia, Africa, and the Americas. The major helminthiases include 600–800 million people with one or more soil-transmitted helminth infection, 400–600 million with schistosomiasis, more than 100 million people filarial infections and tens of millions with food-borne trematode infections.

2. Additional studies have revealed that some of the most prevalent parasitic helminths may increase susceptibility to the “big three” diseases, i.e., HIV/AIDS, malaria and tuberculosis or exacerbate the morbidities of the big three diseases.

3. According to some estimates the major parasitic helminth infections together cause a disease burden measured in disability adjusted life years that may rival or even exceed the big three conditions, while additional information indicates that these helminthiases may actually cause poverty through their deleterious effects on child growth and cognitive development, pregnancy outcome and agricultural worker productivity.

The global health community has responded to this public health threat by expanding efforts directed at mass drug administration (MDA). For example, using either diethylcarbamazine citrate or ivermectin together with albendazole, lymphatic filariasis (LF) has been eliminated as a public health problem in more than 20 countries, while through annual treatments with ivermectin, onchocerciasis has been eliminated in Senegal and Mali and may soon be eliminated from the Americas. Simultaneously, large scale financial support from the United States Agency for International Development (USAID), the British Department for International Development (DFID) and the non-profit Global Network for Neglected Tropical Diseases has facilitated combining LF and onchocerciasis MDA efforts with MDA for soil-transmitted helminth infections and schistosomiasis to create “rapid impact” packages of anthelmintic interventions in national programs of helminth control in more than a dozen African countries, in addition to selected countries in Asia, Latin America and the Caribbean.

The promise of MDA for parasitic helminth infections has generated excitement among the international community that it might be possible to one day eliminate several helminthiases globally thereby achieving successes on this front that cannot yet be imagined for any of the big three diseases. However, there are warning signs that MDA with currently available drugs might fail to achieve such expectations: 1) high rates of mebendazole drug failure have been reported for hookworm infection caused by Necator americanus and trichuriasis, i.e., two of the helminth infections with the greatest prevalence; 2) there is the looming specter of benzimidazole drug resistance among gastrointestinal nematodes of humans as has already occurred for nematode parasites of livestock, and 3) it has been shown that high rates of post-treatment re-infection occur for most of the major soil-transmitted helminth infections, schistosomiasis, and opisthorchiasis and other food-borne trematode infections.

Such concerns highlight the urgent need to develop and maintain a pipeline of new anthelmintic drugs in addition to anthelmintic vaccines to prevent infection or re-infection. Sadly, there is a glaring disconnect between the urgency for research and development (R&D) for new anthelmintic products and the global R&D budget for helminthiases. According to the global health think tank, Policy Cures, less than $100 million annually is spent on R&D for all human helminthiases compared to more than $3 billion spent annually on R&D for all the other neglected infections, including the big three diseases.

This volume summarizes the work of dedicated investigators in the medical and veterinary fields who are applying the latest technologies to discover the next generation of anthelmintic drugs and vaccines. Despite the difficulty in working with parasitic helminths in the laboratory, these investigators are overcoming significant hurdles in the study of the world's most important helminths affecting more than a billion people worldwide and countless livestock.

Their work is leading to a new generation of advances and represents the best in science and in the pursuit of humanitarian goals.

Peter Hotez MD PhD is Dean of the National School of Tropical Medicine and Professor of Pediatrics and Molecular Virology Microbiology, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA

Preface

Parasitic helminths continue to plague the lives of billions of people, and those of farm and domestic animals. Their capacity to persist in the environment is infuriating, costly (health-wise and economically), and fascinating depending on one's perspective as a livestock farmer, medical provider, or research scientist. For the animal health industry, the intrinsic capacity of helminths to resist drug pressure drives the never-ending quest to bring new anthelmintic drugs to market. In recent years, we have seen the fruits of that industry with the registration of new drugs containing emodepside, monepantel, and derquantel. These drugs and other compounds in the pipeline are critical not just for staying “one up” on resistant parasites of animals, but also for their potential to cross-over to human medicine, as has occurred with earlier anthelmintics that have been of immeasurable value to improving global health. That contribution becomes all the more relevant today given the increasing concerns over the continued efficacy of many first-generation anthelmintic drugs relied upon to treat human helminthiases, not least the benzimidazoles and the “wonder drug” ivermectin, and the serious implications for public health should these drugs fail.

This volume is intended to showcase the state-of-the-art in the fields of drug and vaccine development for parasitic helminths as well as draw attention to the challenges associated with bringing such products to market. The book is Volume 3 in the series Drug Discovery in Infectious Diseases and expands on some of the themes raised in Volume 1, Antiparasitic and Antibacterial Drug Discovery: From Molecular Targets to Drug Candidates. Contributions from the animal health industry figure prominently with a focus on the discovery and development of new chemical entities. Importantly, however, the book also covers the increasingly relevant contribution of academia, not just in its traditional strengths of identifying new drug targets or understanding how drug resistance arises, but also in the ways and means of preclinical and translational drug discovery through highly collaborative and interdisciplinary research. Indeed, this exciting movement into the traditional domain of the pharmaceutical industry can be viewed as a natural consequence of the central importance and success of academia in the public–private consortia that currently maintain dynamic drug development portfolios for other global parasitic diseases such as malaria and the trypanosomatid diseases. The creativity and productivity of academic scientists are highlighted in the many chapters covering the development and expansion of genomics and functional genomic tools, and the application of automated screening technologies to prosecute anthelmintic drug discovery with rigor.

Finally, this volume discusses the need for, and the particular difficulties associated with, developing anthelmintic vaccines for both humans and animals – for many the “holy grail” in providing the tool (including in combination with chemotherapy) to ultimately control and, hopefully, eliminate helminth diseases. Great progress has been made in identifying a number of candidates with proven efficacy in target animal species or that are now entering human trials, thanks in part to the establishment of the necessary national and transnational institutional infrastructures.

To all of the authors, my sincere thanks for their time, insights, and patience in contributing to an important collection of on-topic discussions. My thanks also to the book series editor, Paul M. Selzer of Intervet Innovation GmbH, and to my colleagues at the Sandler Center for Drug Discovery at the University of California San Francisco for their constructive input.

Conor R. Caffrey

March 2012

San Francisco

List of Contributors

David Abraham Thomas Jefferson University Department of Microbiology and Immunology 233 South 10th Street Philadelphia, PA 19107 USA

Fernán Agüero* Universidad de San Martín Instituto de Investigaciones Biotecnológicas 25 de Mayo y Francia San Martín B 1650 HMP, Buenos Aires Argentina E-mail: [email protected], [email protected]

Cristian Alvarez University of Melbourne Veterinary Clinical Center 250 Princes Highway Werribee Victoria 3030 Australia

Raffi V. Aroian* University of California San Diego Section of Cell and Developmental Biology Division of Biological Sciences 9500 Gilman Dr La Jolla, CA 92093-0322 USA E-mail: [email protected]

Jeffrey M. Bethony* George Washington University Medical Center Clinical Immunology Laboratory Department of Microbiology, Immunology and Tropical Medicine 2300 Eye Street, NW Washington, DC 20052 USA E-mail: [email protected]

and

FIOCRUZ Clinical Immunology Laboratory Laboratório de Imunologia Celular e Molecular Centro de Pesquisas René Rachou Av. Augusto de Lima 1715 Belo Horizonte Minas Gerais 30190-002 Brazil

Maria Elena Bottazzi National School of Tropical Medicine Sabin Vaccine Institute and Texas Children's Center for Vaccine Development Section of Pediatric Tropical Medicine Baylor College of Medicine 1102 Bates St. Houston, TX 77030 USA

Collette Britton* University of Glasgow Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences Bearsden Road Glasgow G61 1QH UK E-mail: [email protected]

Andrew R. Burns University of Toronto Department of Molecular Genetics and The Donnelly Centre for Cellular and Biomolecular Research 160 College Street, Rm1202 Toronto Ontario, M5S 1A8 Canada

Samuel K. Buxton Iowa State University Department of Biomedical Sciences Ames, IA 50011 USA

Jacques Cabaret INRA UR1282 Infectiologie Animale et Santé Publique 37380 Nouzilly France

Conor R. Caffrey* University of California San Francisco Sandler Center for Drug Discovery and the Department of Pathology 1700 4th Street San Francisco, CA 94158-2330 USA E-mail: [email protected]

Bronwyn E. Campbell The University of Melbourne Faculty of Veterinary Science Corner Flemington Road and Park Drive Parkville Victoria 3010 Australia

Cinzia Cantacessi The University of Melbourne Faculty of Veterinary Science Corner Flemington Road and Park Drive Parkville Victoria 3010 Australia

Carlos Carmona Universidad de la República Unidad de Biología Parasitaria Instituto de Biología Facultad de Ciencias Av. A. Navarro 3051 CP 11600 Montevideo Uruguay

Santiago J. Carmona Universidad de San Martín Instituto de Investigaciones Biotecnológicas 25 de Mayo y Francia San Martín B 1650 HMP, Buenos Aires Argentina

Claude L. Charvet INRA UR1282 Infectiologie Animale et Santé Publique 37380 Nouzilly France

Christophe Chassaing Intervet Innovation GmbH MSD Animal Health Zur Propstei 55270 Schwabenheim Germany

Donato Cioli National Research Council Cell Biology and Neurobiology Institute 32 Via Ramarini Monterotondo 00015 Rome Italy

George A. Conder Pfizer Animal Health Veterinary Medicine Research & Development 7000 Portage Road Kalamazoo, MI 49001 USA

Linsey R. Cozzie Merial Ltd Clinical R&D Americas East 115 Transtech Drive Athens, GA 30601 USA

Gregory J. Crowther University of Washington Department of Medicine Division of Allergy and Infectious Diseases 1959 NE Pacific Street Seattle, WA 98195-7185 USA

Akram A. Da’dara Tufts University Molecular Helminthology Laboratory Division of Infectious Diseases Department of Biomedical Sciences Cummings School of Veterinary Medicine 200 Westboro Road Grafton, MA 01536 USA

John P. Dalton McGill University Institute of Parasitology 21111 Lakeshore Road St Anne de Bellevue Quebec H9X 3V9 Canada

David Diemert Sabin Vaccine Development PDP 723-D Ross Hall 2300 Eye Street NW Washington, DC 20037 USA

Sheila M. Donnelly University of Technology Sydney ithree Institute Level 6, Building 4 Corner of Thomas and Harris Street Sydney New South Wales 2007 Australia

Denise Doolan Queensland Institute of Medical Research Division of Infectious Diseases 300 Herston Rd Brisbane Queensland 4006 Australia

Patrick Driguez Queensland Institute of Medical Research Division of Infectious Diseases 300 Herston Rd Brisbane Queensland 4006 Australia

Rebecca Fankhauser Merial Ltd Clinical R&D Americas East 115 Transtech Drive Athens, GA 30601 USA

Philip Felgner University of California Irvine School of Medicine 3052 Hewitt Hall Irvine, CA 92697 USA

Louise Ford Liverpool School of Tropical Medicine Molecular and Biochemical Parasitology Pembroke Place Liverpool L3 5QA UK

Jeremy M. Foster New England Biolabs Division of Molecular Parasitology 240 County Road Ipswich, MA 01938 USA

Robin B. Gasser* The University of Melbourne Faculty of Veterinary Science Corner Flemington Road and Park Drive Parkville Victoria 3010 Australia E-mail: [email protected]

Charles G. Gauci University of Melbourne Veterinary Clinical Center 250 Princes Highway Werribee Victoria 3030 Australia

Soraya Gaze James Cook University Queensland Tropical Health Alliance McGregor Rd, Smithfield Cairns Queensland 4878 Australia

Timothy G. Geary* McGill University Institute of Parasitology 21111 Lakeshore Road Ste-Anne-de-Bellevue Quebec H9X 3V9 Canada E-mail: [email protected]

Ross S. Hall The University of Melbourne Faculty of Veterinary Science Corner Flemington Road and Park Drive Parkville Victoria 3010 Australia

Lance G. Hammerland* Merial Ltd Pharmaceutical R&D 3239 Satellite Boulevard Duluth, GA 30096 USA E-mail: [email protected]

Anja. R. Heckeroth Intervet Innovation GmbH MSD Animal Health Zur Propstei 55270 Schwabenheim Germany

Achim Hoerauf University Clinic Bonn Institute for Medical Microbiology, Immunology, and Parasitology Sigmund-Freud Strasse 25 53105 Bonn Germany

Lindy Holden-Dye* University of Southampton Centre for Biological Sciences University Road Southampton SO17 1BJ UK E-mail: [email protected]

Eugenio L. de Hostos* OneWorld Health Suite 250 280 Utah Avenue South San Francisco, CA 94080 USA E-mail: [email protected]

Peter Hotez* National School of Tropical Medicine Sabin Vaccine Institute and Texas Children's Center for Vaccine Development Section of Pediatric Tropical Medicine Baylor College of Medicine 1102 Bates St. Houston, TX 77030 USA E-mail: [email protected]

Yan Hu University of California San Diego Section of Cell and Developmental Biology Division of Biological Sciences 9500 Gilman Dr La Jolla, CA 92093-0322 USA

Abdul Jabbar The University of Melbourne Veterinary Clinical Center 250 Princes Highway Werribee Victoria 3030 Australia

Amar R. Jariwala George Washington University Medical Center Clinical Immunology Laboratory Department of Microbiology, Immunology and Tropical Medicine 2300 Eye Street, NW Washington, DC 20052 USA

Aaron R. Jex The University of Melbourne Department of Veterinary Science Corner Flemington Road and Park Drive Parkville Victoria 3010 Australia

Sandra S. Johnson Pfizer Animal Health Veterinary Medicine Research & Development 7000 Portage Road Kalamazoo, MI 49001 USA

Ronald Kaminsky* Novartis Center de Recherche Santé Animale Route de la Petite Glâne 1566 Saint Aubin Switzerland E-mail: [email protected]

Jennifer Keiser Swiss Tropical and Public Health Institute Department of Medical Parasitology and Infection Biology PO Box 4002 Basel Switzerland

Thomas R. Klei Louisiana State University School of Veterinary Medicine Skip Bertman Drive Baton Rouge, LA 70803 USA

David Knox* Moredun Research Institute Parasitology Division Bush Loan Penicuik EH26 0PZ UK E-mail: [email protected]

Sanjay Kumar New England Biolabs Division of Molecular Parasitology 240 County Road Ipswich, MA 01938 USA

Kristin Lees* University of Manchester Faculty of Life Sciences Oxford Road Manchester M13 9PT UK E-mail: [email protected]

Marshall W. Lightowlers* University of Melbourne Veterinary Clinical Center 250 Princes Highway Werribee Victoria 3030 Australia E-mail: [email protected]

Alex Loukas* James Cook University Queensland Tropical Health Alliance McGregor Rd, Smithfield Cairns Queensland 4878 Australia E-mail: [email protected]

Sara Lustigman* New York Blood Center Laboratory of Molecular Parasitology Lindsley F. Kimball Research Institute 310 East 67th Street New York, NY 10065 USA E-mail: [email protected]

Jürgen Lutz Intervet Innovation GmbH MSD Animal Health Zur Propstei 55270 Schwabenheim Germany

Steven J. Maeder Pfizer Animal Health Veterinary Medicine Research & Development 38–42 Wharf Road West Ryde Sydney New South Wales 2114 Australia

Richard J. Martin* Iowa State University Department of Biomedical Sciences Ames, IA 50011 USA E-mail: [email protected]

James H. McKerrow University of California San Francisco Sandler Center for Drug Discovery and Department of Pathology California Institute for Quantitative Biosciences 1700 4th Street San Francisco, CA 94158-2330 USA

Donald P. McManus Queensland Institute of Medical Research Division of Infectious Diseases 300 Herston Rd Brisbane Queensland 4006 Australia

Bakela Nare Scynexis Inc. Department 3501C Tricenter Boulevard Durham, NC 27713 USA

Cedric Neveu INRA UR1282 Infectiologie Animale et Santé Publique 37380 Nouzilly France

Tue Nguyen OneWorld Health Suite 250 280 Utah Avenue South San Francisco, CA 94080 USA

Matthew J. Nolan The University of Melbourne Faculty of Veterinary Science Corner Flemington Road and Park Drive Parkville Victoria 3010 Australia

Sandra M. O’Neill Dublin City University Parasite Immune Modulation Group School of Nursing Collins Avenue Glasnevin Dublin 9 Ireland

Mark Pearson James Cook University Queensland Tropical Health Alliance McGregor Rd, Smithfield Cairns Queensland 4878 Australia

Maria Victoria Periago George Washington University Medical Center Clinical Immunology Laboratory Department of Microbiology, Immunology and Tropical Medicine 2300 Eye Street, NW Washington, DC 20052 USA

and

FIOCRUZ Clinical Immunology Laboratory Laboratório de Imunologia Celular e Molecular Centro de Pesquisas René Rachou Av. Augusto de Lima 1715 Belo Horizonte Minas Gerais 30190-002

Ken Pfarr University Clinic Bonn Institute for Medical Microbiology, Immunology, and Parasitology Sigmund-Freud Strasse 25 53105 Bonn Germany

Livia Pica-Mattoccia* National Research Council Cell Biology and Neurobiology Institute 32 Via Ramarini Monterotondo 00015 Rome Italy E-mail: [email protected]

David Piedrafita Monash University Biotechnology Research Laboratories Wellington Road Clayton Victoria 3800 Australia

Kerrie Powell Scynexis Inc. Department 3501C Tricenter Boulevard Durham, NC 27713 USA

Sreekanth Puttachary Iowa State University Department of Biomedical Sciences Ames, IA 50011 USA

Stuart A. Ralph University of Melbourne Department of Biochemistry and Molecular Biology Bio21 Molecular Science and Biotechnology Institute 30 Flemington Road Parkville Victoria 3010 Australia

Celso Raul Romero Ramos FIOCRUZ Laboratório de Esquistossomose Experimental Av. Brasil 4365 Manguinhos Rio de Janeiro 21-045-900 Brazil

Alan P. Robertson Iowa State University Department of Biomedical Sciences Ames, IA 50011 USA

Mark W. Robinson* University of Technology Sydney ithree Institute Level 6, Building 4 Corner of Thomas and Harris Street Sydney New South Wales 2007 Australia E-mail: [email protected]

Andreas Rohwer Intervet Innovation GmbH MSD Animal Health Zur Propstei 55270 Schwabenheim Germany

and

Roche Diagnostics Deutschland GmbH Sandhofer Strasse 116 68305 Mannheim Germany

David S. Roos University of Pennsylvania Department of Biology and Penn Genomics Institute 415 South University Ave Philadelphia, PA 19104 USA

Peter J. Roy* University of Toronto Department of Molecular Genetics, The Donnelly Centre for Cellular and Biomolecular Research and the Collaborative Programme in Developmental Biology 160 College Street, Rm1202 Toronto Ontario, M5S 1A8 Canada E-mail: [email protected]

Lucien Rufener Novartis Center de Recherche Santé Animale Route de la Petite Glâne 1566 Saint Aubin Switzerland

David Sattelle University of Manchester Faculty of Life Sciences Oxford Road Manchester M13 9PT UK

Dhanasekaran Shanmugam Division of Biochemical Sciences National Chemcial Laboratories Dr. Homi Bhabha Road Pune, 411008 India

Niroda Shannan University of Manchester Faculty of Life Sciences Oxford Road Manchester M13 9PT UK

Paul M. Selzer* Intervet Innovation GmbH MSD Animal Health Zur Propstei 55270 Schwabenheim Germany E-mail: [email protected]

Andrew J.G. Simpson Ludwig Institute for Cancer Research New York Branch at Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York, NY 10021 USA

Rahul Singh* San Francisco State University Department of Computer Science 1600 Holloway Avenue San Francisco, CA 94132 USA E-mail:[email protected]

Patrick J. Skelly* Tufts University Molecular Helminthology Laboratory Division of Infectious Diseases Department of Biomedical Sciences Cummings School of Veterinary Medicine 200 Westboro Road Grafton, MA 01536 USA E-mail: [email protected]

Barton E. Slatko New England Biolabs Division of Molecular Parasitology 240 County Road Ipswich, MA 01938 USA

Ann E. Sluder Scynexis Inc. Department 3501C Tricenter Boulevard Durham, NC 27713 USA

Peter M. Smooker RMIT University School of Applied Sciences Plenty Road Bundoora Victoria 3083 Australia

Terry W. Spithill* La Trobe University Department of Agricultural Sciences and Center for AgriBioscience Kingsbury Drive Bundoora Victoria 3086 Australia E-mail: [email protected]

Mark J. Taylor* Liverpool School of Tropical Medicine Molecular and Biochemical Parasitology Pembroke Place Liverpool L3 5QA UK E-mail: [email protected]

Miriam Tendler* FIOCRUZ Laboratório de Esquistossomose Experimental Av. Brasil 4365 Manguinhos Rio de Janeiro 21-045-900 Brazil E-mail: [email protected]

David P. Thompson Pfizer Animal Health Veterinary Medicine Research & Development 7000 Portage Road Kalamazoo, MI 49001 USA

Manfred Uphoff Intervet Innovation GmbH MSD Animal Health Zur Propstei 55270 Schwabenheim Germany

Jürg Utzinger Swiss Tropical and Public Health Institute Department of Epidemiology and Public Health PO Box 4002 Basel Switzerland

Robert J. Walker University of Southampton Centre for Biological Sciences University Road Southampton SO17 1BJ UK

Sally M. Williamson University of Georgia Department of Infectious Diseases & Center for Tropical and Emerging Global Disease Athens, GA 30602 USA

Adrian J. Wolstenholme University of Georgia Department of Infectious Diseases & Center for Tropical and Emerging Global Disease Athens, GA 30602 USA

Debra J. Woods* Pfizer Animal Health Veterinary Medicine Research & Development 7000 Portage Road Kalamazoo, MI 49001 USA E-mail: [email protected]

Neil D. Young* The University of Melbourne Faculty of Veterinary Science Corner Flemington Road and Park Drive Parkville, Victoria 3010 Australia E-mail: [email protected]

Part One

Targets

Chapter 1

Ligand-Gated Ion Channels as Targets for Anthelmintic Drugs: Past, Current, and Future Perspectives

Kristin Lees*, Ann Sluder, Niroda Shannan, Lance Hammerland, and David Sattelle

Abstract

Ligand-gated ion channels (LGIC) are targets for anthelmintic drugs used in human health and veterinary applications. Given the diverse physiological roles of LGICs in neuromuscular function, the nervous system, and elsewhere, it is not surprising that random chemical screening programs often identify drug candidates targeting this superfamily of transmembrane proteins. Such leads provide the basis for further chemical optimization, resulting in important commercial products. Currently, members of three LGIC families are known to be targeted by anthelmintics. These include the nicotinic acetylcholine receptors gating cation channels, glutamate-gated chloride channels, and γ-aminobutyric acid-gated chloride channels. The recent impact of genomics on model invertebrates and parasitic species has been far-reaching, leading to the description of new helminth LGIC families. Among the current challenges for anthelmintic drug discovery are the assessment of newly discovered LGICs as viable targets (validation) and circumventing resistance when exploring further the well-established targets. Recombinant expression of helminth LGICs is not always straightforward. However, new developments in the understanding of LGIC chaperones and automated screening technologies may hold promise for target validation and chemical library screening on whole organisms or preparations. Here, we describe LGIC targets for the current anthelmintics of commercial importance and discuss the potential impact of that knowledge on screening for new compounds. In addition, we discuss some new technologies for anthelmintic drug hunting, aimed at the discovery of novel treatments to control veterinary parasites and some neglected human diseases.