Neuropeptide Systems as Targets for Parasite and Pest Control (eBook)

TIMOTHY G. GEARY is a Tier I Canada Research Chair and is Professor and Director of the Institute of Parasitology at McGill University in Montréal, Québec, Canada. Geary received a BSc degree from the University of Notre Dame in South Bend, IN (USA) and a PhD in Pharmacology from the University of Michigan in Ann Arbor, MI (USA, 1980). He worked on malaria chemotherapy at Michigan State University in East Lansing, MI (USA) until 1985, when he joined The Upjohn Company in Kalamazoo, MI (USA) as a staff scientist working on discovery of antiparasitic drugs. Geary joined the Faculty at McGill in 2005; research interests include proteomics and genomics analyses of the host-parasite interface, discovery of anthelmintics and the pharmacology of antiparasitic drugs. AARON G. MAULE is a Director of Research for Molecular Biosciences and Professor of Molecular Parasitology at Queen’s University Belfast, Northern Ireland. Maule was awarded a BSc(Hons) in Biology (1986) and a PhD in Experimental Parasitology (1989) at Queen’s where he began working on parasite neuromuscular systems. He focused on molecular aspects of parasite neurobiology during postdoctoral positions at Queen’s and at The Upjohn Company in Kalamazoo, MI (USA). Maule returned to Queen’s as a member of academic staff in 1995 to pursue the basic biology of helminth signaling systems. Research interests include parasite neurobiology and the development and exploitation of gene silencing platforms for target validation and parasite control.

Title Page 3
Copyright Page 4
PREFACE 5
ABOUT THE EDITORS... 7
ABOUT THE EDITORS... 8
PARTICIPANTS 9
Table of Contents 12
Chapter 1 Receptor-Based Discovery Strategiesfor Insecticides and Parasiticides:A Review 16
Introduction 16
Mechanistic Receptor-Based Screens 18
Selection of Compounds for Screening 20
‘Hit-to-Lead’: Converting a Mechanistic Screen Active into a Lead Molecule 21
Lead-to-Candidate: Identification of Molecules for Progression to Market 22
Conclusion and Discussion 23
References 23
Chapter 2 Nonpeptide Ligands for PeptidergicG Protein-Coupled Receptors 25
Introduction 25
Druggable Targets in Neuropeptidergic Signaling 26
Neuropeptide-Targeted Drugs: Basic Features 27
Peptides as Drugs 27
Interference with Peptide Production or Stability 28
Drug-Receptor Interactions 28
Historical Perspectives 30
Screening for Novel Nonpeptide Ligands 31
Discovery of Novel Nonpeptide Ligands through Screening 32
Complicating Issues: Subtype- and Species-Specificity 33
Complicating Issues: Pharmacology of Agonists and Antagonists 34
Design 35
Current Status 35
Applications in Invertebrate Systems: General Considerations 35
Screening Targets: GPCRs 36
Screening Targets: Peptide Processing 38
What to Screen 38
Conclusion 39
References 39
Chapter 3 Interaction of Mimetic Analogsof Insect Kinin Neuropeptideswith Arthropod Receptors 42
Introduction 42
Functional Analysis of Arthropod Receptors Selective for Insect Kinins 43
Chemical, Conformational and Stereochemical Aspects of Receptor Interaction 44
Interaction of Biostable Insect Kinin Analogs with Receptors and Activity in In Vitro and In Vivo Bioassays 47
C-Terminal Aldehyde Analogs of Insect Kinins 51
H. Zea Larval Weight Gain Inhibition Bioassay 52
In Vitro and In Vivo Housefly Diuretic Bioassays 52
Nonpeptide Mimetic Agonists/Antagonists of Expressed Insect Kinin Receptors 56
Prospects for Enhanced Topical and/or Oral Bioavailability 57
Topical Activity 57
Oral Activity 58
Conclusion 60
References 61
Chapter 4 Neuropeptides in Helminths:Occurrence and Distribution 64
Introduction 64
Nematode Neuropeptides 66
Nematode FMR Famide-Like Peptides (FLPs) 66
Nematode FLP Distribution/Expression 70
Nematode Insulin-Like Peptides (INSs) 72
Nematode INS Distribution/Expression 72
Nematode Neuropeptide-Like Proteins (NLPs) 76
Nematode NLP Distribution/Expression 80
Platyhelminth Neuropeptides 81
Platyhelminth Neuropeptide F (NPF) 81
Platyhelminth NPF Distribution/Expression 82
Platyhelminth FMRFamide-Like Peptides (FLPs) 82
Platyhelminth FLP Distribution/Expression 84
Targets for Parasite Control 85
Conclusion 85
Note Added in Proof 86
References 87
Chapter 5 Neuropeptide Physiology in Helminths 93
Introduction 93
Neuropeptide Function in Nematodes 94
FLP Function in Control and Modulation of Somatic Body Wall 94
FLP Function in Reproductive Muscle Control—Ascaris suum 96
FLP Function in Pharyngeal Muscle Control—Ascaris suumand Caenorhabditis elegans 97
FLP Effects on Motorneuron Activity—Ascaris suum 99
FLP Effects on Second Messenger Systems—Ascaris suum and Ascaridida galli 100
FLP Function in Behaviour, Locomotion and Body Posture—Ascaris suum 101
FLP Function Determined by Gene Knockout Studies—Caenorhabditis elegans 102
FLP Function Determined by RNA Interference Studies—Globodera pallidaand Caenorhabditis elegans 103
NLP Function in Nematodes: Introduction 104
NLP Function in Control and Modulation of Somatic Body Walland Reproductive Muscle—Ascaris suum 104
NLP Function in Behaviour, Locomotion and Body Posture—Ascaris suum 104
NLP Role as Anti-Microbial Peptides—Caenorhabditis elegans 104
FLP Function Determined by RNA Interference Studies—Caenorhabditiselegans 104
INS Function Determined by Gene Knockout Studies—Caenorhabditis elegans 105
Neuropeptide Function in Platyhelminths 105
FLP Function in Platyhelminths 105
NPF Function in Platyhelminths 106
Conclusion 107
References 108
Chapter 6 Neuropeptide Gene Familiesin Caenorhabditis elegans 113
Identification of Neuropeptide Genes in C. elegans 113
Expression of Neuropeptide Genes 120
Cleavage and Processing of Neuropeptides 136
Cleavage of Neuropeptide Precursors by Proprotein Convertases 136
Subsequent Cleavage of Neuropeptide Precursors by Carboxypeptidases 138
Neuropeptides Are Released from Dense Core Vesicles 139
Biochemical Isolation of Neuropeptides 140
Neuropeptide Function 140
The Insulin-Like Gene Family 141
The flp Family 142
The nlp Family 144
Behaviors Affected by Multiple Classes of Neuropeptides 144
Neuropeptide Receptors 144
Pharmacology of FLP Neuropeptides 146
Conclusion 147
References 147
Chapter 7 Control of Nematode Parasiteswith Agents Acting onNeuro-Musculature Systems:Lessons for Neuropeptide Ligand Discovery 153
The Existing Anti-Nematodal Drugs with Effects on Neuromuscular Systems 154
GABA Agonists 155
Nicotinic Agonists 155
Nicotinic Antagonists 156
Organophosphorous Compounds 156
Avermectins 157
Benzimidazoles 157
Latrotoxin Receptor Agonist 158
Glutamate Gated Cation Channels Agonists and Antagonists 158
Resistance Is Predicted 159
General Comments 159
Polygenic Resistance 159
Fitness 160
The Development of Resistance 161
Cross Resistance of Novel Neuropeptide Anthelmintic with Existing Anthelmintics 163
Broad Spectrum or Narrow Spectrum 163
Potential Problems Associated with Neuropeptide Receptors as Target Sites for Anthelmintics 164
High-Throughput Screens for Neuropeptide Ligands 164
Toxicity and Safety 165
Conclusion 166
References 166
Chapter 8 Neuropeptide Signaling in Insects 170
Introduction 170
Neuropeptides: Their Biosynthesis, Processing and Expression 171
Neuropeptides Families, GPCRs and Peptide Functions 172
Insect Neuropeptides as Potential Targets for Pest Management 175
Conclusion 176
Addendum 176
References 177
Chapter 9 Neuropeptide Physiology in Insects 181
Introduction 181
Neuropeptide Biosynthesis and Action 183
Potential Physiological Targets for Pest Control 190
Energy Metabolism 190
Muscle Contraction 191
Water Balance and Feeding Behaviour 193
Growth and Reproduction 194
Growth and Development 195
Future Developments 196
Targeting Transcription Factors 196
Inhibiting Gene Expression through RNA Interference 196
Crossing the Cuticle Barrier 197
Insect Immunity 198
Conclusion 199
References 199
Chapter 10 Neuropeptide Biology in Drosophila 207
Introduction: Drosophila as a Model to Study Neuropeptide Signaling 207
Bioinformatics 208
Neuropeptidomics 209
Deorphanization of Drosophila Neuropeptide GPCRs 213
Functional Role of Neuropeptides: Localization, Reverse Genetics and Bioassays 213
Localization 213
Reverse Genetics and Bioassays 217
Other Neuronal Molecules as Potential Targets for Insecticides 221
Conclusion 221
References 222
Chapter 11 Neuropeptide Receptorsas Possible Targets for Developmentof Insect Pest Control Agents 226
Introduction 226
Receptors Controlling Insect Development 227
Allatostatin Receptors 227
Leucine-Rich Repeat Containing G Protein-Coupled Receptors 230
Insulin Receptors 230
Diuretic Hormone Receptors as Regulators of Water and Salt Balances 231
AKH Receptors Are Involved in the Control of Energy Metabolism 232
Receptors with a Role in Behavior 232
Tachykinin Receptors 232
NPF/NPY Receptors 233
Receptors Controlling Ecdysis Behavior 234
Receptors Controlling Insect Reproduction 235
PK/PBAN Receptors 235
Conclusion and Future Prospects 235
Note Added in Proof 236
References 236
INDEX 242