Neglected Tropical Diseases Drug Discovery and Development

A Personal Foreword xiii

Preface xvii

1 Drug Discovery Strategies for Neglected Tropical Diseases: Repurposing Knowledge, Mechanisms and Therapeutics to Increase Discovery Efficiency 1
David C. Swinney and Michael P. Pollastri

1.1 Introduction 1

1.2 First-line Therapies for NTDs and Mechanisms of Action 1

1.3 Drug Discovery Efficiency 3

1.3.1 Drug Discovery Process 3

1.3.2 Drug Discovery Strategies 5

1.3.3 PDD versus TDD for NTDs 6

1.4 Critical Components for Successful Drug Discovery 7

1.4.1 Finding a Starting Point 7

1.4.2 Assays Robustness and Hit Selection Criteria 7

1.4.3 Optimization Processes 8

1.5 Repurposing Knowledge Mechanisms and Therapeutics 9

1.6 Summary 10

References 10

Part I Virus 15

2 Toward Antiviral Therapies for the Treatment of Zika Virus Infection: Lessons Learned from Dengue Virus 17
Sarah K. Stevens, Paul C. Jordan, Andreas Jekle, and Jerome Deval

2.1 Zika Virus: History and Epidemiology 17

2.2 Detection, Clinical Presentation, and Medical Need 20

2.3 ZIKV Replication Cycle 21

2.4 Lessons Learned from Dengue Antiviral Research 23

2.4.1 Host Targeting Agents 24

2.4.2 Direct Antiviral Agents 24

2.5 In Vitro Tools for Anti-ZIKV Drug Discovery 25

2.5.1 Cell-Based Assays 25

2.5.2 Biochemical Assays and Tools for Structure-Based Drug Design 26

2.5.2.1 The NS5 MTase and Polymerase 26

2.5.2.2 The NS2B–NS3 Protease 27

2.5.2.3 The NS3 Helicase 27

2.6 Animal Models for Evaluating In Vivo Efficacy 28

2.7 ZIKV NS5 RdRp and MTase Inhibitors 30

2.7.1 Ribavirin and T-705 (Favipiravir) 30

2.7.2 2′-C-Methylated Nucleosides 32

2.7.3 NITD008 33

2.7.4 BCX4430 33

2.7.5 MTase Inhibitors 33

2.8 NS3 Protease and Helicase Inhibitors 34

2.9 Other Classes of Small Molecules against ZIKV 36

2.10 Conclusions and Future Directions on ZIKV Inhibition 37

References 37

3 Developing Therapeutics for Ebola Virus Disease: A Multifaceted Approach 49
Michael K. Lo, Jessica R. Spengler, Bobbie Rae Erickson, and Christina F. Spiropoulou

3.1 Overview of Ebola Virus Disease (EVD) 49

3.2 Ebola Virus Diagnostics: Challenges and Innovations 50

3.3 Ebola Virus Genome Structure, Components, and Replication Cycle 52

3.4 In vitro Toolbox: Cell-Based Assays 54

3.5 In Vivo Toolbox: Animal Models for Efficacy Testing 54

3.6 Therapeutic Strategies 57

3.6.1 Host-Directed Antivirals 57

3.6.1.1 S-Adenosyl-Homocysteine Hydrolase Inhibitors 57

3.6.1.2 Kinases and Phosphatases 60

3.6.1.3 Protein Folding and Processing 60

3.6.1.4 Non-Proteolytic Endosomal Targets 63

3.6.1.5 Priming Host Immune Responses 65

3.6.1.6 Other Host Targets 67

3.6.2 Direct-Acting Antivirals 67

3.6.2.1 Antibody-Based Therapeutics 67

3.6.2.2 Inhibitors of Viral Protein Interactions 69

3.6.2.3 Nucleic Acid Inhibitors 70

3.6.2.4 Nucleoside Analogs/Polymerase Inhibitors 71

3.7 Conclusions 74

Acknowledgments 74

References 74

Part II Kinetoplastids 93

4 Designing Drugs to Target Trypanosoma cruzi, the Etiological Agent of Chagas Disease: When Chemistry needs Biology 95
Martine Keenan and Eric Chatelain

4.1 Introduction 95

4.2 Chagas Disease Overview 95

4.3 Toward Sterile Cure in a Chagas Disease Mouse Model: Which Way Forward? 96

4.3.1 Feeding the Chagas Disease Pipeline: Compound Selection and Identification of Potential Hits/Starting Points 98

4.3.2 Choosing the “Right” Starting Points 98

4.3.3 Using In Vitro Assays to Guide Structural Optimization 101

4.3.4 Getting Compounds to the Site of Action 103

4.3.5 Mechanism of Action: Is There a Need for Target Deconvolution before Starting a Lead Optimization Program? 106

4.4 Conclusion 107

Acknowledgments 108

References 109

5 Drug Discovery and Development for Human African Trypanosomiasis 115
Andrew Spaulding, Mitchell F. Gallerstein, and Lori Ferrins

5.1 Overview of Disease 115

5.2 Etiology and Epidemiology 115

5.3 Current Treatments 119

5.3.1 Stage 1 Treatments 119

5.3.2 Stage 2 Treatments 122

5.4 Diagnostics 123

5.5 Medicinal Chemistry 125

5.6 Future Drug Candidates 129

5.7 Conclusion 132

References 132

6 Discovery of Drugs for Leishmaniases: A Progress Report 139
Baljinder Singh, Frederick S. Buckner, and Michael P. Pollastri

6.1 Visceral Leishmaniasis (VL) 139

6.1.1 Current Treatment Regimens for VL 140

6.2 Cutaneous Leishmaniasis (CL) 141

6.2.1 Current Treatment Regimens for CL 142

6.3 Mucosal Leishmaniasis (ML) 143

6.3.1 Current Treatment Regimens for ML 143

6.4 Medicinal Chemistry 144

6.4.1 Phenotypic Screening Approach Versus Target-Based Approach 144

6.4.2 Phenotypic Screening Approaches 144

6.4.3 Target-Based Approaches 150

6.4.4 In Silico Computational Approaches 152

6.5 Conclusion 153

References 154

Part III Helminths 161

7 Onchocerciasis Drug Discovery 163
Natalie A. Hawryluk and Ivan Scandale

7.1 Introduction 163

7.1.1 The Vector 163

7.1.2 Life Cycle of O. volvulus 164

7.2 Epidemiology 165

7.3 Clinical Manifestation 166

7.3.1 Skin Lesions 166

7.3.2 Nodules 166

7.3.3 Eye Lesions 166

7.3.4 Nodding Syndrome 167

7.4 Diagnostics 168

7.4.1 Clinical Diagnosis 168

7.4.2 Ultrasonography 168

7.4.3 Mazzotti Test 168

7.4.4 Parasitological Diagnosis 168

7.4.5 Immunological Tests and PCR 169

7.5 Current Therapies and Approaches 169

7.5.1 Direct-Acting Approach 169

7.5.1.1 Diethylcarbamazine 170

7.5.1.2 Ivermectin 170

7.5.1.3 Albendazole 171

7.5.1.4 Suramin 171

7.5.2 Antibacterial Approach 171

7.5.2.1 Tetracycline Derivatives 171

7.5.3 Nodulectomy 172

7.6 Discovery Models 172

7.6.1 Primary In Vitro Assays 172

7.6.2 In Vivo Efficacy Models 173

7.7 Medicinal Chemistry Approaches 173

7.7.1 Benzimidazoles 173

7.7.1.1 Flubendazole (FLBZ) 173

7.7.1.2 UMF-078 174

7.7.1.3 Boron-Derived Benzimidazoles 175

7.7.2 Macrocyclic Lactones 175

7.7.2.1 Milbemycins 175

7.7.2.2 Cyclooctadepsipeptides 176

7.7.2.3 Tylosins 177

7.7.3 Natural Products 178

7.7.3.1 Corallopyronin A 178

7.7.4 Small Molecules 180

7.7.4.1 Pyrazolopyridine 180

7.8 Conclusion 180

References 180

8 Drug Discovery and Development for Schistosomiasis 187
Conor R. Caffrey, Nelly El-Sakkary, Patrick Mäder, Reimar Krieg, Katja Becker, Martin Schlitzer, David H. Drewry, Jonathan L. Vennerstrom, and Christoph G. Grevelding

8.1 Schistosomiasis: The Disease and the One Drug We Have for Treatment, Praziquantel 187

8.2 Drug Discovery for Schistosomiasis: Strategies, Tools, Targets, and a Note on the Target Product Profile 189

8.3 Drug Repurposing 190

8.4 Structure-Based Drug Design 195

8.5 Phenotypic Approaches 196

8.6 Organometallics 199

8.7 Natural Products 200

8.8 Perspective on Schistosome Kinases as Potential Drug Targets 202

8.9 Case Study 1: Biarylalkyl Carboxylic Acids (BACAs) as Antischistosomals 206

8.10 Case Study 2: Arylmethylamino Steroids (AASs) as Antischistosomals 212

8.11 Brief Summary of the Drug Development Pipeline 213

Acknowledgments 215

References 215

9 Soil-transmitted Helminthiasis – Challenges with Discovery of Novel Anthelmintics 227
Graham M. Kyne,Michael P. Curtis, Jennifer Keiser, and Debra J.Woods

9.1 Current Therapies and Unmet Needs for Soil-transmitted Helminthiases (STHs) 227

9.2 Anthelmintic Research and Development in Animal Health: Value Drivers 229

9.3 Anthelmintic Discovery: State of the Art (2005–2017) 232

9.3.1 New Molecules from the Patent Literature 232

9.3.2 Medicinal Chemistry Approaches to New Molecules 235

9.3.2.1 Intervet Multicyclics 235

9.3.2.2 Vesicular Acetylcholine Transporter (VAChT) Inhibitors 238

9.3.2.3 Cyclooctadepsipeptides 242

9.4 Discussion 245

Acknowledgment 245

References 245

10 Drug Discovery and Development for the Treatment of Echinococcosis, Caused by the Tapeworms Echinococcus granulosus and Echinococcus multilocularis 253
Andrew Hemphill, Reto Rufener, Dominic Ritler, Luca Dick, and Britta Lundström-Stadelmann

10.1 Echinococcus and Echinococcosis 253

10.2 The Biological Features of E. granulosus and E. multilocularis: Similar, but Different 254

10.3 Clinical Hallmarks, Diagnosis, and Prevention and Control of CE and AE 255

10.4 Currently Applied Benzimidazole Treatments for CE and AE 257

10.5 In vitro and in vivo Models to Study Drug Efficacy and Drug Targets in Echinococcus 261

10.6 Drug Repurposing as the Only Strategy for Discovering Novel Compounds to Treat Echinococcosis 264

10.6.1 Drug Repurposing for the Discovery of Novel Compounds to Treat AE 265

10.6.1.1 Anti-Infective Agents 265

10.6.1.2 Anticancer Drugs 269

10.6.2 Drug Repurposing for the Discovery of Novel Compounds to Treat CE 272

10.7 Where to Go from Here? 274

Acknowledgments 276

References 276

11 New Insights into the Treatment of Foodborne Trematode Infections 289
Rafael Toledo, Alba Cortés, Maria Álvarez-Izquierdo, CarlaMuñoz-Antoli, and J. Guillermo Esteban

11.1 Introduction 289

11.2 Morphology and Biology of Foodborne Trematodes 290

11.3 Epidemiology and Global Impact 292

11.4 Major Foodborne Trematodes 293

11.4.1 Liver Foodborne Trematode Infections 293

11.4.1.1 Clonorchiasis and Opisthorchiasis 293

11.4.1.2 Fascioliasis 294

11.4.2 Lung Foodborne Trematode Infections (Paragonimiasis) 294

11.4.3 Intestinal Foodborne Trematode Infections 295

11.4.3.1 Diplostomiasis 295

11.4.3.2 Echinostomiasis 295

11.4.3.3 Fasciolopsiasis 296

11.4.3.4 Gymnophalloidiasis 296

11.4.3.5 Heterophyasis 296

11.5 Current Drugs Used Against Foodborne Intestinal Trematodes 296

11.5.1 Praziquantel 296

11.5.2 Triclabendazole 299

11.5.3 Tribendimidine 301

11.5.4 Other Drugs 303

11.6 Natural Products and Drug Discovery against Foodborne Trematodes 304

Acknowledgments 312

References 312

Part IV Bacteria 325

12 Buruli Ulcer 327
Nicole Scherr and Gerd Pluschke

12.1 Etiology and Epidemiology 327

12.2 Current Treatments 328

12.3 Unmet Needs 329

12.4 Diagnostics 329

12.5 Discovery Models 330

12.5.1 In Vitro Test Formats 330

12.5.2 In Vivo Testing 331

12.6 Testing of Compounds for Activity Against M. ulcerans 332

12.6.1 Preclinical Profiling of Currently Recommended Antibiotic Treatment Regimens for BU 332

12.6.2 Repurposing of Tuberculosis Drug Candidates 332

12.6.3 Compound Screening 336

12.7 Clinical Studies 336

12.8 Future Directions and Opportunities 338

References 339

13 Drug Discovery and Development for Leprosy 349
Carlos Franco-Paredes

13.1 Unmet Medical Needs in the Treatment of Leprosy 349

13.2 Current Therapies for Leprosy 350

13.2.1 Direct-Acting Antibacterial Therapy 350

13.3 Innovative Therapeutic Strategies 355

13.3.1 Host-Directed Therapy 355

13.4 Conclusions 358

References 358

Index 363

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