Neglected Tropical Diseases

David Swinney, PhD, is the chief executive officer of the Institute for Rare and Neglected Diseases Drug Discovery (iRND3). Dr. Swinney has devoted the majority of his career to analyzing and implementing drug discovery strategies that will increase the chance of success. Michael Pollastri holds the chair of chemistry and chemical biology at Northeastern University in Boston. He came to NEU from Pfizer, where he worked for 10 years as a research chemist. His research focus is discovery of new therapeutics for neglected tropical diseases.

• A Personal Foreword xiiiPreface xvii1 Drug Discovery Strategies for Neglected Tropical Diseases: Repurposing Knowledge, Mechanisms and Therapeutics to Increase Discovery Efficiency 1David C. Swinney and Michael P. Pollastri1.1 Introduction 11.2 First-line Therapies for NTDs and Mechanisms of Action 11.3 Drug Discovery Efficiency 31.3.1 Drug Discovery Process 31.3.2 Drug Discovery Strategies 51.3.3 PDD versus TDD for NTDs 61.4 Critical Components for Successful Drug Discovery 71.4.1 Finding a Starting Point 71.4.2 Assays Robustness and Hit Selection Criteria 71.4.3 Optimization Processes 81.5 Repurposing Knowledge Mechanisms and Therapeutics 91.6 Summary 10References 10Part I Virus 152 Toward Antiviral Therapies for the Treatment of Zika Virus Infection: Lessons Learned from Dengue Virus 17Sarah K. Stevens, Paul C. Jordan, Andreas Jekle, and Jerome Deval2.1 Zika Virus: History and Epidemiology 172.2 Detection, Clinical Presentation, and Medical Need 202.3 ZIKV Replication Cycle 212.4 Lessons Learned from Dengue Antiviral Research 232.4.1 Host Targeting Agents 242.4.2 Direct Antiviral Agents 242.5 In Vitro Tools for Anti-ZIKV Drug Discovery 252.5.1 Cell-Based Assays 252.5.2 Biochemical Assays and Tools for Structure-Based Drug Design 262.5.2.1 The NS5 MTase and Polymerase 262.5.2.2 The NS2B–NS3 Protease 272.5.2.3 The NS3 Helicase 272.6 Animal Models for Evaluating In Vivo Efficacy 282.7 ZIKV NS5 RdRp and MTase Inhibitors 302.7.1 Ribavirin and T-705 (Favipiravir) 302.7.2 2′-C-Methylated Nucleosides 322.7.3 NITD008 332.7.4 BCX4430 332.7.5 MTase Inhibitors 332.8 NS3 Protease and Helicase Inhibitors 342.9 Other Classes of Small Molecules against ZIKV 362.10 Conclusions and Future Directions on ZIKV Inhibition 37References 373 Developing Therapeutics for Ebola Virus Disease: A Multifaceted Approach 49Michael K. Lo, Jessica R. Spengler, Bobbie Rae Erickson, and Christina F. Spiropoulou3.1 Overview of Ebola Virus Disease (EVD) 493.2 Ebola Virus Diagnostics: Challenges and Innovations 503.3 Ebola Virus Genome Structure, Components, and Replication Cycle 523.4 In vitro Toolbox: Cell-Based Assays 543.5 In Vivo Toolbox: Animal Models for Efficacy Testing 543.6 Therapeutic Strategies 573.6.1 Host-Directed Antivirals 573.6.1.1 S-Adenosyl-Homocysteine Hydrolase Inhibitors 573.6.1.2 Kinases and Phosphatases 603.6.1.3 Protein Folding and Processing 603.6.1.4 Non-Proteolytic Endosomal Targets 633.6.1.5 Priming Host Immune Responses 653.6.1.6 Other Host Targets 673.6.2 Direct-Acting Antivirals 673.6.2.1 Antibody-Based Therapeutics 673.6.2.2 Inhibitors of Viral Protein Interactions 693.6.2.3 Nucleic Acid Inhibitors 703.6.2.4 Nucleoside Analogs/Polymerase Inhibitors 713.7 Conclusions 74Acknowledgments 74References 74Part II Kinetoplastids 934 Designing Drugs to Target Trypanosoma cruzi, the Etiological Agent of Chagas Disease: When Chemistry needs Biology 95Martine Keenan and Eric Chatelain4.1 Introduction 954.2 Chagas Disease Overview 954.3 Toward Sterile Cure in a Chagas Disease Mouse Model: Which Way Forward? 964.3.1 Feeding the Chagas Disease Pipeline: Compound Selection and Identification of Potential Hits/Starting Points 984.3.2 Choosing the “Right” Starting Points 984.3.3 Using In Vitro Assays to Guide Structural Optimization 1014.3.4 Getting Compounds to the Site of Action 1034.3.5 Mechanism of Action: Is There a Need for Target Deconvolution before Starting a Lead Optimization Program? 1064.4 Conclusion 107Acknowledgments 108References 1095 Drug Discovery and Development for Human African Trypanosomiasis 115Andrew Spaulding, Mitchell F. Gallerstein, and Lori Ferrins5.1 Overview of Disease 1155.2 Etiology and Epidemiology 1155.3 Current Treatments 1195.3.1 Stage 1 Treatments 1195.3.2 Stage 2 Treatments 1225.4 Diagnostics 1235.5 Medicinal Chemistry 1255.6 Future Drug Candidates 1295.7 Conclusion 132References 1326 Discovery of Drugs for Leishmaniases: A Progress Report 139Baljinder Singh, Frederick S. Buckner, and Michael P. Pollastri6.1 Visceral Leishmaniasis (VL) 1396.1.1 Current Treatment Regimens for VL 1406.2 Cutaneous Leishmaniasis (CL) 1416.2.1 Current Treatment Regimens for CL 1426.3 Mucosal Leishmaniasis (ML) 1436.3.1 Current Treatment Regimens for ML 1436.4 Medicinal Chemistry 1446.4.1 Phenotypic Screening Approach Versus Target-Based Approach 1446.4.2 Phenotypic Screening Approaches 1446.4.3 Target-Based Approaches 1506.4.4 In Silico Computational Approaches 1526.5 Conclusion 153References 154Part III Helminths 1617 Onchocerciasis Drug Discovery 163Natalie A. Hawryluk and Ivan Scandale7.1 Introduction 1637.1.1 The Vector 1637.1.2 Life Cycle of O. volvulus 1647.2 Epidemiology 1657.3 Clinical Manifestation 1667.3.1 Skin Lesions 1667.3.2 Nodules 1667.3.3 Eye Lesions 1667.3.4 Nodding Syndrome 1677.4 Diagnostics 1687.4.1 Clinical Diagnosis 1687.4.2 Ultrasonography 1687.4.3 Mazzotti Test 1687.4.4 Parasitological Diagnosis 1687.4.5 Immunological Tests and PCR 1697.5 Current Therapies and Approaches 1697.5.1 Direct-Acting Approach 1697.5.1.1 Diethylcarbamazine 1707.5.1.2 Ivermectin 1707.5.1.3 Albendazole 1717.5.1.4 Suramin 1717.5.2 Antibacterial Approach 1717.5.2.1 Tetracycline Derivatives 1717.5.3 Nodulectomy 1727.6 Discovery Models 1727.6.1 Primary In Vitro Assays 1727.6.2 In Vivo Efficacy Models 1737.7 Medicinal Chemistry Approaches 1737.7.1 Benzimidazoles 1737.7.1.1 Flubendazole (FLBZ) 1737.7.1.2 UMF-078 1747.7.1.3 Boron-Derived Benzimidazoles 1757.7.2 Macrocyclic Lactones 1757.7.2.1 Milbemycins 1757.7.2.2 Cyclooctadepsipeptides 1767.7.2.3 Tylosins 1777.7.3 Natural Products 1787.7.3.1 Corallopyronin A 1787.7.4 Small Molecules 1807.7.4.1 Pyrazolopyridine 1807.8 Conclusion 180References 1808 Drug Discovery and Development for Schistosomiasis 187Conor R. Caffrey, Nelly El-Sakkary, Patrick Mäder, Reimar Krieg, Katja Becker, Martin Schlitzer, David H. Drewry, Jonathan L. Vennerstrom, and Christoph G. Grevelding8.1 Schistosomiasis: The Disease and the One Drug We Have for Treatment, Praziquantel 1878.2 Drug Discovery for Schistosomiasis: Strategies, Tools, Targets, and a Note on the Target Product Profile 1898.3 Drug Repurposing 1908.4 Structure-Based Drug Design 1958.5 Phenotypic Approaches 1968.6 Organometallics 1998.7 Natural Products 2008.8 Perspective on Schistosome Kinases as Potential Drug Targets 2028.9 Case Study 1: Biarylalkyl Carboxylic Acids (BACAs) as Antischistosomals 2068.10 Case Study 2: Arylmethylamino Steroids (AASs) as Antischistosomals 2128.11 Brief Summary of the Drug Development Pipeline 213Acknowledgments 215References 2159 Soil-transmitted Helminthiasis – Challenges with Discovery of Novel Anthelmintics 227Graham M. Kyne,Michael P. Curtis, Jennifer Keiser, and Debra J.Woods9.1 Current Therapies and Unmet Needs for Soil-transmitted Helminthiases (STHs) 2279.2 Anthelmintic Research and Development in Animal Health: Value Drivers 2299.3 Anthelmintic Discovery: State of the Art (2005–2017) 2329.3.1 New Molecules from the Patent Literature 2329.3.2 Medicinal Chemistry Approaches to New Molecules 2359.3.2.1 Intervet Multicyclics 2359.3.2.2 Vesicular Acetylcholine Transporter (VAChT) Inhibitors 2389.3.2.3 Cyclooctadepsipeptides 2429.4 Discussion 245Acknowledgment 245References 24510 Drug Discovery and Development for the Treatment of Echinococcosis, Caused by the Tapeworms Echinococcus granulosus and Echinococcus multilocularis 253Andrew Hemphill, Reto Rufener, Dominic Ritler, Luca Dick, and Britta Lundström-Stadelmann10.1 Echinococcus and Echinococcosis 25310.2 The Biological Features of E. granulosus and E. multilocularis: Similar, but Different 25410.3 Clinical Hallmarks, Diagnosis, and Prevention and Control of CE and AE 25510.4 Currently Applied Benzimidazole Treatments for CE and AE 25710.5 In vitro and in vivo Models to Study Drug Efficacy and Drug Targets in Echinococcus 26110.6 Drug Repurposing as the Only Strategy for Discovering Novel Compounds to Treat Echinococcosis 26410.6.1 Drug Repurposing for the Discovery of Novel Compounds to Treat AE 26510.6.1.1 Anti-Infective Agents 26510.6.1.2 Anticancer Drugs 26910.6.2 Drug Repurposing for the Discovery of Novel Compounds to Treat CE 27210.7 Where to Go from Here? 274Acknowledgments 276References 27611 New Insights into the Treatment of Foodborne Trematode Infections 289Rafael Toledo, Alba Cortés, Maria Álvarez-Izquierdo, CarlaMuñoz-Antoli, and J. Guillermo Esteban11.1 Introduction 28911.2 Morphology and Biology of Foodborne Trematodes 29011.3 Epidemiology and Global Impact 29211.4 Major Foodborne Trematodes 29311.4.1 Liver Foodborne Trematode Infections 29311.4.1.1 Clonorchiasis and Opisthorchiasis 29311.4.1.2 Fascioliasis 29411.4.2 Lung Foodborne Trematode Infections (Paragonimiasis) 29411.4.3 Intestinal Foodborne Trematode Infections 29511.4.3.1 Diplostomiasis 29511.4.3.2 Echinostomiasis 29511.4.3.3 Fasciolopsiasis 29611.4.3.4 Gymnophalloidiasis 29611.4.3.5 Heterophyasis 29611.5 Current Drugs Used Against Foodborne Intestinal Trematodes 29611.5.1 Praziquantel 29611.5.2 Triclabendazole 29911.5.3 Tribendimidine 30111.5.4 Other Drugs 30311.6 Natural Products and Drug Discovery against Foodborne Trematodes 304Acknowledgments 312References 312Part IV Bacteria 32512 Buruli Ulcer 327Nicole Scherr and Gerd Pluschke12.1 Etiology and Epidemiology 32712.2 Current Treatments 32812.3 Unmet Needs 32912.4 Diagnostics 32912.5 Discovery Models 33012.5.1 In Vitro Test Formats 33012.5.2 In Vivo Testing 33112.6 Testing of Compounds for Activity Against M. ulcerans 33212.6.1 Preclinical Profiling of Currently Recommended Antibiotic Treatment Regimens for BU 33212.6.2 Repurposing of Tuberculosis Drug Candidates 33212.6.3 Compound Screening 33612.7 Clinical Studies 33612.8 Future Directions and Opportunities 338References 33913 Drug Discovery and Development for Leprosy 349Carlos Franco-Paredes13.1 Unmet Medical Needs in the Treatment of Leprosy 34913.2 Current Therapies for Leprosy 35013.2.1 Direct-Acting Antibacterial Therapy 35013.3 Innovative Therapeutic Strategies 35513.3.1 Host-Directed Therapy 35513.4 Conclusions 358References 358Index 363