Neglected Tropical Diseases

A drug discovery reference to the crippling tropical diseases that affect more than 1 billion people.

Neglected Tropical Diseases is the first book of its kind to offer a guide that follows the World Health Organization's list of neglected tropical diseases. The authors - all are experts on the topic - address the development of effective treatments for 12 crippling infectious diseases that affect almost 20% of the world's popluation.

The book includes information on the common approaches and the most important factors that lead to the development of new drugs for treating tropical diseases. Individual chapters review 12 neglected tropical diseases that are grouped by infectious agent, from viruses to bacteria to eukaryotic parasites. For each of these diseases, the book explains the unmet medical need and explores the current and potential drug discovery strategies. The book also includes information on potential drug compounds derived from natural products. This important book:

• Ties together information from different sources for developing novel treatsments forneglected tropical diseases
• Is aligned with WHO's initiative to eradicate tropical diseases
• Outlines current and potential drugs for treating tropical diseases
• Provides a standard reference for the entire field

Written for medicinal chemists, pharmaceutical chemists, pharmaceutical industry, virologists, parasitologists, and specialists on tropics medicine, Neglected Tropical Diseases offers an essential guide and a systematic reference for the development of successful treatments for 12 crippling infectious diseases.

Auteur
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.

Contenu

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 NS2BNS3 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 Assay...