New antiviral drugs are urgently needed. Recent outbreaks caused by viruses with great epidemiological impact such as Zika, or extraordinary virulence such as Ebola, Nipah, Lassa, Crimean-Congo haemorrhagic fever highlight the current lack of clinically proven vaccines and treatments for these potentially catastrophic agents. Antiviral Discovery for Highly Pathogenic Emerging Viruses comprehensively outlines the state of the art in antiviral drug discovery including identification of targets, screening strategies and the current pipeline of antiviral candidates including regulatory issues. The book also addresses the challenges faced in proceeding from pre-clinical studies to animal models and clinical trials with these highly pathogenic agents.
Ideal for drug discovery scientists and medicinal chemists with an interest in antiviral drug discovery and development, this book provides a complete overview of the latest progress in the field, recent advances and the challenges that remain in developing these highly pathogenic agents. Illustrated throughout with case studies this book is a valuable resource in this complex and multidisciplinary field.
Author(s): César Muñoz-Fontela, Rafael Delgado
Series: Drug Discovery Series
Publisher: Royal Society of Chemistry
Year: 2021
Language: English
Pages: 308
City: London
Cover
Preface
Contents
1 Overview of Antiviral Drug Discovery and Development: Viral Versus Host Targets
1.1 Introduction
1.2 Viral Targets for Antiviral Drugs
1.2.1 Viral Polymerases
1.2.1.1 HIV Reverse Transcriptase
1.2.1.2 HBV Polymerase
1.2.1.3 HCV NS5B Polymerase
1.2.1.4 HCMV Polymerase
1.2.1.5 Influenza Polymerase
1.2.1.6 HSV Polymerase
1.2.1.7 RSV Polymerase
1.2.1.8 VZV Polymerase
1.2.2 Viral Integrase
1.2.2.1 HIV Integrase
1.2.3 Viral Proteases
1.2.3.1 HIV Protease
1.2.3.2 HCV NS3/4A Protease
1.2.4 Structural Proteins
1.2.4.1 HIV gp120 and gp41
1.2.4.2 Influenza Hemagglutinin and Neuraminidase
1.2.4.3 RSV Fusion Glycoprotein
1.2.4.4 Smallpox VP37 Envelope Wrapping Protein
1.2.5 Accessory Proteins
1.2.5.1 HCV NS5A Phosphoprotein
1.2.5.2 Influenza Matrix Protein 2
1.2.5.3 HCMV Terminase
1.3 Host Targets for Antiviral Drugs
1.3.1 Host Chemokine Receptors
1.3.1.1 CCR5 and CXCR4
1.3.2 Host Glycoproteins
1.3.2.1 CD4
1.3.2.2 NTCP
1.3.2.3 LAMP1
1.3.3 Host Kinases
1.3.3.1 VCP/p97
1.3.3.2 AMPK
1.3.3.3 AAK1 and GAK
1.3.4 Other Host Proteins
1.3.4.1 BRD4
1.3.4.2 RACK1
1.3.4.3 Hsp27
1.4 Viral
Host Targets
1.4.1 Strengths and Weaknesses of Viral Targets
1.4.2 Strengths and Weaknesses of Host Targets
1.5 Conclusion
Conflicts of Interest
Acknowledgements
References
2 Advances in Prophylaxis and Therapy of Arenavirus Hemorrhagic Fevers
2.1 Introduction
2.2 Therapeutic Approaches Against Arenaviruses
2.2.1 Immunotherapeutic Approaches
2.2.2 Antivirals
2.3 Prophylaxis of Arenavirus Infections
2.4 Concluding Remarks
References
3 Vaccines and Antiviral Developments for SARS-CoV-2 in the Emergence of the COVID-19 Pandemicy
3.1 Origin of the COVID-19 Pandemic Produced by SARS-CoV-2
3.2 Coronavirus and Zoonotic Risk
3.3 Human Coronaviruses
3.4 Structure and Genomic Organization of SARS-CoV-2
3.5 Mechanism of Infection and Pathogenesis of SARS-CoV-2
3.6 Diagnosis and Kinetics of Respiratory Infection by SARS-CoV-2
3.7 The Immune Response to SARS-CoV-2
3.8 Vaccine Development for COVID-19
3.9 Monoclonal Antibodies Against SARS-CoV-2 for COVID-19 Treatment
3.10 Antiviral Development for SARS-CoV-2/COVID-19
References
4 Small-molecule and Synthetically Derived Antivirals for Ebola Virus and Other Filovirusesy
4.1 Introduction
4.2 Broad-spectrum Nucleobase, Nucleoside, and Nucleotide Antivirals
4.2.1 Remdesivir
4.2.2 Galidesivir
4.2.3 Favipiravir
4.2.4 Other Small Molecules
4.2.4.1 Brincidofovir
4.2.4.2 Amodiaquine
4.2.4.3 3-Deazaneplanocin A
4.2.4.4 Niemann–Pick C1 Inhibitors of Viral Entry
4.3 Emerging Small-molecule and Antiviral Concepts
4.3.1 Kinase Inhibitors
4.3.2 Compounds with Unknown Mechanisms of Action
4.3.3 Alpha-glucosidase Inhibitors
4.3.4 Repurposed Drugs
4.3.5 β-D-N4-Hydroxycytidine
4.3.6 Immunomodulators
4.4 Nucleic Acid-based Antivirals
4.4.1 Antisense Therapeutics
4.4.1.1 AVI-7537 and AVI-7288
4.4.1.2 Host Immune-targeted Peptide-conjugated PMO
4.5 Small Interfering RNAs
4.6 Conclusions
Acknowledgements
References
5 Antiviral Strategies for Ebola Virus and Other Filoviruses: Antibodies
5.1 Introduction
5.2 Introduction to Filoviruses
5.2.1 Role of Abs in Natural Infection
5.2.2 Role of Abs in Understanding Outbreaks
5.2.3 Antibody-dependent Enhancement
5.3 The Role of Abs Generated by Experimental Vaccines
5.4 Development of Antibodies for Filovirus Medical Countermeasures
5.4.1 EBOV mAb Countermeasures
5.4.2 Non-EBOV Filoviruses and pan-Ebolavirus mAbs in NHPs
5.4.3 Clinical Evaluation of Passive Immunization during the 2013–2016 West Africa Outbreak and the 2018–2020 DRC Outbreak
5.4.4 Non-recombinant mAb Alternative Passive Immunization Strategies
5.5 Conclusion
Acknowledgements
References
6 Vaccine Development in the Midst of Ebolavirus Disease Outbreaks
6.1 Introduction
6.2 Regulatory Considerations for the Development of an
6.2 Regulatory Considerations for the Developmentof an Ebolavirus Vaccine
6.2.1 Regulatory Strategy
6.2.2 Requirements for Licensure
6.2.2.1 Manufacturing Requirements
6.2.2.2 Non-clinical Safety and Efficacy Requirements
6.2.2.3 Clinical Safety and Efficacy Requirements
6.2.2.4 Marketing Authorization Application
6.2.3 Importance of Interactions with Regulators and Use of Expedited Pathways
6.2.3.1 Prior to Filing
6.2.3.2 At Filing
6.2.4 Access to Vaccine Prior to Licensure
6.3 Ebolavirus Vaccine Manufacturing
6.3.1 Manufacturing History
6.3.2 Considerations for Manufacturing Process Development
6.3.3 Considerations for Analytical Test Method Development
6.3.4 Production Facility Design
6.3.5 Validation of the Manufacturing Process and Analytical Test Methods
6.3.6 Vaccine Supply
6.4 Non-clinical Immunogenicity and Efficacy Overview
6.4.1 Animal Models for Ebolavirus Vaccine Immunogenicity and Efficacy
6.4.2 Role of NHP Studies in Ebolavirus Vaccine Licensure
6.4.3 Immunoassay Development for NHP Studies
6.5 Non-clinical Safety Overview
6.5.1 Neurovirulence Assessment
6.5.2 Repeat-dose Non-clinical Toxicology Studies
6.5.3 Developmental and Reproductive Toxicity
6.5.4 Biodistribution
6.6 Clinical Development Program
6.6.1 The Collaborative Partnership
6.6.2 Clinical Trials Assessing Safety, Immunogenicity, and Efficacy
6.6.3 Manufacturing Lot Consistency
6.6.4 Overall Assessment of Safety
6.6.5 Overall Assessment of Immunogenicity
6.6.6 Response to Ongoing Outbreaks
6.7 Summary
Conflicts of Interest
List of Abbreviations
Acknowledgements
References
7 Remdesivir: Investigational Antiviral Drug with Activity Against Ebola and Other Emerging and Neglected Viruses
7.1 Major Viral Outbreak Threats on the List of WHO High-priority Diseases
7.2 Remdesivir and Its Mechanism of Action
7.3 Broad-spectrum In Vitro Antiviral Activity
of Remdesivir
7.4 In Vivo Efficacy of Remdesivir in Animal Models
7.4.1 Ebola Virus
7.4.1.1 Efficacy of Remdesivir Treatment Against Ebola Virus Kikwit/1995 in Rhesus Monkeys
7.4.1.2 Efficacy of Remdesivir Treatment Against Ebola Virus Makona/2014 in Rhesus Monkeys
7.4.2 Marburg Virus
7.4.2.1 Efficacy of Delayed Remdesivir Treatment Against Marburg Virus Angola/2005 in Cynomolgus Monkeys
7.4.3 MERS Coronavirus
7.4.3.1 Prophylactic and Therapeutic Efficacy of Remdesivir Treatment Against MERS Coronavirus Infection in Mice
7.4.3.2 Prophylactic Efficacy of Remdesivir Treatment Against MERS Coronavirus Infection in Rhesus Monkeys
7.4.4 SARS Coronavirus
7.4.4.1 Prophylactic and Therapeutic Efficacy of Remdesivir Treatment Against SARS Coronavirus Infection in Mice
7.4.5 Nipah Virus
7.4.5.1 Therapeutic Efficacy of Remdesivir Treatment Against Nipah Virus Infection in African Green Monkeys
7.4.6 Remdesivir has a High Barrier to Resistance Emergence
7.5 Remdesivir Drug Products
7.6 Use of Remdesivir in Humans
7.7 Summary
Abbreviations
References
8 Therapeutics Against Nipah and Hendra Virus
8.1 Introduction
8.1.1 Henipaviruses
8.1.2 Hendra and Nipah Virus Outbreaks
8.1.3 Clinical Disease
8.1.4 Henipavirus Biology
8.2 Animal Models of Henipaviral Disease
8.2.1 Syrian Hamster Model
8.2.2 Ferret Model
8.2.3 African Green Monkey Model
8.3 Development of Therapeutics – In Vitro
Screening of Compounds
8.4 Henipavirus Therapeutics
8.4.1 Virus-inactivating Compounds
8.4.2 Entry/Fusion Inhibitors
8.4.2.1 Heptad-repeat Peptides
8.4.2.2 Neutralizing Monoclonal Antibodies
8.4.2.3 Other Entry/Fusion Inhibitors
8.4.3 Inhibition of RNA Replication
8.4.3.1 Nucleoside Analogs
8.4.3.2 Small Interfering RNA
8.4.4 Host Cell Targets
8.4.4.1 Cathepsin L Cleavage
8.4.4.2 Other Host Cell Targets
8.5 Discussion
Acknowledgements
References
9 Glycomimetics as Promising Inhibitors of Ebola Virus, Flavivirus and HIV Infections
9.1 Introduction
9.1.1 Glycans and C-type Lectin Receptors: A Major Interface for Sensing Friends or Foes
9.1.2 Viral Diversion of C-type Lectin Receptors
9.1.3 Designing Drugs Targeting CLRs for Viral Entry Inhibition: Challenges and Bottlenecks
9.2 Monovalent Ligands: The Role of Glycomimetics
9.3 Carbohydrate Multivalent Ligands as Pathogen Inhibitors
9.3.1 Dendron and Dendrimer Scaffolds
9.3.2 Carbon Nanoform Scaffolds
9.3.3 Metallic Nanoparticle Scaffolds
9.3.4 Miscellaneous Scaffolds
9.4 Conclusions
Acknowledgements
References
10 Repurposing Approved Drugs to Block Highly Pathogenic Emerging Viruses
10.1 Introduction to Antiviral Drug Repurposing
10.2 Strategies for the Identification of Approved Drugs with Repurposing Potential as Antivirals
10.3 Antiviral Drug Repurposing for Highly Pathogenic Emerging Viruses
10.3.1 Arenaviruses
10.3.2 Ebola Virus and Other Filoviruses
10.3.3 Zika Virus and West Nile Virus
10.3.4 Highly Pathogenic Coronaviruses
10.3.5 Nipah and Hendra Virus
10.3.6 Influenza Viruses
10.4 Future Perspectives
Abbreviations
Acknowledgements
References
11 Receptors on Primary Phagocytes as Therapeutic Targets Against Highly Pathogenic Emerging Viruses
11.1 Introduction
11.2 Viral Entry into Myeloid Phagocytes
11.3 Glycoprotein-dependent Host Attachment Factors
11.4 Glycoprotein-independent Host Attachment Factors
11.5 Post-attachment Factors Required for Viral Infection
11.6 Therapeutic Agents to Block Viral Entry into Myeloid Phagocytes
11.7 Concluding Remarks
Author Contribution
Competing Interest
Acknowledgements
References
Subject Index
