New Drug Development for Known and Emerging Viruses

Cover
Series Page
Title Page
Copyright Page
Contents
Preface
In Memoriam: Farah Elawar
Introduction
References
Chapter 1 HIV—Disease Overview, Targets for Therapy and Open Issues
1.1 HIV—Disease Overview
1.2 Targets for Antiretroviral Therapy
1.3 Currently Open Issues in HIV/AIDS Research
References
Chapter 2 Curing Hepatitis C with Direct-Acting Antiviral Therapy
2.1 Introduction
2.2 Tools to Enable Drug Discovery
2.3 Drug Discovery Targets
2.4 NS5B Polymerase Inhibitors
2.4.1 Nucleoside and Nucleotide Inhibitors of NS5B Polymerase
2.4.2 Non-nucleoside NS5B Inhibitors
2.5 HCV NS3/4A Protease Inhibitors
2.5.1 HCV NS3/4A Protease Acyclic Reversible Inhibitors
2.5.2 HCV NS3/4A Protease Acyclic Covalent Binding Inhibitors
2.5.3 HCV NS3/4A Protease Macrocyclic Reversible Inhibitors
2.5.4 HCV NS3/4 Protease P2–P4 Macrocyclic Inhibitors
2.6 HCV NS5A Inhibitors
2.7 The Evolution of DAA Combination Therapies
2.8 Conclusion
Acknowledgment
References
Chapter 3 Antiviral Drugs Against Influenza Virus
3.1 The Influenza Virus
3.2 The Pathogenesis of Influenza
3.3 Influenza Drugs and Targets
3.4 Adamantanes and Derivatives
3.5 Neuraminidase Inhibitors
3.5.1 Oseltamivir
3.5.2 Zanamivir
3.5.3 Peramivir
3.5.4 Laninamivir
3.5.5 Summary
3.6 Polymerase-Inhibitors
3.6.1 Baloxavir Marboxil (BAM)
3.6.2 Favipiravir
3.6.3 Pimodivir
3.6.4 Summary
3.7 Monoclonal Antibodies
3.7.1 MHAA4549A
3.7.2 MEDI8852
3.7.3 VIS410
3.7.4 Summary
3.8 Host-Targeting Candidates
3.8.1 DAS181
3.8.2 Nitazoxanide
3.8.3 LASAG
3.8.4 Summary
References
Chapter 4 Respiratory Syncytial Virus Immunoreactivity, Vaccine Development, and Therapeutics
4.1 Introduction
4.1.1 The Burden of RSV Infection on Human Health
4.1.2 RSV Transmission
4.1.3 The Current Therapeutic Options and Opportunity for the Development of Treatments for RSV Infection
4.1.4 The Unique Challenge of RSV Vaccine Development
4.1.5 The Virus and the Replication Cycle
4.1.6 The Nucleoprotein–RNA Complex
4.1.7 The L Polymerase Protein
4.1.8 The P Phosphoprotein
4.1.9 The M2-1 Protein
4.1.10 The RSV-G Glycoprotein
4.1.11 The RSV-F Fusion Glycoprotein
4.1.12 The RSV-SH Glycoprotein
4.1.13 Antigenic Variation of RSV Surface Glycoproteins
4.1.14 Adaptation of RSV in the Community by Emergent High Titer Clades
4.2 RSV Longevity, Immune Evasion, and the Role of IgA
4.2.1 Evasion or Suppression of Immune Memory
4.3 The Impact of Immunoprophylaxis on the Health Burden of Respiratory Syncytial Virus
4.4 Distinct RSV Symptoms
4.4.1 Wheeze
4.4.2 The Effect of Immunoprophylaxis on the Development of Asthma
4.4.3 Epidemiology and Clinical Aspects of Adult RSV Disease
4.5 History of RSV and Vaccine Development
4.5.1 The Tragic History of RSV Vaccine Development in the First Failed RSV Vaccine Trials of the 1960s
4.6 New Developments in RSV Vaccine Development
4.6.1 Conformational Breathing of RSV-F Affects Neutralization Sensitivity
4.6.2 Measles Versus RSV Vaccine Development
4.6.3 The Lack of Immunogenicity, Immune Evasion, or Immune Suppression
4.6.4 Recent RSV Vaccines
4.6.5 A Resurgence in Attenuated Replication-Competent Vaccines
4.6.5.1 Mechanisms of Protection from RSV that Require Attention in Vaccine Development
4.7 Antivirals and Therapeutic Antibodies
4.7.1 Immunoprophylaxis
4.7.2 RSV-IGIV
4.7.3 Palivizumab
4.8 Therapeutics for Treating Active RSV Infections (Table 4.1)
4.8.1 Immunotherapy under Clinical Development
4.9 Drug Targets
4.9.1 Novel Antivirals Undergoing Clinical Development
4.9.2 Other Investigational Treatments and Broad-Spectrum Antivirals
4.10 Conclusions
References
Chapter 5 Herpes Simplex Viruses
5.1 Introduction
5.2 Overview of the Viral Replication Cycle
5.3 Treatment of HSV Infections
5.4 Approved Anti-HSV Drugs
5.4.1 5-Substituted 2-Deoxyuridine Analogues
5.4.2 Vidarabine
5.4.3 Acyclic Guanosine Analogues
5.4.4 Foscarnet
5.4.5 Docosanol
5.5 Anti-HSV Drugs in Advanced Development or Recently Entering the Market
5.5.1 Helicase–Primase Inhibitors
5.5.2 Monoclonal Antibodies
5.5.3 Therapeutic Vaccines
5.5.4 Immunomodulators
5.6 HSV Resistance to Antiviral Drugs
5.6.1 Epidemiology and Manifestation
5.6.2 Resistance Mechanisms
5.6.3 Management of Resistant HSV
5.7 HSV and Alzheimer’s Disease
5.8 Conclusion
References
Chapter 6 Antiviral Strategies Against the Human Cytomegalo Virus: Inhibitors of Viral Terminase
6.1 The Need for Novel Drugs against CMV and Attempts of the Past
6.2 The Strategy for the Discovery of Letermovir
6.3 The Link between Preclinical Models and Clinical Efficacy
6.4 Clinical Experience
6.4.1 Resistance Mutations and Resistance Development
6.4.2 Resistance Observed in Clinical Studies
6.5 Other Potential Indications for Letermovir
6.6 Conclusions
References
Chapter 7 Antiviral Targeting of the Complex Epstein Barr Virus Life Cycle
7.1 Disease Overview
7.2 Antiviral Strategies
7.2.1 Pharmacological Inhibition
7.2.2 B Cell Depleting Therapy
7.2.3 Adoptive T Cell Transfer and Immune Checkpoint Blockade
7.2.4 Vaccination
7.3 Open Issues
Acknowledgements
References
Chapter 8 Kaposi’s Sarcoma-associated Herpesvirus—Antiviral Treatment
8.1 Introduction to Kaposi’s Sarcoma-associated Herpesvirus (KSHV)
8.2 Epidemiological Considerations
8.3 Disease Overview
8.3.1 Kaposi’s Sarcoma
8.3.2 Primary Effusion Lymphoma (PEL)
8.3.3 Multicentric Castleman’s Disease (MCD)
8.3.4 KSHV and Polyclonal Post-transplant Lymphoproliferative Disease
8.3.5 Kaposi Sarcoma Herpesvirus-Associated Inflammatory Cytokine Syndrome (KICS)
8.3.6 KSHV and Hemophagocytosis, Bone Marrow Failure, and Hepatitis
8.4 Antiviral Strategies
8.4.1 Established Antiviral Strategies
8.4.1.1 Inhibitors of the KSHV DNA Polymerase (Table 8.1)
8.4.1.1.1 Activity in Tissue Culture
8.4.1.1.2 Activity in KSHV-infected Patients
8.4.1.1.3 Treatment of Kaposi Sarcoma
8.4.1.1.4 Treatment of PEL
8.4.1.1.5 Treatment of MCD
8.4.2 Kinase Inhibitors Against KSHV-associated Disease (Table 8.2)
8.4.2.1 Clinical Experience
8.4.2.2 Preclinical Studies
8.4.3 Other Established and Experimental Therapies Targeting KSHV-infected Cells (Table 8.2)
8.4.3.1 Interfering with Cellular Cytokines—Clinical Experience
8.4.3.2 Preclinical Data on Other Cellular Targets
8.5 New Antiviral Strategies Against KSHV in Preclinical Development
8.5.1 New Approaches to Target Productive (Lytic) KSHV DNA Replication and/or Packaging (Table 8.1)
8.5.2 Targeting KSHV Capsid Assembly (Table 8.1)
8.5.3 Targeted Immunotoxins (Table 8.1)
8.5.4 Targeting the Latency Phase of the KSHV Life Cycle
8.5.4.1 LANA (Latency-associated Nuclear Antigen) (Table 8.1)
8.5.4.2 vFLIP (Viral FLICE-inhibitory Protein) (Table 8.1)
8.5.4.2.1 Outlook
References
Chapter 9 Direct-Acting Antivirals for the Treatment of Chronic Hepatitis B Virus (HBV) Infection
9.1 Nucleos(t)ide Analog Reverse Transcriptase Inhibitors
9.2 HBV Entry Inhibitors
9.3 HBV Capsid Assembly Modulators (CAMs)
9.3.1 HBV Core Protein
9.3.2 First-Generation CAMs
9.3.3 Recent Progress in Novel CAMs
9.3.4 Modes of Action of CAMs
9.3.5 Resistance Profile of CAMs
9.3.6 CAMs in Clinical Trials
9.4 Concluding Remarks
References
Chapter 10 Hepatitis E Virus—Current Developments in Antiviral Strategies
10.1 Introduction
10.2 Genetic Diversity and Molecular Virology of HEV
10.3 Clinical Course of HEV Infections
10.4 HEV Therapy
10.5 Development of Novel Antivirals Against HEV
10.6 Prevention of Infection and Vaccination Strategies
10.7 Conclusions
References
Chapter 11 Antiviral Therapy of Adenovirus Infections
11.1 Human Adenovirus
11.2 Adenovirus in Human Stem Cell Transplantation
11.2.1 Incidence, Transmission, and Clinical Manifestation
11.2.2 Current Therapy Strategies and Antiviral Agents
11.2.2.1 Ribavirin
11.2.2.2 (Val)Ganciclovir
11.2.2.3 Cidofovir
11.2.3 Novel Antiviral Approaches in Clinical Development
11.2.3.1 Brincidofovir
11.3 Ocular Adenovirus Infections
11.3.1 Incidence, Transmission, and Clinical Manifestation
11.3.2 Current Therapy Strategies and Antiviral Agents
11.3.2.1 Corticosteroids
11.3.2.2 Povidone-iodine and SHP640
11.3.2.3 Nucleoside Analogues
11.3.2.4 Palliative Treatment
11.3.3 Novel Antiviral Approaches in Clinical Development
11.3.3.1 OKG-0301
11.3.3.2 iVIEW-1201
11.4 Drug Targets for Direct Acting Antivirals
11.4.1 Virus Attachment and Entry
11.4.2 Virus Genome Replication
11.4.3 Particle Maturation
11.5 Conclusion
References
Chapter 12 ssDNA-Viruses: Human Parvovirus Infection
12.1 Introduction
12.2 Classification
12.3 Molecular Biology
12.4 Parvovirus Replication
12.5 Diseases Associated with Parvovirus Infection
12.5.1 Parvovirus B19
12.5.2 HBoV
12.6 Antiviral Chemotherapy of Parvovirus B19-infection
12.7 Therapeutic Options and Recommendations
12.7.1 Acute B19V-infection Associated with Transient Aplastic Crisis (TAC)
12.7.2 Prolonged B19V-symptoms in Immunocompetents
12.7.3 Fetal Disease
12.7.4 Immunocompromised Patients
References
Chapter 13 Antiviral Targets and Strategies to Treat and Prevent Human Norovirus Infections
13.1 Introduction
13.1.1 Disease Burden and Pathogenesis
13.1.2 Viral Genome
13.1.3 Replication Cycle
13.1.4 In Vitro Models
13.1.5 In Vivo Models
13.1.5.1 Human Norovirus
13.1.5.2 The Murine Norovirus as a Surrogate for In Vivo Studies
13.2 Antiviral Targets
13.2.1 Binding and Entry
13.2.2 Nonstructural Proteins
13.2.2.1 NS1/2 (p48)
13.2.2.2 NS3 (NTPase/Helicase)
13.2.2.3 NS4 (p22)
13.2.2.4 NS5 (VPg)
13.2.2.5 NS6 (Protease)
13.2.2.6 NS7 (RNA-Dependent RNA Polymerase)
13.2.3 Host Factors
13.2.4 Antibodies
13.2.5 Gut Microbiota
13.2.6 Unknown Targets
13.3 Vaccine Development
13.4 Conclusion and Perspectives
References
Chapter 14 Antiviral Strategies Against (Non-polio) Picornaviruses
14.1 Classification and Clinical Impact
14.2 The Enterovirus Replication Cycle
14.2.1 Virion Structure
14.2.2 Genome Structure
14.2.3 Replication Cycle Stages
14.2.3.1 Entry
14.2.3.2 Translation and Replication
14.2.3.3 Assembly and Release
14.3 Prevention
14.4 Antiviral Strategies Against Enteroviruses
14.4.1 Directly Acting Antivirals
14.4.1.1 Early-Stage Inhibitors
14.4.1.2 Viral Protease Inhibitors
14.4.1.3 2C Targeting Molecules
14.4.1.4 RNA-dependent RNA Polymerase (RdRp) “(3D) Inhibitors”
14.4.2 Host-targeting Antivirals
14.4.2.1 Inhibitors of Lipid Processing
14.4.2.2 Assembly Inhibitors
14.4.3 Monoclonal Antibodies
14.4.4 Alternative Strategies
14.4.4.1 Direct Targeting of the RNA Genome
14.4.4.2 Dual Target Therapeutics
14.5 Conclusions
References
Chapter 15 Novel Antiviral Strategies Against Emerging Arbovirus Infections
15.1 Introduction
15.1.1 Zika Virus
15.1.2 Yellow Fever Virus
15.1.2.1 Dengue Virus
15.1.3 West Nile Virus
15.1.4 Chikungunya Virus
15.2 Intervention Strategies
15.3 Genome Organization and Viral Replication Cycle
15.4 Targets For Antiviral Therapy
15.5 Direct-acting Antivirals (DAAs)
15.6 RNA-dependent RNA Polymerase Inhibitors
15.7 Protease/Helicase Inhibitors
15.8 Envelope Protein Inhibitors
15.9 Capsid Protein Inhibitors
15.10 NS4B Inhibitors
15.11 Methyltransferase Inhibitors
15.12 Inhibitors with Nonspecific Action
15.13 Host Targeting Antivirals
15.14 Host Cell Nucleoside Biosynthesis Inhibitors
15.15 Host Cell Lipid Biosynthesis Inhibitors
15.16 Host Kinase Inhibitors
15.17 Protein Metabolism Inhibitors
15.18 Endocytosis and Membrane Fusion Inhibitors
15.19 Conclusion and Future Perspectives
References
Chapter 16 Current Therapies for Biosafety Level 4 Pathogens
16.1 Introduction
16.2 Filoviruses
16.2.1 Virus and Disease Overview
16.2.2 Antiviral Strategies
16.2.2.1 Immunotherapies
16.2.2.2 Postexposure Prophylaxis
16.2.2.3 Small Molecules
16.2.2.4 Antisense Therapy
16.2.2.5 Host-directed Therapies
16.3 Henipaviruses
16.3.1 Disease Overview
16.3.2 Antiviral Strategies
16.3.2.1 Small Molecules
16.3.2.2 Immunotherapies
16.4 Arenaviruses
16.4.1 Old World Arenaviruses
16.4.1.1 Disease Overview
16.4.1.2 Antiviral Strategies
16.4.1.2.1 Small Molecules
16.4.1.2.2 Immunotherapies
16.4.2 New World Arenaviruses
16.4.2.1 Disease Overview
16.4.2.2 Antiviral Strategies
16.4.2.2.1 Immunotherapies
16.4.2.2.2 Small Molecules
16.5 Bunyaviruses
16.5.1 Disease Overview
16.5.2 Antiviral Strategies
16.5.2.1 Immunotherapies
16.5.2.2 Small Molecules
16.6 Considerations for the Development of Treatment Strategies Against Viral Hemorrhagic Fever Viruses
References
Chapter 17 A Focus on Severe Acute Respiratory Syndrome (SARS) Coronavirus (SARS-CoVs) 1 and 2
17.1 Overview on Coronavirus (CoV)
17.1.1 CoV Epidemiology
17.1.2 HCoV Replication
17.1.3 Human Corona Virus (HCoV) Diseases Natural History
17.2 Licensed and Clinical Investigational Drugs Against CoVs
17.2.1 Licensed Drugs Against CoVs
17.2.2 Clinical Investigational Drugs Against CoVs
17.3 Medicinal Chemistry Approaches Toward the Identification of New Drugs
17.3.1 SARS-CoVs RdRp: Structure, Function, and Inhibition
17.3.2 The CoVs 3CLpro (or Main Protease): Structure, Function, and Inhibitors
17.3.3 The S Protein: Structure, Function, and Inhibition
17.4 Conclusions
References
Index
EULA