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