Antiviral Drug Discovery and Development

Preface
Contents
Contributors
Chapter 1: Antiviral Drugs Against Herpesviruses
	1.1 Introduction
	1.2 Herpesviruses Replicative Life Cycle
	1.3 The Viral DNA Polymerase
		1.3.1 Antiviral Agents Targeting the Viral DNA Polymerase
		1.3.2 Resistance of Herpesviruses to Viral DNA Polymerase Inhibitors
	1.4 The Viral Terminase Complex
		1.4.1 Antiviral Agents Targeting the Viral Terminase Complex
		1.4.2 Resistance of HCMV to Viral Terminase Inhibitors
	1.5 The Viral pUL97 Kinase
		1.5.1 Antiviral Agents Targeting the Viral pUL97 Kinase
		1.5.2 Resistance of HCMV to pUL97 Kinase Inhibitors
		1.5.3 Antiviral Agents Targeting Both the pUL97 Kinase and the DNA Polymerase
		1.5.4 Resistance of HCMV to Filociclovir
	1.6 The Helicase-Primase Complex
		1.6.1 Antiviral Agents Targeting the Helicase-Primase Complex
		1.6.2 Resistance of Herpesviruses to Helicase-Primase Inhibitors
	1.7 Conclusions
	References
Chapter 2: An Update on Antiretroviral Therapy
	2.1 Introduction
	2.2 Currently Approved Antiretroviral Therapies
		2.2.1 Combination Antiretroviral Therapies
	2.3 Antiretroviral Drug Toxicity
	2.4 Acquired and Transmitted Drug Resistance
	2.5 Novel Antiretroviral Drugs
		2.5.1 RT Inhibitors
		2.5.2 Integrase Inhibitors
		2.5.3 Protease Inhibitors
		2.5.4 Assembly and Maturation Inhibitors
		2.5.5 Entry Inhibitors and Neutralizing Antibodies
		2.5.6 Other Antiretroviral Targets
	2.6 Implementation of Current Antiretroviral Therapies for Prevention
		2.6.1 Pre-Exposure Prophylaxis
		2.6.2 Long-Acting Antiretroviral Drugs
	2.7 HIV Cure and Prospective Drugs
	2.8 Conclusions and Future Perspectives
	References
Chapter 3: Structural Insights to Human Immunodeficiency Virus (HIV-1) Targets and Their Inhibition
	3.1 Introduction
	3.2 Structural Information for Rational Drug Design
		3.2.1 Entry and Fusion Inhibitors
		3.2.2 Crystal Structures and Ligand-Binding Site of CCR5
		3.2.3 Resistance to Entry and Fusion Inhibitors
		3.2.4 Reverse Transcriptase Inhibitors
		3.2.5 Crystal Structures and Ligand-Binding Site of RT and RNase H
		3.2.6 Resistance to RT Inhibitors
		3.2.7 Integrase Inhibitors
		3.2.8 Crystal Structure and Ligand-Binding Site of Integrase
		3.2.9 Resistance to Integrase Inhibitors
		3.2.10 Protease Inhibitors
		3.2.11 Crystal Structure and Ligand-Binding Site of Proteases
		3.2.12 Resistance to Protease Inhibitors
		3.2.13 Budding and Maturation Inhibitors
	3.3 Protein-Ligand Interaction Fingerprint Analysis
		3.3.1 PLIF Analysis of NNRTIs
		3.3.2 PLIF Analysis of Protease Inhibitors
	3.4 Conclusion
	References
Chapter 4: LEDGINs, Inhibitors of the Interaction Between HIV-1 Integrase and LEDGF/p75, Are Potent Antivirals with a Potentia...
	4.1 Introduction
	4.2 Obstacles on the Road Toward an HIV-1 Cure
	4.3 Molecular Drivers of HIV Persistence
	4.4 LEDGF/p75, the ``Global Positioning System (GPS)´´ of HIV, Mediates HIV-1 Integration
		4.4.1 The Domain Structure of LEDGF/p75
		4.4.2 The Interaction Between the IBD of LEDGF/p75 and HIV Integrase
		4.4.3 Interaction of LEDGF/p75 with Chromatin
		4.4.4 LEDGF/p75 Represents Two Distinct Drug Targets
	4.5 LEDGINs Are Antivirals Blocking the Interaction Between LEDGF/p75 and HIV-1 Integrase That Display a Multimodal Mechanism ...
		4.5.1 A Block-and-Lock Strategy for a Functional Cure of HIV Infection
		4.5.2 Place Your Bets
	References
Chapter 5: Moving Fast Toward Hepatitis B Virus Elimination
	5.1 Introduction
	5.2 HBV Pathogenicity (Immunological Background)
	5.3 HBV Replication
		5.3.1 Replication Cycle
		5.3.2 Role of cccDNA
	5.4 Overview of Current Therapies
	5.5 Drugs in the Pipeline
		5.5.1 Direct-Acting Antiviral Agents (DAAs)
			5.5.1.1 Capsid Assembly Effectors or Modulators (CAM)
			5.5.1.2 Entry Inhibitors
			5.5.1.3 Small Interfering RNA (siRNA)
			5.5.1.4 Nucleic Acid Polymers (NAPs)
				HBsAg Inhibitors
				STOPs (s-Antigen Transport Inhibiting Oligonucleotide Polymers)
			5.5.1.5 Antisense Molecules
			5.5.1.6 Nucleoside Analogs
			5.5.1.7 RNAseH Inhibitors
		5.5.2 Indirectly Acting Antiviral Agents (Immune Therapy)
			5.5.2.1 Therapeutic Vaccines
			5.5.2.2 Innate Immune Stimulation
			5.5.2.3 Host Acting Pathway
			5.5.2.4 Gene Editing
			5.5.2.5 Other Mechanisms
	5.6 Conclusions
	References
Chapter 6: Discovery and Development of Antiviral Therapies for Chronic Hepatitis C Virus Infection
	6.1 Introduction
	6.2 HCV Replication
	6.3 HCV Variability
	6.4 HCV Therapy
	6.5 DAA Resistance
	6.6 HCV Eradication
	References
Chapter 7: Phytoconstituents as Lead Compounds for Anti-Dengue Drug Discovery
	7.1 Introduction
	7.2 Structural Composition and Replication of Dengue Virus
	7.3 Clinical Manifestations and Clinical Features
	7.4 Treatment of Dengue Infection
	7.5 Phytoconstituents with Potential Anti-Dengue Activity
		7.5.1 Flavonoids
			7.5.1.1 Baicalein
			7.5.1.2 Quercetin and Catechin
			7.5.1.3 Fisetin
			7.5.1.4 5-Hydroxy-7-Methoxy-6-Methylflavone
			7.5.1.5 Luteolin
			7.5.1.6 Sophoroflavenone G
			7.5.1.7 Biflavonoids
			7.5.1.8 Mono- and Dialkylated Flavanones (Chartaceones)
			7.5.1.9 Flavone Glycosides
				Pectolinarin and Acacetin-7-O-Rutinoside
				Flavanone Apiofuranoside
				Glycosides of Quercetin, Kaempferol and Other Flavonoids
		7.5.2 Alkaloids
			7.5.2.1 Carpaine
			7.5.2.2 Bisbenzylisoquinoline Alkaloids
			7.5.2.3 Indole Alkaloids
			7.5.2.4 Ficuseptine and Antofine
		7.5.3 Terpenoids
			7.5.3.1 Andrographolide
			7.5.3.2 Azadirachtin
			7.5.3.3 Celastrol
			7.5.3.4 Betulinic Acid and Betulinic Aldehyde
			7.5.3.5 Lupeol
			7.5.3.6 Limonoids
		7.5.4 Miscellaneous
			7.5.4.1 Tannins: Geraniin
			7.5.4.2 Honokiol
			7.5.4.3 α-Mangostin
			7.5.4.4 Phenolic Acids
			7.5.4.5 Arylpropanoid Glycosides
			7.5.4.6 Galactomannans
			7.5.4.7 Acetylenic Acids and Other Acids
			7.5.4.8 Coumarins
			7.5.4.9 Tatanan A
			7.5.4.10 Resveratrol
	7.6 Herbal Extracts with Anti-Dengue Activity
		7.6.1 Doratoxylum apetalum
		7.6.2 Lonicera japonica
		7.6.3 Hippophae rhamnoides
		7.6.4 Senna angustifolia
		7.6.5 Tridax procumbens
		7.6.6 Vernonia cinerea
	7.7 Strategies for Anti-Dengue Drug Discovery
	7.8 Conclusion
	References
Chapter 8: Anti-Influenza Drug Discovery and Development: Targeting the Virus and Its Host by All Possible Means
	8.1 Introduction
	8.2 From Existing Classic Antiviral Drugs to New Pre-Clinical Candidates
		8.2.1 M2 Ion Channel Blockers (Amantadine/Rimantadine)
		8.2.2 Neuraminidase (NA) and Hemagglutinin (HA) Inhibitors
			8.2.2.1 NA Inhibitors
			8.2.2.2 Hemagglutinin Inhibitors
		8.2.3 Polymerase/Nucleoprotein/RNA inhibitors
			8.2.3.1 Polymerase/Endonuclease Inhibitor (Favipiravir, Baloxavir Marboxil)
			8.2.3.2 Pre-clinical Compounds Targeteinf the Polymerase PA, PB1 and PA subunits, Escape Mutations and Resistance
			8.2.3.3 Broad-Spectrum Inhibitors
			8.2.3.4 Pre-Clinical Compounds Targeting the Polymerase PB2 Subunit
			8.2.3.5 Pre-Clinical Compounds Targeting the Nucleoprotein or the Nucleoprotein-RNA Interactions
		8.2.4 Drugs Targeting the Non-structural Protein-1 (NS1)
	8.3 Host-Targeting and Drug Repurposing Approaches for the Treatment of Influenza
		8.3.1 Drugs Targeting Host Cell Component at Different Stages of Influenza Replication Cycle
		8.3.2 Drugs Targeting Host Cell Signaling Pathways and Host Response that Are Crucial for Influenza Replication Cycle
	8.4 Perspectives and Concluding Remarks
	References
Chapter 9: Search, Identification, and Design of Effective Antiviral Drugs Against Pandemic Human Coronaviruses
	9.1 Introduction
	9.2 Genomic Organization, Structure, and Replicative Cycle of Pandemic Coronaviruses
	9.3 COVID-19 Disease Progression and Therapeutic Intervention
	9.4 RdRp Inhibitors
		9.4.1 RdRp Structure and Mechanism of Action of Remdesivir
		9.4.2 Remdesivir Resistance
		9.4.3 Clinical Trials with Remdesivir
		9.4.4 Favipiravir and Other Approved Nucleotide Prodrugs
		9.4.5 Other Nucleoside Analogues
	9.5 Helicase (nsp13)
	9.6 Coronavirus Entry: Antiviral Agents Targeting the Spike Glycoprotein
	9.7 Coronavirus Protease Inhibitors
	9.8 Antiviral Agents Targeting Host Cell Proteins
		9.8.1 ACE2 Inhibitors
		9.8.2 Inhibitors Targeting the Surface Transmembrane Protease, Serine 2 (TMPRSS2)
		9.8.3 Endosomal Proteinase Cathepsin L (CTSL) Inhibitors
		9.8.4 Compounds Interfering with Endosomal Acidification
		9.8.5 Eukaryotic Translation Initiation and Elongation Factors and DEAD-Box RNA Helicases as Targets of Antiviral Drugs Agains...
		9.8.6 Comprehensive Interaction Maps Between SARS-CoV-2 and Host Proteins
		9.8.7 Inhibitors of the Host Dihydroorotate Dehydrogenase
		9.8.8 Cyclophilin Inhibitors
		9.8.9 Interferons as Therapeutic Options Against Coronavirus Infections
	9.9 Antiviral Agents with Unknown Mechanisms of Action
		9.9.1 Nitazoxanide, Dipyridamole, Lycorine, Ivermectin, Suramin, Artemisinin, and Cenicriviroc
		9.9.2 Drugs Derived from Large-Scale Compound Repurposing Screening
	9.10 Conclusions, Perspectives, and Future Developments in the Design and Development of Antiviral Drugs Against Coronaviruses
	References
Chapter 10: Peptide-Based Antiviral Drugs
	10.1 Introduction
	10.2 Organics, Peptides, and Biologics as Drugs
	10.3 Approaches for Improving Drug-Like Properties and Stability of Peptides
		10.3.1 Amino Acid Substitution Method
		10.3.2 Amino Acid Cyclization
		10.3.3 Amide Bond Modification
		10.3.4 Peptidomimetic Method
		10.3.5 Stapling, PEGylation, and Glycosylation
	10.4 Chemical Space and Conformational Space of Peptides
	10.5 Viral Infections in Plants, Animals, and Humans
	10.6 Peptide Drugs for Treating Viral Infection
		10.6.1 HIV
		10.6.2 Influenza Virus
		10.6.3 West Nile Virus
		10.6.4 SARS-CoV
		10.6.5 MERS-CoV
		10.6.6 SARS-CoV-2
	10.7 Strategies for Developing Peptide Therapeutics for Viruses with Envelope Proteins
	10.8 Sources of Antiviral Peptides
		10.8.1 Peptide Synthesis
		10.8.2 Recombinant DNA Technology
		10.8.3 Other Sources
	10.9 Challenges and Opportunities
	10.10 Design of Antiviral Peptide Drugs
	10.11 FDA-Approved Antiviral Therapeutic Peptides
	10.12 Conclusions
	References
Chapter 11: Covalent Antiviral Agents
	11.1 Introduction
	11.2 Classification of Covalent Inhibitors
		11.2.1 Covalent Reversible Inhibitors
		11.2.2 Covalent Irreversible Inhibitors
	11.3 Covalent Inhibitors Against Viruses
		11.3.1 Covalent Inhibitors Against SARS-CoV-2
			11.3.1.1 Mpro: The Most Important Target in SARS-CoV-2
			11.3.1.2 Diversity in the Structures of Covalent Inhibitors
		11.3.2 Covalent Inhibitors Against Dengue Virus (DV)
			11.3.2.1 Structure of Dengue Virus Serine Protease (DENVP)
			11.3.2.2 Structures and Mechanisms of Covalent Inhibitors against DENVP
		11.3.3 Covalent Inhibitors Against Enterovirus 71 (EV71)
			11.3.3.1 Structure of 3C Cysteine Protease
			11.3.3.2 Structures and Mechanisms of Covalent Inhibitors against EV71
		11.3.4 Covalent Inhibitors against Hepatitis C Virus (HCV)
			11.3.4.1 Structure of NS34A Serine Protease
			11.3.4.2 Structures and Mechanisms of Covalent Inhibitors against HCV
				Aldehydes
				Boronates
				α-Keto Inhibitors
		11.3.5 Covalent Inhibitors against Human Immunodeficiency Virus (HIV)
			11.3.5.1 Structure of NCp7
			11.3.5.2 Structures and Mechanisms of Covalent Inhibitors against NCp7
			11.3.5.3 Covalent Inhibitors against Reverse Transcriptase (RT)
			11.3.5.4 Covalent Inhibitors against HIV-1 Protease
			11.3.5.5 Covalent Inhibitors against HIV-1 Capsid
		11.3.6 Covalent Inhibitors against Influenza
			11.3.6.1 Structure of Neuraminidase
			11.3.6.2 Structures and Mechanisms of Covalent Inhibitors against Neuraminidase
	11.4 In Silico Approaches in the Search for Covalent Inhibitors as Antiviral Agents
		11.4.1 Covalent Inhibitor Identification against SARS-CoV-2 Main Protease by In Silico Study
	11.5 Conclusions and Future Perspectives
	References
Chapter 12: Safe-in-Man Broad Spectrum Antiviral Agents
	12.1 Introduction
	12.2 The Case for Safe-in-Man Drug Repurposing and Broad-Spectrum Agents
	12.3 Methods for Safe-in-Man Broad Spectrum Antiviral Development
		12.3.1 In Silico Methods for Drug Discovery
			12.3.1.1 Molecular Docking
			12.3.1.2 Network-Based Modelling
			12.3.1.3 Text Mining-Based Approaches
		12.3.2 In Vitro Studies
			12.3.2.1 Cell Lines
			12.3.2.2 Primary Cells and Stem Cell-Derived Cells
			12.3.2.3 3D Cultures and Organoids
		12.3.3 In Vivo Studies
			12.3.3.1 Mice
			12.3.3.2 Non-human Primates
		12.3.4 Clinical Trials
	12.4 Structure-Activity Relationships
	12.5 BSAA Combinations
	12.6 Useful Tools for Antiviral Drug Repurposing Studies
		12.6.1 Pharmacological Databases
			12.6.1.1 DrugBank
			12.6.1.2 DrugCentral Database
			12.6.1.3 Pharmacogenomic Knowledgebase (PharmGKB)
			12.6.1.4 DrugVirus Database
		12.6.2 Proteomics Databases
			12.6.2.1 The RCSB Protein Data Bank
			12.6.2.2 Proteopedia
			12.6.2.3 UniProt Knowledgebase
		12.6.3 Chemical Structure Databases
			12.6.3.1 PubChem
			12.6.3.2 ChEMBL
			12.6.3.3 ChemDB
		12.6.4 Viral Databases
			12.6.4.1 Virus Pathogen Resource (ViPR)
			12.6.4.2 ViralZone
	12.7 Conclusion and Future Perspectives
	References
Chapter 13: Exploiting Ubiquitin Ligases for Induced Target Degradation as an Antiviral Strategy
	13.1 The Ubiquitin-Proteasome System (UPS)
	13.2 Role of Ubiquitin in the Life Cycle of Viruses
		13.2.1 Viral Entry
		13.2.2 Viral Uncoating
		13.2.3 Viral Transcription and Replication
		13.2.4 Viral Egress
	13.3 Role of Ubiquitin in Antiviral Immunity
	13.4 Viruses Hijack Ub Ligases to Circumvent Cellular Defenses
	13.5 PROTACs: Chimeric Molecules that Degrade and Inactivate Targets by Inducing their Proximity to a Ub Ligase
	13.6 PROTACs as Emergent Antiviral Therapeutics
	References