Virus Entry Inhibitors: Stopping the Enemy at the Gate

Preface
Acknowledgments
Contents
1: Virus Entry Inhibitors: Past, Present, and Future
1.1 Introduction
1.2 Peptide-Based Virus Entry Inhibitors
1.2.1 Viral Fusion Protein Targeting
1.2.2 Host Protein or Pathway Targeting
1.2.3 The Future of Peptide-Based Virus Entry Inhibitors
1.3 Small-Molecule-Based Virus Entry Inhibitors
1.3.1 Viral Fusion Protein Targeting
1.3.2 Host Protein or Pathway Targeting
1.3.3 The Future of Small-Molecule-Based Virus Entry Inhibitors
1.4 Protein-Based Virus Entry Inhibitors
1.4.1 Viral Fusion Protein Targeting
1.4.2 Host Protein or Pathway Targeting
1.4.3 The Future of Protein-Based Virus Entry Inhibitors
1.5 Conclusion and Prospect
References
2: Peptide-Based HIV Entry Inhibitors
2.1 Introduction
2.2 Peptides Targeting Cellular Receptors
2.3 Peptides Targeting Virus
2.3.1 Peptides Targeting CD4-Binding Site (CD4bs) or Co-Receptor-Binding Site (CoRbs) in the HIV-1 gp120
2.3.2 Peptides Inactivating Cell-Free Virions
2.4 Peptides Blocking Virus-Cell or Cell-Cell Fusion
2.4.1 Peptides Targeting Fusion Peptide (FP) in gp41
2.4.2 Peptide Blocking Six-Helix Bundle (6-HB) Formation
2.4.3 Peptides Targeting the Disulfide Loop Region of gp41
2.5 Conclusion
References
3: Small-Molecule HIV Entry Inhibitors Targeting gp120 and gp41
3.1 Structure and Function of gp120 and gp41
3.2 Small-Molecule HIV-1 Entry Inhibitors Targeting gp120
3.2.1 NBD-556 and Analogs
3.2.2 CD4 Mimics Binding Competitively with gp120 Suppress the Binding of gp120 to CD4
3.2.3 The Acylhydrazone-Containing Small Molecule 18A
3.3 Small-Molecule HIV Entry Inhibitors Target gp41
3.3.1 ADS-J1 and Its Resistance Profile
3.3.2 NB-2, NB-64, A12, GLS-22, and Analogs
3.3.3 NB-206, 12m and Analogs
3.3.4 Indole-Based Compounds, as Small-Molecule HIV-1 Fusion Inhibitors Targeting gp41, Identified
3.3.5 5M038, 5M041 and Analogs Identified by Fluorescence Polarization Assay Using gp41-5 as the Target
3.3.6 Alpha-Helical Mimicry and Colorimetric, Affinity-Based Selection Assay
3.3.7 Natural Polyanionic Ingredient
3.4 Future of HIV-1 Small-Molecule Entry/Fusion Inhibitors and Screening Assay
References
4: The Genesis and Future Prospects of Small Molecule HIV-1 Attachment Inhibitors
4.1 Introduction
4.2 Discovery and SAR of Fostemsavir-Related Series (BMS Series)
4.3 Alternate Chemotypes for Targeting gp120 Unrelated to Keto Amides
4.4 Application of HIV gp120 Inhibitors
4.4.1 As Microbicides
4.4.2 As Target Recognition Element in Conjugates
4.4.3 As Immuno-Protectants or Immuno-Stimulators
4.4.4 As Agents Against Cytopathic and Non-cytopathic Effects of gp120
4.5 Future Directions
4.6 Conclusions
References
5: Endogenous Peptide Inhibitors of HIV Entry
5.1 Introduction
5.2 Antiviral Host Defense Peptides
5.2.1 Defensins
5.2.2 LL-37
5.3 Endogenous Ligands Targeting CXCR4-Mediated HIV Infection
5.3.1 CXCL12
5.3.2 EPI-X4
5.3.3 Other CXCR4 Ligands
5.4 Chemokine Ligands of CCR5 Inhibit CCR5-Tropic HIV-1
5.5 CysC Fragments Inhibit GPR15-Mediated HIV-2 and SIV Infection
5.6 VIRIP Blocks Fusion Peptide Insertion into the Cell Membrane
5.7 Conclusions and Perspectives
References
6: Peptide-Based Dual HIV and Coronavirus Entry Inhibitors
6.1 Introduction
6.2 Common Hexameric Coiled-Coils in Viral Envelope Proteins as Conserved Drug Target Sites
6.3 Virus-Specific Peptide-Based Fusion Inhibitors That Antagonize 6-HB Formation
6.4 Pan-Coronavirus Fusion Inhibitors Possess Cross-Inhibitory Activity Against HIV Infection
6.5 HIV-1 Fusion Inhibitors Possess Cross-Inhibitory Activity Against Coronaviruses Infection
6.6 Design of Dual HIV/HCoV Entry Inhibitors Based on Artificial Peptide Sequences
6.7 Conclusion and Outlook
References
7: Coronavirus Entry Inhibitors
7.1 Introduction
7.2 Epidemiology and Pathogenesis of Human Coronavirus (HCoVs)
7.3 Structure of Human Coronavirus Virion
7.4 Life Cycle of Human Coronaviruses
7.5 Entry Inhibitors Targeting Receptor Binding Domain
7.5.1 Neutralizing Antibodies Targeting RBD
7.5.1.1 SARS-CoV Neutralizing Antibodies
7.5.1.2 MERS-CoV Neutralizing Antibodies
7.5.1.3 SARS-CoV-2 Neutralizing Antibodies
7.5.2 Recombinant Proteins and Peptide Analogues
7.5.3 Other Entry Inhibitors Targeting Receptor Binding Domain
7.6 Entry Inhibitors Targeting N-terminal Domain
7.7 Entry Inhibitors Targeting Proteolytic Activation of Spike Protein
7.8 Entry Inhibitors Targeting Membrane Fusion
7.8.1 Peptide Entry Inhibitor
7.8.2 Other Entry Inhibitors Targeting Membrane Fusion
7.9 Entry Inhibitors with Other Mechanisms
7.10 Future Perspectives
References
8: Influenza Virus Entry inhibitors
8.1 Introduction
8.2 The Process of Influenza Virus Entry and Antiviral Targets
8.3 Assay Methods for Influenza Entry Inhibitors
8.4 Influenza Entry Inhibitors
8.4.1 Small Molecule-Based Entry Inhibitors
8.4.2 Peptides-Base Entry Inhibitors
8.4.3 Natural Product-Based Entry Inhibitors
8.5 Other Novel Entry Inhibitors
8.5.1 Monoclonal Antibodies (mAb)
8.5.2 Novel Influenza Entry Inhibitor Target Host Factor
8.6 Conclusion and Prospect
References
9: Broad-spectrum Respiratory Virus Entry Inhibitors
9.1 Risks of Respiratory Virus Infection
9.1.1 Risks from Emerging Viruses
9.1.2 Risks from the Lack of Antiviral Drugs
9.1.3 Risks from Human Activities
9.2 Challenges of Broad-Spectrum Antiviral Development
9.2.1 Challenges from the Relative High Mutation Rates of RNA Viruses
9.2.2 Challenges from Viruses Without Highly Conserved Proteins
9.2.3 Challenge from Viral Quasispecies
9.3 The Entry Processes of Respiratory Viruses
9.4 Broad-Spectrum Entry Inhibitors for Respiratory Viruses
9.4.1 Targeting Viral Attachment
9.4.2 Conformation Change Inhibitors
9.4.3 Fusion Peptide Inhibitors
9.4.4 Targeting Membrane Components
9.4.5 Targeting Endocytic Pathway
9.5 Future of Broad-Spectrum Entry Inhibitors for Respiratory Viruses
9.6 Outlook
References
10: Ebola Virus Entry Inhibitors
10.1 Ebola Virus Entry and Potential Drug Targets
10.1.1 A Brief Description of EBOV Entry
10.1.2 EBOV GP and GP Mediated Fusion Events
10.1.3 Unresolved Puzzles of EBOV Entry
10.1.4 Potential Therapeutic Targets During EBOV Entry
10.2 Established EBOV Models for Entry Inhibitor Development
10.2.1 EBOV GP-Based Pseudotyping System
10.2.2 Replication-Competent rVSV Encoding EBOV GP
10.2.3 Ebola Virus-Like Particles
10.3 REGN-EB3, Ansuvimab, and Other mAb Therapeutics
10.3.1 REGN-EB3
10.3.2 Ansuvimab
10.3.3 Other mAb Therapeutics
10.4 Repurposing Old Drugs as New EBOV Entry Inhibitors
10.4.1 Forward Repurposing Screen of EBOV Entry Inhibitors
10.4.2 Reverse Repurposing Screen of EBOV Entry Inhibitors
10.5 Development of Novel EBOV Entry Inhibitors
10.5.1 Small Molecule Inhibitors
10.5.2 Natural Product Derived Inhibitors
10.5.3 Peptide-Based Inhibitors
10.5.4 Nanotechnology-Based Inhibitors
10.6 Conclusions
References
11: Flavivirus Entry Inhibitors
11.1 Introduction
11.2 Small Molecule Entry Inhibitors
11.2.1 Inhibition of Viral Binding to Receptors
11.2.2 Inhibition of Viral Endocytosis
11.2.3 Inhibition of Membrane Fusion
11.2.3.1 Drug Screening Using Membrane Fusion Models
11.2.3.2 Occupying the EDI-EDII β-OG Pocket Region
11.2.3.3 Inhibiting the Formation of E Protein Trimer
11.2.4 Small Molecule Viral Inactivators
11.2.5 Other Types of Viral Entry Inhibitors
11.3 Antibody Entry Inhibitors
11.3.1 Structural-Based Quaternary Epitopes
11.3.2 EDI/EDII Epitopes
11.3.3 EDIII Epitopes
11.3.4 Strategies to Eliminate ADE
11.4 Peptide Entry Inhibitors
11.4.1 Peptide Membrane Fusion Inhibitors
11.4.2 Peptide Viral Inactivators
11.5 Conclusion and Prospect
References
12: Entry Inhibitors of Hepatitis B and D Viruses
12.1 Introduction
12.2 HBV/HDV Envelope Proteins
12.3 Host Receptor
12.4 HBV/HDV Entry Inhibitors
12.5 Perspectives
References
13: Entry Inhibitors of Hepatitis C Virus
13.1 Introduction
13.2 HCV Entry into Host Cells
13.2.1 Initial Non-specific Attachment and Binding
13.2.2 Post-Binding Interactions with Essential Host Entry Factors
13.2.3 Clathrin-Mediated Endocytosis and Subsequent Membrane Fusion
13.3 Conclusions and Perspectives
References
14: Human Papillomavirus (HPV) Entry Inhibitors
14.1 HPV Structure and Encoded Proteins
14.2 HPV Classification and Subtypes
14.3 HPV Life Cycle
14.4 HPV-Related Diseases
14.5 HPV Vaccines
14.6 Chemical Antivirals that Inhibit HPV Replication
14.7 HPV Entry Inhibitors
14.7.1 Small Compounds
14.7.2 Peptides
14.7.3 Neutralizing Antibodies
14.7.4 Non-Antibody Proteins
14.7.5 Polysaccharides
14.8 Clinical Effect of HPV Entry Inhibitors
14.8.1 Carrageenan Gel
14.8.2 3HP-β-LG Gel
14.9 Conclusion
References