Entry inhibitors: New advances in HCV treatment

Figures & data

Figure 1 HCV entry into hepatocytes and antiviral agents targeting entry factors. The HCV lipoviral particle (LVP) is recruited and binds to glycosaminoglycans and low-density lipoprotein receptor on host cells. After binding, the virions interact with a series of entry factors. SRB1 plays a role in both binding and post-binding. CD81 interacts with HCV E2, forms a complex with claudin-1 (CLDN1), and mediates HCV movement to the tight-junction areas. This process is regulated by the receptor tyrosine kinase (RTK) family, including epidermal growth factor receptor (EGFR) and ephrin receptor A2 (EphA2). The virions internalize into host cells by clathrin-mediated endocytosis. Transferrin receptor 1 (TfR1) facilitates viral entry after CD81, possibly during HCV particle endocytosis. Niemann Pick C1-like 1 (NPC1L1) plays an important role in cholesterol transportation and is a cofactor for HCV entry during post-binding steps. Low pH-dependent membrane fusion between endosome and HCV particle. Red words and lines indicate the antiviral agents targeting different stages and factors of HCV entry.

Table 1 The process of viral entry and targets for antiviral agents with their development stage

Process of entry	Target	Representatives of compounds	Developmental stage	References
Attachment		Lectin cyanovirin-N	Cell culture	^Citation26
		BA-LNC	Cell culture	^Citation27
		Ficolin	Cell culture	^Citation28,Citation29
		Heparin and heparin-derived compounds	Cell culture	^Citation21,Citation28
		Heparanase	Cell culture	^Citation21
		EGCG and its derivatives	Cell culture	^Citation30,Citation31,Citation32
		Lactoferrin	Phase I	^Citation33,Citation34,Citation35
		A p7 ion channel-derived peptide H2-3	Cell culture	^Citation36
Post-binding interactions with entry factors	CD81	Imidazole-based compounds	Cell culture	^Citation37
		Anti-CD81 mAbs	Mouse model	^Citation38,Citation39,Citation40,Citation41,Citation42,Citation43
		Soluble CD81 LEL	Cell culture	^Citation42,Citation44,Citation45,Citation46,Citation47,Citation48
	SRB1	Serum amyloid A	Cell culture	^Citation49,Citation50
		Anti-SRB1 pAb and mAb	Mouse model	^Citation51,Citation52,Citation53,Citation54
		ITX5061	Phase I/IIa	^Citation55,Citation56,Citation57,Citation58
	CLDN1	Anti-CLDN1 peptides	Cell culture	^Citation59
		Anti-CLDN1 pAb and mAb	Mouse model	^Citation60,Citation61,Citation62
	EGFR	Erlotinib	Phase I/IIa	^Citation63
	EphA2	Dasatinib	Cell culture	^Citation63
	TfR1	Anti-TfR1 mAbs	Cell culture	^Citation64
		Ferristatin	Cell culture	^Citation64
	NPC1L1	Anti-NPC1L1 mAbs	Cell culture	^Citation65
		Ezetimibe	Mouse model	^Citation66
Clathrin-mediated endocytosis		Chlorpromazine	Cell culture	^Citation67
		Arbidol	Cell culture	^Citation68
Fusion and uncoating	Endosome acidification	Concanamycin A	Cell culture	^Citation69
		Bafilomycin A	Cell culture	^Citation69
		Chloroquine	Cell culture	^Citation70,Citation71
		Ammonium chloride	Cell culture	^Citation70,Citation71
	Lipid composition of virus or host cell	Arbidol	Cell culture	^Citation72
		Phenothiazines	Cell culture	^Citation73
		RAFIs (aUY11)	Cell culture	^Citation74,Citation75
		LJ001	Cell culture	^Citation76
		Silymarin	Cell culture	^Citation77,Citation78
	Unclear mechanism	Ferroquine	Cell culture	^Citation79
		PS-ONs	Mouse model	^Citation80
Natural compounds and small molecules		Flavonoids, terpenoids, tannic acid, gallic acid, PF-429242	Cell culture	^Citation81,Citation82,Citation83,Citation84,Citation85,Citation86
FDA-approved drugs		CCZ, sorafenib, aspirin	Phase Ib Cell culture	^Citation87,Citation88,Citation89

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