Bona fide receptor for hepatitis B and D viral infections: Mechanism, research models and molecular drug targets

Figures & data

Fig. 1 Diagram of the HBV receptor and viral entry.

HBV from the blood initially crosses into the liver and attaches to HSPGs, which is followed by the virus binding to the bona fide receptor, NTCP. Next, the HBV virions are uncoated, and the rcDNA is transported into the nucleus, where the highly stable cccDNA serves as a template for viral transcription. HSPG, heparan sulfate proteoglycan; NTCP, sodium taurocholate cotransporting polypeptide; cccDNA, covalently closed circular DNA; rcDNA, relaxed circular DNA

HBV/HDV entry inhibitors reported so far

Molecular compound	Category	Antiviral activity (IC50)			Cell culture		NTCP transporter activity (IC50)	Reference
		HBsAg	HBeAg	HDV	HBsAg/HBeAg	HDV
Myrcludex B	Myristoylated lipopeptide	669 pM	83 pM	NA	PHH	NA	52.5 nM	^Citation78
		140 pM	NA	NA	HepaRG	NA	NA	^Citation10
CsA	Immunosuppressant	1.17±0.22 µM	<4 µM	NA	HepaRG	NA	1.12 µM	^Citation77
		372 nM	311 nM	4–8 µM	PHH	HuH7-hNTCP	3.3 µM	^Citation78
		1.25 µM	NA	NA	HepG2-hNTCP-C4	NA	NA	^Citation81
		<8 µM	1.27±0.43 µM	NA	HepG2-hNTCP-C4/PHH	NA	1.49±0.1 µM	^Citation79
CsA derivatives	Nonimmunosuppressant
SCYX618806		0.43±0.12 µM	NA	NA	HepaRG	NA	NA	^Citation77
SCYX827830		0.38±0.08 µM	NA	NA	HepaRG	NA	NA	^Citation77
SCYX1454139		0.17±0.02 µM	NA	NA	HepaRG	NA	NA	^Citation77
SCY806		<8 µM	1.05±0.33 µM	NA	HepG2-hNTCP-C4/PHH	NA	>10 µM	^Citation79
SCY446		<8 µM	0.54±0.13 µM	NA	HepG2-hNTCP-C4/PHH	NA	1.92±0.08 µM	^Citation79
SCY450		<8 µM	0.91±0.19 µM	NA	HepG2-hNTCP-C4/PHH	NA	>10 µM	^Citation79
SCY995		<8 µM	1.97±0.04 µM	NA	HepG2-hNTCP-C4/PHH	NA	>25 µM	^Citation79
CsB	Immunosuppressant	0.8 µM	NA	NA	HepG2-hNTCP-C4	NA	NA	^Citation81
UDCA	Non-conjugated bile acid	<100 µM	<100 µM	NA	HepaRG	NA	NA	^Citation77
		<100 µM	NA	NA	HepG2-hNTCP-C4	NA	NA	^Citation81
		<25 µM	20 µM	NA	HepaRG/HepG2-NTCP	NA	NA	^Citation36
TUDCA	Conjugated bile acid	NA	NA	NA	NA	NA	<10 µM	^Citation77
		<25 µM	0.37–1.11 µM	NA	HepaRG/HepG2-NTCP	NA	1.1–3.3 µM	^Citation36
Progesterone	Sex hormone	<40 µM	<40 µM	NA	HepaRG	NA	NA	^Citation77
		<40 µM	NA	NA	HepG2-hNTCP-C4	NA	NA	^Citation81
Bromosulfophthalein	For liver function test	<100 µM	NA	NA	HepG2-hNTCP-C4	NA	NA	^Citation81, Citation95
22(S)-hydroxycholesterol	Oxysterol	<11 µM	NA	NA	HepG2-hNTCP-C4	NA	NA	^Citation81
		0.3–0.9 µM	NA	NA	HepaRG	NA	NA	^Citation81
Ezetimibe	Cholesterol absorption inhibitor	18 µM	18 µM	NA	HepaRG	NA	NA	^Citation83
		NA	NA	<10.4 µM	NA	Huh7-hNTCP	NA	^Citation88
Irbesartan	Angiotensin II receptor inhibitor	35v	35 µM	NA	HepG2-NTCP	NA	NA	^Citation87
		NA	NA	<9.4 µM	NA	Huh7-hNTCP	NA	^Citation88
		17–50 µM	6–17 µM	50–150 µM	HepaRG	HepaRG	NA	^Citation86
Ritonavir	HIV protease inhibitor	NA	NA	<9.1 µM	NA	Huh7-hNTCP	NA	^Citation88
EGCG	Green tea polyphenol	10–20 µM	NA	NA	HuS-E/2	NA	NA	^Citation85
Vanitaracin A	Fungal tricyclic polyketide	0.61±0.23 µM	<45 µM	<6.25 µM	PHH/HepG2-hNTCP-C4	HepG2-hNTCP-C4	2–4 µM	^Citation84
Ro41-5253	Antagonist of retinoic acid receptor	5–10 µM	<100 µM	NA	HepaRG	NA	NA	^Citation57
Interleukin-6	Cell factor	<0.15 ng/ml	NA	NA	HepaRG	NA	0.15–0.62 ng/ml	^Citation55
		0.15–0.62 ng/ml	NA	NA	PHH	NA	2.5–10 ng/ml	^Citation55
PAC	Oligomeric flavonoid	7.8±0.75 µM	NA	<20 µM	PHH	PHH	>20 µM	^Citation91
OHBF-C	Oligomeric flavonoid	4.3±1.2 µM	NA	NA	HepG2-hNTCP-C4	NA	NA	^Citation91
Rosiglitazone	PPARγ agonists	17–50 µM	6–17 µM	17–50 µM	HepaRG	HepaRG	5.1 µM	^Citation86, Citation96
Zafirlukast	Leukotriene receptor antagonist	17 µM	6–17 µM	17–50 µM	HepaRG	HepaRG	6.5 µM	^Citation86, Citation97
TRIAC	Suppress pituitary secretion of TSH	17–50 µM	6–17 µM	17–50 µM	HepaRG	HepaRG	6.9 µM	^Citation86, Citation98
Sulfasalazine	Immunosuppressant	17–50 µM	17–50 µM	50–150 µM	HepaRG	HepaRG	9.6 µM	^Citation86, Citation99
Chicago sky blue 6B	VGLUTs inhibitor	6–17 µM	6–17 µM	17 µM	HepaRG	HepaRG	7.1 µM	^Citation86, Citation100
2H5-A14	Humanized monoclonal antibody	<50 pM	<50 pM	NA	HepG2-hNTCP-C4	NA	NA	^Citation92
Bosentan	Endothelin-receptor antagonist	<100 µM	<100 µM	NA	HepaRG	NA	NA	^Citation77
Propranolol	β-receptor blocker	100 µM	NA	NA	HepaRG	NA	NA	^Citation77

CsA cyclosporin A, CsB cyclosporin B, UDCA ursodeoxycholic acid, TUDCA tauroursodeoxycholic acid, EGCG epigallocatechin-3-gallate, PAC proanthocyanidin, OHBF-C oolonghomobisflavan C, HIV human immunodeficiency virus, PPARγ peroxisome proliferator-activated receptor gamma, TSH thyroid ttimulating hormone, VGLUT vesicular glutamate transporter, HBV hepatitis B virus, HDV hepatitis delta virus, PHH primary cultures of human hepatocyte, NTCP sodium taurocholate cotransporting polypeptide, IC50 half maximal inhibitory concentration, NA not applicable

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