Concept of Viral Inhibitors via NTCP

Kento Fukano; Senko Tsukuda; Koichi Watashi; Takaji Wakita

doi:10.1055/s-0038-1676804

Seminars in Liver Disease, Inhaltsverzeichnis

Semin Liver Dis 2019; 39(01): 078-085
DOI: 10.1055/s-0038-1676804

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Concept of Viral Inhibitors via NTCP

Authors

Kento Fukano^*

¹Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan

²Department of Analytical Biochemistry, Meiji Pharmaceutical University, Kiyose, Japan
Senko Tsukuda^*

¹Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan

³Liver Cancer Prevention Research Unit, RIKEN Center for Integrative Medical Sciences (IMS), Wako, Japan
Koichi Watashi

¹Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan

⁴Department of Applied Biological Science, Tokyo University of Science, Noda, Japan

⁵JST CREST, Saitama, Japan
Takaji Wakita

¹Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan

Abstract

Identification of sodium taurocholate cotransporting polypeptide (NTCP) as an entry receptor for hepatitis B and D viruses (HBV and HDV) has not only promoted our understanding of the mechanism underlying the viral entry process, but also provided cell culture models supporting viral infection. These models have greatly facilitated cell-based chemical screening for the discovery of entry inhibitors, and mode of action studies using such inhibitors have shown the advantages of NTCP as a drug target. Furthermore, in vitro chemical screening by application of high-throughput affinity-based technologies that target NTCP has identified a variety of unique small molecules that interfere with viral entry. This review summarizes this hot topic in the development of HBV/HDV entry inhibitors, with special focus on the use of NTCP as a drug target.

Keywords

HBV - HDV - NTCP - entry - screening

Volltext

Referenzen

References
1 Revill PA, Locarnini SA. New perspectives on the hepatitis B virus life cycle in the human liver. J Clin Invest 2016; 126 (03) 833-836
2 Cornberg M, Wong VW-S, Locarnini S, Brunetto M, Janssen HLA, Chan HL-Y. The role of quantitative hepatitis B surface antigen revisited. J Hepatol 2017; 66 (02) 398-411
3 Testoni B, Durantel D, Zoulim F. Novel targets for hepatitis B virus therapy. Liver Int 2017; 37 (Suppl. 01) 33-39
4 Levrero M, Subic M, Villeret F, Zoulim F. Perspectives and limitations for nucleo(t)side analogs in future HBV therapies. Curr Opin Virol 2018; 30: 80-89
5 Liang TJ, Block TM, McMahon BJ. , et al. Present and future therapies of hepatitis B: From discovery to cure. Hepatology 2015; 62 (06) 1893-1908
6 Petersen J, Thompson AJ, Levrero M. Aiming for cure in HBV and HDV infection. J Hepatol 2016; 65 (04) 835-848
7 Yan H, Zhong G, Xu G. , et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife 2012; 1: e00049
8 Li W, Urban S. Entry of hepatitis B and hepatitis D virus into hepatocytes: basic insights and clinical implications. J Hepatol 2016; 64 (1, Suppl): S32-S40
9 Watashi K, Wakita T. Hepatitis B virus and hepatitis d virus entry, species specificity, and tissue tropism. Cold Spring Harb Perspect Med 2015; 5 (08) a021378
10 Cooper A, Shaul Y. Clathrin-mediated endocytosis and lysosomal cleavage of hepatitis B virus capsid-like core particles. J Biol Chem 2006; 281 (24) 16563-16569
11 Macovei A, Radulescu C, Lazar C. , et al. Hepatitis B virus requires intact caveolin-1 function for productive infection in HepaRG cells. J Virol 2010; 84 (01) 243-253
12 Urban S, Bartenschlager R, Kubitz R, Zoulim F. Strategies to inhibit entry of HBV and HDV into hepatocytes. Gastroenterology 2014; 147 (01) 48-64
13 Patient R, Hourioux C, Roingeard P. Morphogenesis of hepatitis B virus and its subviral envelope particles. Cell Microbiol 2009; 11 (11) 1561-1570
14 Lempp FA, Ni Y, Urban S. Hepatitis delta virus: insights into a peculiar pathogen and novel treatment options. Nat Rev Gastroenterol Hepatol 2016; 13 (10) 580-589
15 Flores R, Owens RA, Taylor J. Pathogenesis by subviral agents: viroids and hepatitis delta virus. Curr Opin Virol 2016; 17: 87-94
16 Le Seyec J, Chouteau P, Cannie I, Guguen-Guillouzo C, Gripon P. Role of the pre-S2 domain of the large envelope protein in hepatitis B virus assembly and infectivity. J Virol 1998; 72 (07) 5573-5578
17 Abou-Jaoudé G, Sureau C. Entry of hepatitis delta virus requires the conserved cysteine residues of the hepatitis B virus envelope protein antigenic loop and is blocked by inhibitors of thiol-disulfide exchange. J Virol 2007; 81 (23) 13057-13066
18 Salisse J, Sureau C. A function essential to viral entry underlies the hepatitis B virus “a” determinant. J Virol 2009; 83 (18) 9321-9328
19 Ni Y, Sonnabend J, Seitz S, Urban S. The pre-s2 domain of the hepatitis B virus is dispensable for infectivity but serves a spacer function for L-protein-connected virus assembly. J Virol 2010; 84 (08) 3879-3888
20 Bremer CM, Sominskaya I, Skrastina D. , et al. N-terminal myristoylation-dependent masking of neutralizing epitopes in the preS1 attachment site of hepatitis B virus. J Hepatol 2011; 55 (01) 29-37
21 Jaoudé GA, Sureau C. Role of the antigenic loop of the hepatitis B virus envelope proteins in infectivity of hepatitis delta virus. J Virol 2005; 79 (16) 10460-10466
22 Sureau C, Salisse J. A conformational heparan sulfate binding site essential to infectivity overlaps with the conserved hepatitis B virus a-determinant. Hepatology 2013; 57 (03) 985-994
23 Schulze A, Gripon P, Urban S. Hepatitis B virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycans. Hepatology 2007; 46 (06) 1759-1768
24 Persing DH, Varmus HE, Ganem D. The preS1 protein of hepatitis B virus is acylated at its amino terminus with myristic acid. J Virol 1987; 61 (05) 1672-1677
25 Bruss V, Hagelstein J, Gerhardt E, Galle PR. Myristylation of the large surface protein is required for hepatitis B virus in vitro infectivity. Virology 1996; 218 (02) 396-399
26 Gripon P, Le Seyec J, Rumin S, Guguen-Guillouzo C. Myristylation of the hepatitis B virus large surface protein is essential for viral infectivity. Virology 1995; 213 (02) 292-299
27 De Falco S, Ruvo M, Verdoliva A. , et al. N-terminal myristylation of HBV preS1 domain enhances receptor recognition. J Pept Res 2001; 57 (05) 390-400
28 Le Seyec J, Chouteau P, Cannie I, Guguen-Guillouzo C, Gripon P. Infection process of the hepatitis B virus depends on the presence of a defined sequence in the pre-S1 domain. J Virol 1999; 73 (03) 2052-2057
29 Glebe D, Urban S, Knoop EV. , et al. Mapping of the hepatitis B virus attachment site by use of infection-inhibiting preS1 lipopeptides and tupaia hepatocytes. Gastroenterology 2005; 129 (01) 234-245
30 Engelke M, Mills K, Seitz S. , et al. Characterization of a hepatitis B and hepatitis delta virus receptor binding site. Hepatology 2006; 43 (04) 750-760
31 Gripon P, Cannie I, Urban S. Efficient inhibition of hepatitis B virus infection by acylated peptides derived from the large viral surface protein. J Virol 2005; 79 (03) 1613-1622
32 Barrera A, Guerra B, Notvall L, Lanford RE. Mapping of the hepatitis B virus pre-S1 domain involved in receptor recognition. J Virol 2005; 79 (15) 9786-9798
33 Dawson PA, Lan T, Rao A. Bile acid transporters. J Lipid Res 2009; 50 (12) 2340-2357
34 Hagenbuch B, Meier PJ. Sinusoidal (basolateral) bile salt uptake systems of hepatocytes. Semin Liver Dis 1996; 16 (02) 129-136
35 Weinman SA. Electrogenicity of Na(+)-coupled bile acid transporters. Yale J Biol Med 1997; 70 (04) 331-340
36 Boyer JL, Ng OC, Ananthanarayanan M. , et al. Expression and characterization of a functional rat liver Na+ bile acid cotransport system in COS-7 cells. Am J Physiol 1994; 266 (3 Pt 1): G382-G387
37 Kramer W, Stengelin S, Baringhaus KH. , et al. Substrate specificity of the ileal and the hepatic Na(+)/bile acid cotransporters of the rabbit. I. Transport studies with membrane vesicles and cell lines expressing the cloned transporters. J Lipid Res 1999; 40 (09) 1604-1617
38 Hagenbuch B, Meier PJ. Molecular cloning, chromosomal localization, and functional characterization of a human liver Na+/bile acid cotransporter. J Clin Invest 1994; 93 (03) 1326-1331
39 Hata S, Wang P, Eftychiou N. , et al. Substrate specificities of rat oatp1 and ntcp: implications for hepatic organic anion uptake. Am J Physiol Gastrointest Liver Physiol 2003; 285 (05) G829-G839
40 Yanni SB, Augustijns PF, Benjamin Jr DK, Brouwer KLR, Thakker DR, Annaert PP. In vitro investigation of the hepatobiliary disposition mechanisms of the antifungal agent micafungin in humans and rats. Drug Metab Dispos 2010; 38 (10) 1848-1856
41 Greupink R, Dillen L, Monshouwer M, Huisman MT, Russel FGM. Interaction of fluvastatin with the liver-specific Na+ -dependent taurocholate cotransporting polypeptide (NTCP). Eur J Pharm Sci 2011; 44 (04) 487-496
42 Stieger B. The role of the sodium-taurocholate cotransporting polypeptide (NTCP) and of the bile salt export pump (BSEP) in physiology and pathophysiology of bile formation. Handb Exp Pharmacol 2011; 201 (201) 205-259
43 Hallén S, Björquist A, Östlund-Lindqvist AM, Sachs G. Identification of a region of the ileal-type sodium/bile acid cotransporter interacting with a competitive bile acid transport inhibitor. Biochemistry 2002; 41 (50) 14916-14924
44 Mareninova O, Shin JM, Vagin O, Turdikulova S, Hallen S, Sachs G. Topography of the membrane domain of the liver Na+-dependent bile acid transporter. Biochemistry 2005; 44 (42) 13702-13712
45 Ni Y, Lempp FA, Mehrle S. , et al. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology 2014; 146 (04) 1070-1083
46 He W, Cao Z, Mao F. , et al. Modification of three amino acids in sodium taurocholate cotransporting polypeptide renders mice susceptible to infection with hepatitis D virus in vivo. J Virol 2016; 90 (19) 8866-8874
47 Yan H, Peng B, Liu Y. , et al. Viral entry of hepatitis B and D viruses and bile salts transportation share common molecular determinants on sodium taurocholate cotransporting polypeptide. J Virol 2014; 88 (06) 3273-3284
48 Shimura S, Watashi K, Fukano K. , et al. Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity. J Hepatol 2017; 66 (04) 685-692
49 Passioura T, Watashi K, Fukano K. , et al. De novo macrocyclic peptide inhibitors of hepatitis B virus cellular entry. Cell Chem Biol 2018; 25 (07) 906-915.e5
50 Colpitts CC, Verrier ER, Baumert TF. Targeting viral entry for treatment of hepatitis B and C virus infections. ACS Infect Dis 2015; 1 (09) 420-427
51 Schulze A, Schieck A, Ni Y, Mier W, Urban S. Fine mapping of pre-S sequence requirements for hepatitis B virus large envelope protein-mediated receptor interaction. J Virol 2010; 84 (04) 1989-2000
52 Petersen J, Dandri M, Mier W. , et al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat Biotechnol 2008; 26 (03) 335-341
53 Nkongolo S, Ni Y, Lempp FA. , et al. Cyclosporin A inhibits hepatitis B and hepatitis D virus entry by cyclophilin-independent interference with the NTCP receptor. J Hepatol 2014; 60 (04) 723-731
54 Bogomolov P, Alexandrov A, Voronkova N. , et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: First results of a phase Ib/IIa study. J Hepatol 2016; 65 (03) 490-498
55 Watashi K, Sluder A, Daito T. , et al. Cyclosporin A and its analogs inhibit hepatitis B virus entry into cultured hepatocytes through targeting a membrane transporter, sodium taurocholate cotransporting polypeptide (NTCP). Hepatology 2014; 59 (05) 1726-1737
56 König A, Döring B, Mohr C, Geipel A, Geyer J, Glebe D. Kinetics of the bile acid transporter and hepatitis B virus receptor Na+/taurocholate cotransporting polypeptide (NTCP) in hepatocytes. J Hepatol 2014; 61 (04) 867-875
57 Veloso Alves Pereira I, Buchmann B, Sandmann L. , et al. Primary biliary acids inhibit hepatitis D virus (HDV) entry into human hepatoma cells expressing the sodium-taurocholate cotransporting polypeptide (NTCP). PLoS One 2015; 10 (02) e0117152
58 Dong Z, Ekins S, Polli JE. Structure-activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate cotransporting polypeptide (NTCP). Mol Pharm 2013; 10 (03) 1008-1019
59 Blanchet M, Sureau C, Labonté P. Use of FDA approved therapeutics with hNTCP metabolic inhibitory properties to impair the HDV lifecycle. Antiviral Res 2014; 106: 111-115
60 Ko C, Park W-J, Park S, Kim S, Windisch MP, Ryu W-S. The FDA-approved drug irbesartan inhibits HBV-infection in HepG2 cells stably expressing sodium taurocholate co-transporting polypeptide. Antivir Ther 2015; 20 (08) 835-842
61 Wang X-J, Hu W, Zhang T-Y, Mao Y-Y, Liu N-N, Wang S-Q. Irbesartan, an FDA approved drug for hypertension and diabetic nephropathy, is a potent inhibitor for hepatitis B virus entry by disturbing Na(+)-dependent taurocholate cotransporting polypeptide activity. Antiviral Res 2015; 120: 140-146
62 Lucifora J, Esser K, Protzer U. Ezetimibe blocks hepatitis B virus infection after virus uptake into hepatocytes. Antiviral Res 2013; 97 (02) 195-197
63 Paeshuyse J, Kaul A, De Clercq E. , et al. The non-immunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro. Hepatology 2006; 43 (04) 761-770
64 Iwamoto M, Watashi K, Tsukuda S. , et al. Evaluation and identification of hepatitis B virus entry inhibitors using HepG2 cells overexpressing a membrane transporter NTCP. Biochem Biophys Res Commun 2014; 443 (03) 808-813
65 Kaneko M, Watashi K, Kamisuki S. , et al. A novel tricyclic polyketide, vanitaracin a, specifically inhibits the entry of hepatitis B and D viruses by targeting sodium taurocholate cotransporting polypeptide. J Virol 2015; 89 (23) 11945-11953
66 Matsunaga H, Kamisuki S, Kaneko M. , et al. Isolation and structure of vanitaracin A, a novel anti-hepatitis B virus compound from Talaromyces sp. Bioorg Med Chem Lett 2015; 25 (19) 4325-4328
67 Okuyama-Dobashi K, Kasai H, Tanaka T. , et al. Hepatitis B virus efficiently infects non-adherent hepatoma cells via human sodium taurocholate cotransporting polypeptide. Sci Rep 2015; 5: 17047
68 Zhang J, Fu L-L, Tian M. , et al. Design and synthesis of a novel candidate compound NTI-007 targeting sodium taurocholate cotransporting polypeptide [NTCP]-APOA1-HBx-Beclin1-mediated autophagic pathway in HBV therapy. Bioorg Med Chem 2015; 23 (05) 976-984
69 Nio Y, Akahori Y, Okamura H, Watashi K, Wakita T, Hijikata M. Inhibitory effect of fasiglifam on hepatitis B virus infections through suppression of the sodium taurocholate cotransporting polypeptide. Biochem Biophys Res Commun 2018; 501 (03) 820-825
70 Lickteig AJ, Fisher CD, Augustine LM. , et al. Efflux transporter expression and acetaminophen metabolite excretion are altered in rodent models of nonalcoholic fatty liver disease. Drug Metab Dispos 2007; 35 (10) 1970-1978
71 Andrejko KM, Raj NR, Kim PK, Cereda M, Deutschman CS. IL-6 modulates sepsis-induced decreases in transcription of hepatic organic anion and bile acid transporters. Shock 2008; 29 (04) 490-496
72 Le Vee M, Jouan E, Stieger B, Lecureur V, Fardel O. Regulation of drug transporter expression by oncostatin M in human hepatocytes. Biochem Pharmacol 2011; 82 (03) 304-311
73 Aoki K, Nakajima M, Hoshi Y. , et al. Effect of aminoguanidine on lipopolysaccharide-induced changes in rat liver transporters and transcription factors. Biol Pharm Bull 2008; 31 (03) 412-420
74 Denson LA, Auld KL, Schiek DS, McClure MH, Mangelsdorf DJ, Karpen SJ. Interleukin-1beta suppresses retinoid transactivation of two hepatic transporter genes involved in bile formation. J Biol Chem 2000; 275 (12) 8835-8843
75 Green RM, Beier D, Gollan JL. Regulation of hepatocyte bile salt transporters by endotoxin and inflammatory cytokines in rodents. Gastroenterology 1996; 111 (01) 193-198
76 Geier A, Dietrich CG, Voigt S. , et al. Effects of proinflammatory cytokines on rat organic anion transporters during toxic liver injury and cholestasis. Hepatology 2003; 38 (02) 345-354
77 Bouezzedine F, Fardel O, Gripon P. Interleukin 6 inhibits HBV entry through NTCP down regulation. Virology 2015; 481: 34-42
78 Tsukuda S, Watashi K, Iwamoto M. , et al. Dysregulation of retinoic acid receptor diminishes hepatocyte permissiveness to hepatitis B virus infection through modulation of sodium taurocholate cotransporting polypeptide (NTCP) expression. J Biol Chem 2015; 290 (09) 5673-5684
79 Huang H-C, Tao M-H, Hung T-M, Chen J-C, Lin Z-J, Huang C. (-)-Epigallocatechin-3-gallate inhibits entry of hepatitis B virus into hepatocytes. Antiviral Res 2014; 111: 100-111
80 Miyakawa K, Matsunaga S, Yamaoka Y. , et al. Development of a cell-based assay to identify hepatitis B virus entry inhibitors targeting the sodium taurocholate cotransporting polypeptide. Oncotarget 2018; 9 (34) 23681-23694
81 Tsukuda S, Watashi K, Hojima T. , et al. A new class of hepatitis B and D virus entry inhibitors, proanthocyanidin and its analogs, that directly act on the viral large surface proteins. Hepatology 2017; 65 (04) 1104-1116
82 Song M, Sun Y, Tian J. , et al. Silencing retinoid X receptor alpha expression enhances early-stage hepatitis B virus infection in cell cultures. J Virol 2018; 92 (08) 92
83 Donkers JM, Zehnder B, van Westen GJP. , et al. Reduced hepatitis B and D viral entry using clinically applied drugs as novel inhibitors of the bile acid transporter NTCP. Sci Rep 2017; 7 (01) 15307
84 Xia Y, Carpentier A, Cheng X. , et al. Human stem cell-derived hepatocytes as a model for hepatitis B virus infection, spreading and virus-host interactions. J Hepatol 2017; 66 (03) 494-503
85 Osada H. Introduction of new tools for chemical biology research on microbial metabolites. Biosci Biotechnol Biochem 2010; 74 (06) 1135-1140
86 Kaneko M, Futamura Y, Tsukuda S. , et al. Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide. Sci Rep 2018; 8 (01) 2769
87 Ito K, Passioura T, Suga H. Technologies for the synthesis of mRNA-encoding libraries and discovery of bioactive natural product-inspired non-traditional macrocyclic peptides. Molecules 2013; 18 (03) 3502-3528
88 Sierecki E, Giles N, Polinkovsky M, Moustaqil M, Alexandrov K, Gambin Y. A cell-free approach to accelerate the study of protein-protein interactions in vitro. Interface Focus 2013; 3 (05) 20130018
89 Saso W, Tsukuda S, Ohashi H. , et al. A new strategy to identify hepatitis B virus entry inhibitors by AlphaScreen technology targeting the envelope-receptor interaction. Biochem Biophys Res Commun 2018; 501 (02) 374-379
90 Heermann KH, Goldmann U, Schwartz W, Seyffarth T, Baumgarten H, Gerlich WH. Large surface proteins of hepatitis B virus containing the pre-s sequence. J Virol 1984; 52 (02) 396-402
91 Glebe D, Aliakbari M, Krass P, Knoop EV, Valerius KP, Gerlich WH. Pre-s1 antigen-dependent infection of Tupaia hepatocyte cultures with human hepatitis B virus. J Virol 2003; 77 (17) 9511-9521
92 Ryu CJ, Kim YK, Hur H. , et al. Mouse monoclonal antibodies to hepatitis B virus preS1 produced after immunization with recombinant preS1 peptide. Hybridoma 2000; 19 (02) 185-189
93 Hong HJ, Ryu CJ, Hur H. , et al. In vivo neutralization of hepatitis B virus infection by an anti-preS1 humanized antibody in chimpanzees. Virology 2004; 318 (01) 134-141
94 Chi S-W, Maeng C-Y, Kim SJ. , et al. Broadly neutralizing anti-hepatitis B virus antibody reveals a complementarity determining region H3 lid-opening mechanism. Proc Natl Acad Sci U S A 2007; 104 (22) 9230-9235
95 Zhang P, Yu M-YW, Venable R, Alter HJ, Shih JW-K. Neutralization epitope responsible for the hepatitis B virus subtype-specific protection in chimpanzees. Proc Natl Acad Sci U S A 2006; 103 (24) 9214-9219
96 Li D, He W, Liu X. , et al. A potent human neutralizing antibody Fc-dependently reduces established HBV infections. eLife 2017; 6: 213