J Bacteriol Virol.  2020 Sep;50(3):175-180. 10.4167/jbv.2020.50.3.175.

Recent Research and Knowledge on Treatment for Hepatitis B

• Lee Hw
• Choi Y
• Park YK

• KMID: 2512136
• DOI: http://doi.org/10.4167/jbv.2020.50.3.175

Abstract

Hepatitis B virus (HBV) infection is a major public health problem, with some 250 million people currently at high risk of developing chronic liver diseases. The current antiviral treatment for chronic hepatitis B (CHB) is effective in controlling viral replication but fails to achieve a complete cure. Since the identification of sodium taurocholate cotransport polypeptide (NTCP) as an HBV receptor, anti-HBV drugs targeting viral entry, capsid assembly, cccDNA, transcription, and secretion have been developed. In this paper, the potential inhibitors in various steps of the HBV life cycle are summarized.

Keyword

Hepatitis B virus; Drugs; cccDNA; ISG20

Reference

1. Seeger C, Mason WS. Molecular biology of hepatitis B virus infection. Virology 2015;672-86.DOI: 10.1016/j.virol.2015.02.031. PMID: 25759099. PMCID: PMC4424072.

2. Trépo C, Chan HLY, Lok A. Hepatitis B virus infection. Lancet 2014;384:2053-63.DOI: 10.1016/S0140-6736(14)60220-8.

3. Ghany MG, Doo EC. Antiviral resistance and hepatitis B therapy. Hepatology 2009;49:S174-84.DOI: 10.1002/hep.22900. PMID: 19399794. PMCID: PMC2707848.

4. Kim JH, Park YK, Park ES, Kim KH. Molecular diagnosis and treatment of drug-resistant HBV. World J Gastroentrol 2014;20:5708-20.DOI: 10.3748/wjg.v20.i19.5708. PMID: 24914332. PMCID: PMC4024781.

5. Lempp FA, Urban S. Inhibitors of hepatitis B virus attachment and entry. Intervirology 2014;57:151-7.DOI: 10.1159/000360948. PMID: 25034482.

6. Nassal M. HBV cccDNA: viral persistance reservoir and key obstacle for a cure of chronic hepatitis B. Gut 2015;64:1972-84.DOI: 10.1136/gutjnl-2015-309809. PMID: 26048673.

7. 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;79:1613-22.DOI: 10.1128/JVI.79.3.1613-1622.2005. PMID: 15650187. PMCID: PMC544121.

8. Spyrou E, Smith CI, Ghany MG. Hepatitis B: Current Status of Therapy and Future Theapies. Gastroenterol Clin North Am 2020;49:215-38.DOI: 10.1016/j.gtc.2020.01.003. PMID: 32389360.

9. Watashi K, Sluder A, Daito T, Matsunaga S, Ryo A, Nagamori S, et al. Cyclosporine A and its analogs inhibit hepatitis B virus entry into cultured hepatocytes therough targeting a membrane transporter, sodium taurocholate cotransporting polypeptide (NTCP). Hepatology 2014;59:1726-37.DOI: 10.1002/hep.26982. PMID: 24375637. PMCID: PMC4265264.

10. Shimura S, Watashi K, Fukano K, Peel M, Sluder A, Kawai F, et al. Cyclosporin derivatives inhibits hepatitis B virus entry without interfering with NTCP transporter activity. J Hepatol 2017;66:685-92.DOI: 10.1016/j.jhep.2016.11.009. PMID: 27890789. PMCID: PMC7172969.

11. Wang XJ, Hu W, Zhang TY, Mao YY, Liu NN, Wang SQ. 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;120:140-6.DOI: 10.1016/j.antiviral.2015.06.007. PMID: 26086883.

12. Lucifora J, Esser K, Protzer U. Ezetimibe blocks hepatitis B virus infection after virus uptake into hepatocytes. Antiviral Res 2013;97:195-7.DOI: 10.1016/j.antiviral.2012.12.008. PMID: 23266293.

13. Venkatakrishnan B, Katen SP, Francis S, Chirapu S, Finn MG, Zlotnick A. Hepatitis B virus capsids have diverse structural responses to small-molecule ligands bound to the heteroaryldihydropyrimidine pocket. J Virol 2016;90:3994-4004.DOI: 10.1128/JVI.03058-15. PMID: 26842475. PMCID: PMC4810570.

14. Fanning GC, Zoulim F, Hou J, Bertoletti A. Therapeutic strategies for hepatitis B virus infection : towards a cure. Nat Rev Drug Discov 2019;18:827-44.DOI: 10.1038/s41573-019-0037-0. PMID: 31455905.

15. Lam AM, Ren S, Espiritu C, Kelly M, Lau V, Zheng L, et al. Hepatitis B virus capsid assembly modulators, but not nucleoside analogs, inhibit the production of extracellular pregenomic RNA and spliced RNA varients. Antimicrob Agents Chemother 2017;61:e00680-17.DOI: 10.1128/AAC.00680-17. PMID: 28559265. PMCID: PMC5527605.

16. Lam AM, Espiritu C, Vogel R, Ren S, Lau V, Kelly M, et al. Preclinical Characterization of NVR 3-778, a First-in-Class Capsid Assembly Modulator against Hepatitis B Virus. Antimicrob Agents Chemother 2018;63;e01734-18.DOI: 10.1128/AAC.01734-18. PMID: 30373799. PMCID: PMC6325219.

17. Hong X, Kim ES, Guo H. Epigenetic regulation of hepatitis B virus covalently closed circular DNA: implications for epigenetic therapy against chronic hepatitis B. Hepatology 2017;66:2066-77.DOI: 10.1002/hep.29479. PMID: 28833361. PMCID: PMC5696023.

18. Tropberger P, Mercier A, Robinson M, Zhong W, Ganem DE, Holdort M. Mapping of histone modifications in episomal HBV cccDNA uncovers an unusual chromatin organization amenable to epigenetic manipulation. Proc Natl Acad Sci U S A 2015;112:E5715-24.DOI: 10.1073/pnas.1518090112. PMID: 26438841. PMCID: PMC4620859.

19. Karimova M, Beschomer N, Dammermann W, Chemnitz J, Indenbirken D, Bockmann JH, et al. CRISPR/Cas9 nickase-mediated disruption of hepatitis B virus open reading frame S and X. Sci Rep 2015;5:13734.DOI: 10.1038/srep13734. PMID: 26334116. PMCID: PMC4558539.

20. Durantel D, Zoulim F. New antiviral targets for innonvative treatment concepts for hepatitis B virus and hepatitis delta virus. J Hepatol 2016;64:S117-31.DOI: 10.1016/j.jhep.2016.02.016. PMID: 27084032.

21. Levrero M, Testoni B, Zoulim F. HBV cure: why, how, when?. Curr Opin Virol 2016;18:135-43.DOI: 10.1016/j.coviro.2016.06.003. PMID: 27447092.

22. Sato S, Li K, Kameyama T, Hayashi T, Ishida Y, Murakami S, et al. The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus. Immunity 2015;42:123-32.DOI: 10.1016/j.immuni.2014.12.016. PMID: 25557055.

23. Park YK, Lee SY, Lee AR, Kim KC, Kim K, Kim KH, et al. Antiviral activity of interferon-stimulated gene 20, as a putative repressor binding to hepatitis B virus enhancer II and core promoter. J Gastroenterol hepatol 2020;35:1426-36.DOI: 10.1111/jgh.14986. PMID: 31951295. PMCID: PMC7497004.