抗HBV新药展望

张晓东; 赵丽娜

doi:10.3969/j.issn.1001-5256.2021.05.001

抗HBV新药展望

DOI: 10.3969/j.issn.1001-5256.2021.05.001

张晓东^{1, 2, ,},
赵丽娜¹

1.
南开大学生命科学学院肿瘤研究室, 天津 300071
2.
天津医科大学肿瘤医院肿瘤研究所, 天津 300060

基金项目:

国家自然科学基金 (31670769)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：张晓东、赵丽娜负责提出研究选题，撰写论文和修订论文。

详细信息

作者简介:
张晓东(1960—)，男，教授，博士生导师，主要从事抗HBV新药和肝癌分子机制研究

通信作者:
张晓东，zhangxd@nankai.edu.cn

中图分类号: R978.7; R512.62
计量
- 文章访问数: 1209
- HTML全文浏览量: 305
- PDF下载量: 233
- 被引次数: 0
出版历程
- 收稿日期: 2021-02-25
- 录用日期: 2021-03-24
- 出版日期: 2021-05-20

Perspectives in the development of new drugs against hepatitis B virus

Xiaodong ZHANG^{1, 2
, ,},
Lina ZHAO¹

1.
Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
2.
Tianjin Cancer Institute, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China

摘要

摘要: 乙型肝炎是由HBV感染导致的一种以肝脏炎性病变为主要临床表现的慢性感染性疾病，HBV的持续复制可导致肝功能异常、肝硬化，甚至发展为肝癌。目前，已有多种抗HBV药物应用于临床治疗, 但却无法达到理想的治疗效果。因此，急需开发新的抗HBV药物，抗HBV治疗的理念也需要不断更新。针对抗HBV药物和阻断宿主与病毒相互作用的药物的研究进展进行了系统的综述，提出了抗HBV药物和切断宿主与病毒相互作用两种药物联合使用的新见解，对开发新的抗HBV药物进行了展望，以期提高乙型肝炎的治愈率。
- 乙型肝炎病毒 /
- 抗病毒药 /
- 宿主与病原体相互作用
Abstract: Hepatitis B is a chronic infectious disease caused by hepatitis B virus (HBV) infection, with liver inflammatory lesions as the main clinical manifestation, and continuous replication of HBV can lead to abnormal liver function, liver cirrhosis, and even liver cancer. At present, a variety of anti-HBV drugs have been applied in clinical practice, but no satisfactory therapeutic effect has been achieved. Therefore, it is urgent to develop new anti-HBV drugs and constantly update the concept of anti-HBV treatment. This article reviews the research advances in anti-HBV drugs and drugs that block the interaction between the host and the virus, proposes the new idea of the combination of anti-HBV drugs and the drugs blocking the interaction between the host and the virus, and looks into the future of the development of new drugs against HBV, so as to improve the cure rate of hepatitis B.
- Hepatitis B Virus /
- Antiviral Agents /
- Host-Pathogen Interactions

HTML全文

图 1 抗HBV新药作用机制示意图

下载: 全尺寸图片幻灯片

参考文献(43)

[1]	SCHWEITZER A, HORN J, MIKOLAJCZYK RT, et al. Estimations of worldwide prevalence of chronic hepatitis B virus infection: A systematic review of data published between 1965 and 2013[J]. Lancet, 2015, 386(10003): 1546-1555. DOI: 10.1016/S0140-6736(15)61412-X.
[2]	HOOFNAGLE JH, LAU D. New therapies for chronic hepatitis B[J]. J Viral Hepat, 1997, 4(Suppl 1): 41-50. DOI: 10.1111/j.1365-2893.1997.tb00159.x.
[3]	LIANG TJ, BLOCK TM, MCMAHON BJ, et al. Present and future therapies of hepatitis B: From discovery to cure[J]. Hepatology, 2015, 62(6): 1893-1908. DOI: 10.1002/hep.28025.
[4]	SUNG JJ, WONG ML, BOWDEN S, et al. Intrahepatic hepatitis B virus covalently closed circular DNA can be a predictor of sustained response to therapy[J]. Gastroenterology, 2005, 128(7): 1890-1897. DOI: 10.1053/j.gastro.2005.03.009.
[5]	WERLE-LAPOSTOLLE B, BOWDEN S, LOCARNINI S, et al. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy[J]. Gastroenterology, 2004, 126(7): 1750-1758. DOI: 10.1053/j.gastro.2004.03.018.
[6]	GOVAN L, WU O, XIN Y, et al. Comparative effectiveness of antiviral treatment for hepatitis B: A systematic review and Bayesian network meta-analysis[J]. Eur J Gastroenterol Hepatol, 2015, 27(8): 882-894. DOI: 10.1097/MEG.0000000000000376.
[7]	YE X, ZHOU M, HE Y, et al. Efficient inhibition of hepatitis B virus infection by a preS1-binding Peptide[J]. Sci Rep, 2016, 6: 29391. DOI: 10.1038/srep29391.
[8]	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]. J Virol, 2015, 89(23): 11945-11953. DOI: 10.1128/JVI.01855-15.
[9]	DONG Z, EKINS S, POLLI JE. Structure-activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate cotransporting polypeptide (NTCP)[J]. Mol Pharm, 2013, 10(3): 1008-1019. DOI: 10.1021/mp300453k.
[10]	YAN H, LIU Y, SUI J, et al. NTCP opens the door for hepatitis B virus infection[J]. Antiviral Res, 2015, 121: 24-30. DOI: 10.1016/j.antiviral.2015.06.002.
[11]	VOLZ T, ALLWEISS L, BEN MBAREK M, et al. The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus[J]. J Hepatol, 2013, 58(5): 861-867. DOI: 10.1016/j.jhep.2012.12.008.
[12]	BLANK A, MARKERT C, HOHMANN N, et al. First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B[J]. J Hepatol, 2016, 65(3): 483-489. DOI: 10.1016/j.jhep.2016.04.013.
[13]	CARTHEW RW, SONTHEIMER EJ. Origins and Mechanisms of miRNAs and siRNAs[J]. Cell, 2009, 136(4): 642-655. DOI: 10.1016/j.cell.2009.01.035.
[14]	YUEN MF, SCHIEFKE I, YOON JH, et al. RNA interference therapy with ARC-520 results in prolonged hepatitis B surface antigen response in patients with chronic hepatitis B infection[J]. Hepatology, 2020, 72(1): 19-31. DOI: 10.1002/hep.31008.
[15]	GISH RG, YUEN MF, CHAN HL, et al. Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent[J]. Antiviral Res, 2015, 121: 97-108. DOI: 10.1016/j.antiviral.2015.06.019.
[16]	BUTI M, ESTEBAN R. Drugs in development for hepatitis B[J]. Drugs, 2005, 65(11): 1451-1460. DOI: 10.2165/00003495-200565110-00001.
[17]	LIU J, ZHANG S, WANG Q, et al. Seroepidemiology of hepatitis B virus infection in 2 million men aged 21-49 years in rural China: A population-based, cross-sectional study[J]. Lancet Infect Dis, 2016, 16(1): 80-86. DOI: 10.1016/S1473-3099(15)00218-2.
[18]	FUNG J, WONG T, CHOK K, et al. Oral nucleos(t)ide analogs alone after liver transplantation in chronic hepatitis B with preexisting rt204 mutation[J]. Transplantation, 2017, 101(10): 2391-2398. DOI: 10.1097/TP.0000000000001883.
[19]	ZHOU J, LIU YY, LIAN JS, et al. Efficacy and safety of tenofovir disoproxil treatment for chronic hepatitis B patients with genotypic resistance to other nucleoside analogues: A prospective study[J]. Chin Med J (Engl), 2017, 130(8): 914-919. DOI: 10.4103/0366-6999.204107.
[20]	BERKE JM, DEHERTOGH P, VERGAUWEN K, et al. Capsid assembly modulators have a dual mechanism of action in primary human hepatocytes infected with hepatitis B virus[J]. Antimicrob Agents Chemother, 2017, 61(8). DOI: 10.1128/AAC.00560-17.
[21]	KLUMPP K, LAM AM, LUKACS C, et al. High-resolution crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein[J]. Proc Natl Acad Sci U S A, 2015, 112(49): 15196-15201. DOI: 10.1073/pnas.1513803112.
[22]	DEWITT MA, MAGIS W, BRAY NL, et al. Selection-free genome editing of the sickle mutation in human adult hematopoietic stem/progenitor cells[J]. Sci Transl Med, 2016, 8(360): 360ra134. DOI: 10.1126/scitranslmed.aaf9336.
[23]	RAMANAN V, SHLOMAI A, COX DB, et al. CRISPR/Cas9 cleavage of viral DNA efficiently suppresses hepatitis B virus[J]. Sci Rep, 2015, 5: 10833. DOI: 10.1038/srep10833.
[24]	WANG J, CHEN R, ZHANG R, et al. The gRNA-miRNA-gRNA ternary cassette combining CRISPR/Cas9 with RNAi approach strongly inhibits hepatitis B virus replication[J]. Theranostics, 2017, 7(12): 3090-3105. DOI: 10.7150/thno.18114.
[25]	LOK AS, PAN CQ, HAN SH, et al. Randomized phase Ⅱ study of GS-4774 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis B[J]. J Hepatol, 2016, 65(3): 509-516. DOI: 10.1016/j.jhep.2016.05.016.
[26]	MENNE S, TUMAS DB, LIU KH, et al. Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B[J]. J Hepatol, 2015, 62(6): 1237-1245. DOI: 10.1016/j.jhep.2014.12.026.
[27]	LANFORD RE, GUERRA B, CHAVEZ D, et al. GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees[J]. Gastroenterology, 2013, 144(7): 1508-1517, 1517. e1-10. DOI: 10.1053/j.gastro.2013.02.003.
[28]	GANE EJ, LIM YS, GORDON SC, et al. The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection[J]. J Hepatol, 2015, 63(2): 320-328. DOI: 10.1016/j.jhep.2015.02.037.
[29]	JANSSEN H, BRUNETTO MR, KIM YJ, et al. Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B[J]. J Hepatol, 2018, 68(3): 431-440. DOI: 10.1016/j.jhep.2017.10.027.
[30]	SCHINAZI RF, EHTESHAMI M, BASSIT L, et al. Towards HBV curative therapies[J]. Liver Int, 2018, 38(Suppl 1): 102-114. DOI: 10.1111/liv.13656.
[31]	SHIN YW, CHO DH, SONG GW, et al. A New ELISA to overcome the pitfalls in quantification of recombinant human monoclonal Anti-HBs, GC1102, by commercial immunoassays[J]. Biol Proced Online, 2018, 20: 18. DOI: 10.1186/s12575-018-0083-8.
[32]	CHEN J, WANG XM, WU XJ, et al. Intrahepatic levels of PD-1/PD-L correlate with liver inflammation in chronic hepatitis B[J]. Inflamm Res, 2011, 60(1): 47-53. DOI: 10.1007/s00011-010-0233-1.
[33]	GANE E, VERDON DJ, BROOKS AE, et al. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study[J]. J Hepatol, 2019, 71(5): 900-907. DOI: 10.1016/j.jhep.2019.06.028.
[34]	BOCK CT, SCHRANZ P, SCHRZÖDER CH, et al. Hepatitis B virus genome is organized into nucleosomes in the nucleus of the infected cell[J]. Virus Genes, 1994, 8(3): 215-229. DOI: 10.1007/BF01703079.
[35]	BOCK CT, SCHWINN S, LOCARNINI S, et al. Structural organization of the hepatitis B virus minichromosome[J]. J Mol Biol, 2001, 307(1): 183-196. DOI: 10.1006/jmbi.2000.4481.
[36]	DAWSON MA. The cancer epigenome: Concepts, challenges, and therapeutic opportunities[J]. Science, 2017, 355(6330): 1147-1152. DOI: 10.1126/science.aam7304.
[37]	GHOSH SK, PERRINE SP, WILLIAMS RM, et al. Histone deacetylase inhibitors are potent inducers of gene expression in latent EBV and sensitize lymphoma cells to nucleoside antiviral agents[J]. Blood, 2012, 119(4): 1008-1017. DOI: 10.1182/blood-2011-06-362434.
[38]	BARLOW DP. Methylation and imprinting: From host defense to gene regulation?[J]. Science, 1993, 260(5106): 309-310. DOI: 10.1126/science.8469984.
[39]	VIVEKANANDAN P, DANIEL HD, KANNANGAI R, et al. Hepatitis B virus replication induces methylation of both host and viral DNA[J]. J Virol, 2010, 84(9): 4321-4329. DOI: 10.1128/JVI.02280-09.
[40]	SHIM YH, YOON GS, CHOI HJ, et al. p16 Hypermethylation in the early stage of hepatitis B virus-associated hepatocarcinogenesis[J]. Cancer Lett, 2003, 190(2): 213-219. DOI: 10.1016/s0304-3835(02)00613-4.
[41]	ZHENG DL, ZHANG L, CHENG N, et al. Epigenetic modification induced by hepatitis B virus X protein via interaction with de novo DNA methyltransferase DNMT3A[J]. J Hepatol, 2009, 50(2): 377-387. DOI: 10.1016/j.jhep.2008.10.019.
[42]	TROPBERGER P, MERCIER A, ROBINSON M, et al. Mapping of histone modifications in episomal HBV cccDNA uncovers an unusual chromatin organization amenable to epigenetic manipulation[J]. Proc Natl Acad Sci U S A, 2015, 112(42): e5715-e5724. DOI: 10.1073/pnas.1518090112.
[43]	ZHANG W, CHEN J, WU M, et al. PRMT5 restricts hepatitis B virus replication through epigenetic repression of covalently closed circular DNA transcription and interference with pregenomic RNA encapsidation[J]. Hepatology, 2017, 66(2): 398-415. DOI: 10.1002/hep.29133.