抗HBV药物的研究进展

蔡梦芝; 秦刚

doi:10.3969/j.issn.1001-5256.2019.10.037

抗HBV药物的研究进展

DOI: 10.3969/j.issn.1001-5256.2019.10.037

蔡梦芝,
秦刚

1. 南通大学医学院内科学系
2. 南通大学附属南通第三医院肝病中心

基金项目:

江苏省重点病种规范化诊疗项目(BE2015655)；南通市市级临床医学中心项目(HS2016002)；

详细信息

中图分类号: R512.62
计量
- 文章访问数: 1622
- HTML全文浏览量: 72
- PDF下载量: 430
- 被引次数: 0
出版历程
- 收稿日期: 2019-05-31
- 出版日期: 2019-10-20

Research advances in anti-hepatitis B virus drugs

Department of Internal Medicine,Medical School of Nantong University

Research funding:

摘要

摘要: HBV感染严重危害全球公众健康,全球约有20亿人感染过HBV。HBV感染可导致慢性肝炎、肝硬化、肝衰竭甚至肝癌。目前,我国已批准可用于慢性乙型肝炎治疗的药物有核苷(酸)类似物和干扰素两大类。长期应用核苷类似物安全性和耐受性良好,且可以有效抑制病毒复制并降低肝脏相关并发症的发生风险,但疗程长且不确定,存在耐药风险及停药后易复发等问题。干扰素类药物副作用较大,且血清学转换及治愈率有限。因此,研发针对HBV不同靶点的新型抗病毒药物对于治疗慢性乙型肝炎至关重要。主要归纳了针对不同靶点的抗HBV药物的研究进展,旨在为临床及相关科研工作提供参考。
- 乙型肝炎病毒 /
- 抗病毒药 /
- 免疫因子类
Abstract: Hepatitis B virus(HBV) infection has always been a great threat to public health,and about 2 billion people in the world have the history of HBV infection. Chronic HBV infection can lead to chronic hepatitis,liver cirrhosis,and even hepatocellular carcinoma. At present,nucleoside analogues(NAs) and interferons(IFNs) have been approved for the treatment of chronic hepatitis B in China. Long-term use of NAs has good safety and tolerability and can effectively inhibit viral replication and reduce the risk of liver-related complications,but there are still the issues such as long and uncertain course of treatment,risk of drug resistance,and recurrence after drug withdrawal. IFNs have severe side effects with limited seroconversion and cure rate. Therefore,the research and development of new antiviral drugs with different targets of HBV is of vital importance for the treatment of chronic HBV infection. This article summarizes the research advances in anti-HBV drugs with different targets,so as to provide a reference for clinical and research work.
- hepatitis B virus /
- antiviral agents /
- immunologic factors

HTML全文

参考文献(43)

[1] SETO WK,LO YR,PAWLOTSKY JM,et al. Chronic hepatitis B virus infection[J]. Lancet,2018,392(10161):2313-2324.

[2] SORIANO V,YOUNG B,REAU N. Report from the international conference on viral hepatitis-2017[J]. AIDS Rev,2018,20(1):58-70.

[3] HOU JL,WANG GQ,WANG FS,et al. Guideline of prevention and treatment for chronic hepatitis B(2015 update)[J]. J Clin Transl Hepatol,2017,5(4):297-318.

[4] LI Y,ZHAN J,WANG ZF. Prognostic factors for patients with hepatitis B virus-related acute-on-chronic liver failure[J].J Clin Hepatol,2017,33(3):497-501.(in Chinese)李蓥,詹婧,王中峰. HBV相关慢加急性肝衰竭患者预后危险因素分析[J].临床肝胆病杂志,2017,33(3):497-501.

[5] WANG XL,SHAO JG,ZHU YC,et al. Epidemiological analysis of acute-on-chronic liver failure in Nantong,Jiangsu Province,2005-2014[J]. Chin J Infect Dis,2016,34(9):530-535.(in Chinese)汪徐林,邵建国,朱永昌,等.江苏省南通地区2005年至2014年慢加急性肝功能衰竭流行病学调查分析[J].中华传染病杂志,2016,34(9):530-535.

[6] YAN H,ZHONG G,XU G,et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus[J]. Elife,2012,1:e00049.

[7] GEHRING A,PROTZER U. Targeting innate and adaptive immune responses to cure chronic HBV infection[J]. Gastroenterology,2019,156(2):325-337.

[8] LIU H. The curative effect of two drugs in the treatment of HBe Ag positive chronic hepatitis B and the forecast factors analysis of the serological conversion[J]. J Clin Exp Med,2017,16(9):883-886.(in Chinese)刘海.两种药物治疗HBe Ag阳性慢性乙型肝炎的疗效及血清学转换预测因素分析[J].临床和实验医学杂志,2017,16(9):883-886.

[9] SLIJEPCEVIC D,KAUFMAN C,WICHERS CG,et al. Impaired uptake of conjugated bile acids and hepatitis b virus pres1-binding in na(+)-taurocholate cotransporting polypeptide knockout mice[J]. Hepatology,2015,62(1):207-219.

[10] 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.

[11] 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]. J Hepatol,2016,65(3):490-498.

[12] LAI CL,AHN SH,LEE KS,et al. Phase IIb multicentred randomised trial of besifovir(LB80380)versus entecavir in Asian patients with chronic hepatitis B[J]. Gut,2014,63(6):996-1004.

[13] 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.

[14] ZHANG PH,LIU F,GUO F,et al. Characterization of novel hepadnaviral RNA species accumulated in hepatoma cells treated with viral DNA polymerase inhibitors[J]. Antiviral Res,2016,131:40-48.

[15] SCHLUEP T,LICKLITER J,HAMILTON J,et al. Safety,tolerability,and pharmacokinetics of ARC-520 injection,an RNA interference-based therapeutic for the treatment of chronic hepatitis B virus infection,in healthy volunteers[J]. Clin Pharmacol Drug Dev,2017,6(4):350-362.

[16] YE X,TATENO C,THI EP,et al. Hepatitis B virus therapeutic agent ARB-1740 has inhibitory effect on hepatitis Delta virus in a new dually-infected humanized mouse model[J]. ACS Infect Dis,2019,5(5):738-749.

[17] THI EP,DHILLON AP,ARDZINSKI A,et al. ARB-1740,a RNA interference therapeutic for chronic hepatitis B infection[J]. ACS Infect Dis,2019,5(5):725-737.

[18] SHIH YM,SUN CP,CHOU HH,et al. Combinatorial RNA interference therapy prevents selection of pre-existing HBV variants in human liver chimeric mice[J]. Sci Rep,2015,5:15259.

[19] TANG LD,ZHAO Q,WU S,et al. The current status and future directions of hepatitis B antiviral drug discovery[J]. Expert Opin Drug Discov,2017,12(1):5-15.

[20] HU J,FLORES D,TOFT D,et al. Requirement of heat shock protein 90 for human hepatitis B virus reverse transcriptase function[J]. J Virol,2004,78(23):13122-13131.

[21] REN QY,LIU XC,YAN GH,et al. 3-((R)-4-(((R)-6-(2-Bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)propanoic acid(HEC72702),a novel hepatitis B virus capsid inhibitor based on clinical candidate GLS4[J]. J Med Chem,2018,61(3):1355-1374.

[22] REN QY,LIU XC,LUO ZH,et al. Discovery of hepatitis B virus capsid assembly inhibitors leading to a heteroaryldihydropyrimidine based clinical candidate(GLS4)[J]. Bioorg Med Chem,2017,25(3):1042-1056.

[23] WU G,LIU B,ZHANG Y,et al. Preclinical characterization of GLS4,an inhibitor of hepatitis B virus core particle assembly[J]. Antimicrob Agents Chemother,2013,57(11):5344-5354.

[24] BAZINET M,PANTEA V,CEBOTARESCU V,et al. Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection(REP 301 and REP 301-LTF):A non-randomised,open-label,phase 2 trial[J]. Lancet Gastroenterol Hepatol,2017,2(12):877-889.

[25] AL-MAHTAB M,BAZINET M,VAILLANT A. Safety and efficacy of nucleic acid polymers in monotherapy and combined with immunotherapy in treatment-naive bangladeshi patients with HBe Ag+chronic hepatitis B infection[J]. PLo S One,2016,11(6):e0156667.

[26] BAZINET M,PANTEA V,PLACINTA G,et al. THU-154-update on safety and efficacy in the REP 401 protocol:REP 2139-Mg or REP 2165-Mg used in combination with tenofovir disoproxil fumarate and pegylated Interferon alpha-2a in treatment nave caucasian patients with chronic HBe Ag negative HBV[J]. J Hepatol,2017,66(1):s256-s257.

[27] EMERY JS,FELD JJ. Treatment of hepatitis B virus with combination therapy now and in the future[J]. Best Pract Res Clin Gastroenterol,2017,31(3):347-355.

[28] LOMONOSOVA E,DAW J,GARIMALLAPRABHAKARAN AK,et al. Efficacy and cytotoxicity in cell culture of novel alphahydroxytropolone inhibitors of hepatitis B virus ribonuclease H[J]. Antiviral Res,2017,144:164-172.

[29] LIAW YF. Natural history of chronic hepatitis B virus infection and long-term outcome under treatment[J]. Liver Int,2009,29(Suppl 1):100-107.

[30] AGUILAR JC,LOBAINA Y,MUZIO V,et al. Development of a nasal vaccine for chronic hepatitis B infection that uses the ability of hepatitis B core antigen to stimulate a strong Th1 response against hepatitis B surface antigen[J]. Immunol Cell Biol,2004,82(5):539-546.

[31] ROTH Y,CHAPNIK JS,COLE P. Feasibility of aerosol vaccination in humans[J]. Ann Otol Rhinol Laryngol,2003,112(3):264-270.

[32] NEUTRA MR,PRINGAULT E,KRAEHENBUHL JP. Antigen sampling across epithelial barriers and induction of mucosal immune responses[J]. Annu Rev Immunol,1996,14:275-300.

[33] WU SS,TANG YY,CHEN XH,et al. Immune response elicited in HBV-transgenic mice by cytoplasmic transduction peptide-HBcAg18-27-Tapasin adjuvanted with CpG ODN[J].Chin J Clin Pharmacol Ther,2018,23(3):271-276.(in Chinese)吴姗姗,唐余燕,陈小华,等. CTP-HBcAg18-27-Tapasin联合佐剂CpG ODN免疫转基因小鼠的免疫应答研究[J].中国临床药理学与治疗学,2018,23(3):271-276.

[34] BETANCOURT AA,DELGADO CA,ESTEVEZ ZC,et al. Phase I clinical trial in healthy adults of a nasal vaccine candidate containing recombinant hepatitis B surface and core antigens[J]. Int J Infect Dis,2007,11(5):394-401.

[35] AL-MAHTAB M,AKBAR SM,AGUILAR JC,et al. Therapeutic potential of a combined hepatitis B virus surface and core antigen vaccine in patients with chronic hepatitis B[J]. Hepatol Int,2013,7(4):981-989.

[36] PAULSEN D,WEBER O,RUEBSAMEN-SCHAEFF H,et al.AIC649 induces a bi-phasic treatment response in the woodchuck model of chronic hepatitis B[J]. PLo S One,2015,10(12):e0144383.

[37] MARTIN P,DUBOIS C,JACQUIER E,et al. TG1050,an immunotherapeutic to treat chronic hepatitis B,induces robust T cells and exerts an antiviral effect in HBV-persistent mice[J]. Gut,2015,64(12):1961-1971.

[38] LI N,FENG L,HAN HQ,et al. A novel Smac mimetic APG-1387 demonstrates potent antitumor activity in nasopharyngeal carcinoma cells by inducing apoptosis[J]. Cancer Lett,2016,381(1):14-22.

[39] FATTAHI S,KARIMI ALIVIJE M,BABAMAHMOODI F,et al.Cytochrome P450 genes(CYP2E1 and CYP1A1)variants and susceptibility to chronic hepatitis B virus infection[J]. Indian J Clin Biochem,2018,33(4):467-472.

[40] TREPANIER DJ,URE DR,FOSTER RT. Development,characterization, and pharmacokinetic evaluation of a CRV431loaded self-microemulsifying drug delivery system[J]. J Pharm Pharm Sci,2018,21(1s):335s-348s.

[41] TREPANIER DJ,URE DR,FOSTER RT. In vitro phase i metabolism of CRV431,a novel oral drug candidate for chronic hepatitis B[J]. Pharmaceutics,2017,9(4):51.

[42] LUCIFORA J,XIA Y,REISINGER F,et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA[J]. Science,2014,343(6176):1221-1228.

[43] 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.

施引文献

资源附件(0)

访问统计