亲环素抑制剂可减少HBV复制和HBsAg产生

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体外及临床研究表明，亲环素抑制剂具有较强的抗HCV活性。那么，亲环素抑制剂是否对HBV的生命周期也有作用呢？英国伦敦肝病研究所Phillips等近日完成的一项研究表明，应用亲环素抑制剂阿拉泊韦（alisporivir）可减少HBV DNA的复制，并抑制HBsAg的产生和分泌。
　　该研究采用HepG2215（稳定转染HBV）、HuH-7（瞬时转染HBV）、HepaRG细胞（感染HBV）等肝源性细胞系，与阿拉泊韦或安慰剂单独孵育。结果，阿拉泊韦可呈剂量依赖性地减少HepG2215、HuH-7和HepaRG的细胞内HBV DNA水平。而且，联合应用阿拉泊韦和替比夫定，较单用两种药物的抗病毒作用更强。
　　此外，研究者运用小干扰RNA技术对细胞进行亲环素基因敲除后发现，细胞内HBsAg的分泌可显著减少，导致HBsAg的细胞内积累。然而，在添加阿拉泊韦后，细胞内HBsAg水平可显著降低。
　　原文链接：Phillips S, Chokshi S, Chatterji U, et al. Alisporivir Inhibition of Hepatocyte Cyclophilins Reduces HBV Replication and Hepatitis B Surface Antigen Production. Gastroenterology. 2014 Oct 8.

newchinabok

阿拉泊韦（alisporivir），高人查查看，hcv药研发有100多种，能不能治hbv？

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Alisporivir Inhibition of Hepatocyte Cyclophilins Reduces HBV Replication and Hepatitis B Surface Antigen Production

Sandra Phillips∗, Shilpa Chokshi∗, Udayan Chatterji, Antonio Riva, Michael Bobardt, Roger Williams, Philippe Gallay, Nikolai V. Naoumov
∗Author names with designate shared first co-authorship.
Received: December 15, 2013; Received in revised form: September 15, 2014; Accepted: October 5, 2014; Published Online: October 08, 2014
DOI: http://dx.doi.org/10.1053/j.gastro.2014.10.004
Publication stage: In Press Accepted Manuscript
Abstract
Abstract
Background & Aims
Cyclophilins are host factors required for hepatitis C virus (HCV) replication. Cyclophilin inhibitors such as alisporivir have shown strong anti-HCV activity in vitro and in clinical studies. However, little is known about whether hepatocyte cyclophilins are involved in the hepatitis B virus (HBV) life cycle. We investigated the effects of 2 cyclophilin inhibitors (alisporivir and NIM811) on HBV replication and hepatitis B surface antigen (HBsAg) production in cell lines.

Methods
Liver-derived cell lines producing full-length HBV and HBsAg particles, due to stable (HepG2215) or transient (HuH-7) transfection, or infected with HBV (HepaRG cells), were incubated with alisporivir or NIM811 alone, or alisporivir in combination with a direct antiviral (telbivudine). The roles of individual cyclophilins in drug response was evaluated by small interfering RNA knockdown of cyclophilin (CYP)A, CYPC, or CYPD in HepG2215 cells, or CYPA knockdown in HuH-7 cells. The kinetics of antiviral activity were assessed based on levels of HBV DNA and HBsAg and Southern blot analysis.

Results
In HepG2215, HuH-7, and HepaRG cells, alisporivir reduced intracellular and secreted HBV DNA, in a dose-dependent manner. Knockdown of CYPA, CYPC, or CYPD (reduced by 80%) significantly reduced levels of HBV DNA and secreted HBsAg. Knockdown of CYPA significantly reduced secretion of HBsAg, leading to accumulation of intracellular HBsAg; the addition of alisporivir greatly reduced levels of HBsAg in these cells. The combination of alisporivir and telbivudine had greater antiviral effects than those of telbivudine or alisporivir alone.

Conclusions
Alisporivir inhibition of cyclophilins in hepatocyte cell lines reduces replication of HBV DNA and HBsAg production and secretion. These effects are potentiated in combination with direct antiviral agents that target HBV DNA polymerase.

Keywords:
cyclophilin inhibition, direct-acting antiviral agent, peptidyl-prolyl isomerase, viral replication
Abbreviations usedin this paper:
ALV (Alisporivir), CYPA (Cyclophilin A), CYPC (Cyclophilin C), CYPD (Cyclophilin D), GAPDH (Glyceraldehyde 3- Phosphate Dehydrogenase), HBsAg (Hepatitis B Surface Antigen), HBV (Hepatitis B Virus), HCV (Hepatitis C Virus), iHBsAg (intracellular HBsAg), sHBsAg (secreted HBsAg), PCR (Polymerase chain reaction), RT-PCR (real-time PCR), siRNA (small interfering RNA), shRNA (small hairpin RNA), Telbivudine (LdT)

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肝细胞亲环的Alisporivir降低抑制乙肝病毒的复制和乙肝表面抗原生产

桑德拉·菲利普斯，希尔帕Chokshi*，查特吉主席Udayan，安东尼奥·里瓦，迈克尔Bobardt，罗杰·威廉姆斯，菲利普Gallay，尼古拉五Naoumov
*与候共享第一合着作者姓名。
收稿日期：二○一三年十二月十五日;收到修改稿：2014年9月15日;接受日期：2014年10月5日;发表时间：2014年10月8日
DOI：http://dx.doi.org/10.1053/j.gastro.2014.10.004
出版阶段：按接受手稿
摘要
摘要
背景与目的
亲环所需要的丙型肝炎病毒（HCV）复制宿主因素。亲环蛋白抑制剂，如alisporivir已在体外和临床研究中显示了强大的抗HCV活性。然而，鲜为人知的是，肝细胞亲环素是否参与了乙型肝炎病毒（HBV）的生命周期。我们研究了2亲环蛋白抑制剂（alisporivir和NIM811）对HBV复制和B型肝炎表面抗原（HBsAg）的生产细胞系的影响。

方法
生产全长HBV和HBsAg颗粒，由于稳定（HepG2215）或瞬态（的HuH-7）的转染或感染HBV（HepaRG细胞）肝组织来源的细胞系，培养与alisporivir或NIM811单独，或alisporivir组合具有直接抗病毒（替比夫定）。药物反应个体亲环素的作用是通过环素的小分子干扰RNA击倒评价（CYP）A，长江电力，或CYPD在HepG2215细胞，或CYPA击倒在HuH-7细胞。抗病毒活性的动力学，基于HBV DNA和HBsAg和Southern印迹分析的水平进行评估。

结果
在HepG2215，呵呵-7和HepaRG细胞，alisporivir降低细胞内和细胞分泌的HBV DNA，并呈剂量依赖性。 CYPA，长江电力，或CYPD（减少80％）的击倒显著减少HBV DNA的水平和分泌的HBsAg。 CYPA击倒显著减少的HBsAg的分泌，导致细胞内的HBsAg的积累;加入alisporivir大大降低的HBsAg的水平在这些细胞中。 alisporivir和替比夫定的结合有比夫定或alisporivir单独的更大的抗病毒效果。

结论
在肝细胞系Alisporivir抑制亲环素的减少HBV DNA和HBsAg的产生和分泌的复制。这些效果增效与靶向HBV DNA聚合酶直接抗病毒剂的组合。

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alisporivir和NIM811

咬牙硬挺

感谢分享

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            SCY-635  Scynexis   二期   亲环素抑制剂  抗hbv可行，安全

tonychant

细胞实验有效，在人身上有没有效果值得观察

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回复 tonychant 的帖子

应该有效，alisporivir到三期抗hcv有效，因为死了个试验人停下来了，在人体，能抗hcv，估计能抗hbv，亲环素抑制剂类 都可行

肝肠欲断

又是一种新药？