亲环蛋白抑制剂CRV431抑制转基因小鼠中的肝HBV DNA和HBsAg。

StephenW

PLoS One. 2019 Jun 10;14(6):e0217433. doi: 10.1371/journal.pone.0217433. eCollection 2019.
The cyclophilin inhibitor CRV431 inhibits liver HBV DNA and HBsAg in transgenic mice.
Gallay P1, Ure D2, Bobardt M1, Chatterji U1, Ou J3, Trepanier D2, Foster R2.
Author information

1
    Department of Immunology & Microbiology, The Scripps Research Institute, La Jolla, California, United States of America.
2
    ContraVir Pharmaceuticals Inc., Edison, New Jersey, United States of America.
3
    Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, California, United States of America.

Abstract

Hepatitis B virus (HBV) infection is a major health burden worldwide with 240 million chronically infected individuals. Nucleos(t)ide analogs and interferons are the current standards of care due to their suppression of HBV replication, but the treatments rarely eradicate HBV from individuals. Similar to current treatments for human immunodeficiency virus type-1 (HIV-1) and hepatitis C virus (HCV) patients, improved HBV therapies will require the combination of multiple drugs which target distinct steps of the HBV life cycle. In this study, we tested the potential of a cyclophilin inhibitor, CRV431, to affect HBV replication in transgenic mice. We found that oral treatment with CRV431 (50 mg/kg/day) for a period of 16 days significantly reduced liver HBV DNA levels and moderately decreased serum HBsAg levels. We observed an additive inhibitory effect on liver HBV DNA levels in mice treated with a combination of low doses of CRV431 (10 mg/kg/day) and the nucleotide prodrug, tenofovir exalidex (TXL), (5 mg/kg/day). No toxicity was observed in CRV431-treated mice. Although it is well known that CRV431 neutralizes the peptidyl-prolyl isomerase activity of cyclophilins, its anti-HBV mechanism(s) of action remains unknown. Nevertheless, this study provides the first demonstration of a beneficial effect of a cyclophilin inhibitor in vivo in an HBV transgenic mouse model. Altogether our data reveal the potential of CRV431 to be part of improved new therapies for HBV patients.

PMID:
    31181107
DOI:
    10.1371/journal.pone.0217433

StephenW

PLoS One。 2019年6月10日; 14（6）：e0217433。 doi：10.1371 / journal.pone.0217433。 eCollection 2019。
亲环蛋白抑制剂CRV431抑制转基因小鼠中的肝HBV DNA和HBsAg。
Gallay P1，Ure D2，Bobardt M1，Chatterji U1，Ou J3，Trepanier D2，Foster R2。
作者信息

1
美利坚合众国加利福尼亚州拉霍亚斯克里普斯研究所免疫学和微生物学系。
2
ContraVir Pharmaceuticals Inc.，爱迪生，新泽西州，美利坚合众国。
3
美国加利福尼亚州洛杉矶凯克医学院南加州大学分子微生物学和免疫学系。

抽象

乙型肝炎病毒（HBV）感染是全世界主要的健康负担，有2.4亿慢性感染者。 Nucleos（t）ide类似物和干扰素是目前的护理标准，因为它们抑制HBV复制，但治疗很少根除个体的HBV类似于目前对人类免疫缺陷病毒1型（HIV-1）和丙型肝炎病毒的治疗（HCV）患者，改进的HBV疗法将需要多种药物的组合，其针对HBV生命周期的不同步骤。我们测试了亲环蛋白抑制剂CRV431在转基因小鼠中影响HBV复制的潜力。我们发现用CRV431（50 mg / kg /天）口服治疗16天可显着降低肝脏HBV DNA水平，并适度降低血清HBsAg水平。我们观察到用低剂量CRV431（10 mg / kg /天）和核苷酸前药，替诺福韦前Alidex（TXL），（5 mg / kg /天）联合治疗的小鼠肝脏HBV DNA水平的加性抑制作用。在CRV431处理的小鼠中未观察到毒性。尽管众所周知CRV431中和了亲环蛋白的肽基 - 脯氨酰异构酶活性，但它的抗HBV作用机制是HBV转基因小鼠模型的最后一种。总之，我们的数据揭示了CRV431成为改进HBV患者新疗法的潜力。

结论：
31181107
DOI：
10.1371 / journal.pone.0217433

StephenW

https://journals.plos.org/ploson ... &type=printable