The cyclophilin inhibitor CRV431 inhibits liver HBV DNA and HBsAg in transgenic mice

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.

乙型肝炎病毒（Hepatitis B virus, HBV）感染是全球重大健康负担，全球慢性感染者达2.4亿人。现行标准治疗方案为核苷（酸）类似物与干扰素，此类药物可通过抑制HBV复制发挥作用，但几乎无法彻底清除感染者体内的病毒。与人类免疫缺陷病毒1型（human immunodeficiency virus type-1, HIV-1）及丙型肝炎病毒（hepatitis C virus, HCV）感染者的现有治疗策略类似，优化HBV治疗方案需要联合靶向HBV生命周期不同环节的多种药物。本研究中，我们评估了亲环蛋白抑制剂CRV431对转基因小鼠体内HBV复制的影响。实验结果显示，以50 mg/kg/天的剂量口服给予CRV431，连续给药16天后，可显著降低小鼠肝脏内的HBV DNA水平，并适度下调血清乙型肝炎表面抗原（hepatitis B surface antigen, HBsAg）水平。我们还观察到，将低剂量CRV431（10 mg/kg/天）与核苷酸前体药物替诺福韦昔利酯（tenofovir exalidex, TXL，5 mg/kg/天）联合使用时，可对小鼠肝脏HBV DNA水平产生相加抑制效应。仅接受CRV431单药治疗的小鼠未出现任何毒性反应。尽管已知CRV431可中和亲环蛋白的肽基脯氨酰异构酶活性，但其抗HBV的具体作用机制仍未明确。不过，本研究首次证实了亲环蛋白抑制剂在HBV转基因小鼠模型体内的有益治疗效果。综上，本研究数据表明CRV431有望成为优化后的新型HBV治疗方案的组成部分。