Chronic hepatitis B virus infection cannot be cured by current therapies, so new treatments are urgently needed. We recently identified novel inhibitors of the hepatitis B virus ribonuclease H that suppress viral replication in cell culture. Here, we employed immunodeficient FRG KO mice whose livers had been engrafted with primary human hepatocytes to ask whether ribonuclease H inhibitors can suppress hepatitis B virus replication in vivo. Humanized FRG KO mice infected with hepatitis B virus were treated for two weeks with the ribonuclease H inhibitors #110, an α-hydroxytropolone, and #208, an N-hydroxypyridinedione. Hepatitis B virus viral titers and S and e antigen plasma levels were measured. Treatment with #110 and #208 caused significant reductions in plasma viremia without affecting hepatitis B virus S or e antigen levels, and viral titers rebounded following treatment cessation. This is the expected pattern for inhibitors of viral DNA synthesis. Compound #208 suppressed viral titers of both hepatitis B virus genotype A and C isolates. These data indicate that Hepatitis B virus replication can be suppressed during infection in an animal by inhibiting the viral ribonuclease H, validating the ribonuclease H as a novel target for antiviral drug development.

当前的疗法无法治愈慢性乙型肝炎病毒感染，因此迫切需要新的治疗方法。我们最近发现了抑制细胞培养中病毒复制的乙型肝炎病毒核糖核酸酶H的新型抑制剂。在这里，我们使用免疫缺陷的FRG KO小鼠，其肝脏已植入原代人肝细胞，以询问核糖核酸酶H抑制剂是否可以在体内抑制乙型肝炎病毒的复制。将感染了乙型肝炎病毒的人源化FRG KO小鼠分别用核糖核酸酶H抑制剂＃110（α-羟基tropolone和＃208，N-羟基吡啶二酮）处理两周。测量了乙型肝炎病毒的病毒滴度，S和e抗原血浆水平。用＃110和＃208处理可显着降低血浆病毒血症，而不会影响乙型肝炎病毒S或e抗原水平，并且在停止治疗后病毒滴度会反弹。这是病毒DNA合成抑制剂的预期模式。化合物＃208抑制了乙型肝炎病毒基因型A和C分离株的病毒滴度。这些数据表明，在动物中的感染过程中，通过抑制病毒核糖核酸酶H可以抑制乙型肝炎病毒的复制，从而验证了核糖核酸酶H作为抗病毒药物开发的新靶标。