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.

目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。我们最近发现了乙型肝炎病毒核糖核酸酶 H 的新型抑制剂，可以抑制细胞培养中的病毒复制。在这里，我们使用肝脏移植了原代人肝细胞的免疫缺陷FRG KO小鼠来探究核糖核酸酶H抑制剂是否可以抑制体内乙型肝炎病毒的复制。使用核糖核酸酶 H 抑制剂 #110（一种 α-羟基托酚酮）和 #208（一种 N-羟基吡啶二酮）治疗感染乙型肝炎病毒的人源化 FRG KO 小鼠两周。测量了乙型肝炎病毒的病毒滴度以及S和e抗原血浆水平。使用 #110 和 #208 治疗可显着降低血浆病毒血症，而不影响乙型肝炎病毒 S 或 e 抗原水平，并且病毒滴度在治疗停止后反弹。这是病毒 DNA 合成抑制剂的预期模式。化合物#208 抑制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，通过抑制病毒核糖核酸酶 H，可以在动物感染期间抑制乙型肝炎病毒复制，从而验证了核糖核酸酶 H 作为抗病毒药物开发的新靶点。