Hepatitis B virus (HBV) chronically infects >250 million people and kills nearly a million annually, and current antivirals cannot clear the infection or adequately suppress disease. The virus replicates by reverse transcription, and the dominant antiviral drugs are nucleos(t)ide analogs that target the viral reverse transcriptase. We are developing antivirals targeting the other essential viral enzymatic activity, the ribonuclease H (RNaseH). HBV RNaseH inhibitors with efficacies in the low micromolar to nanomolar range against viral replication in culture have been identified in the α-hydroxytropolone and hydroxyimide chemotypes. Here, we review the promise of RNaseH inhibitors, their current structure-activity relationships, and challenges to optimizing the inhibitors into leads for clinical assessment.

中文翻译：

---

抑制乙型肝炎病毒核糖核酸酶H的化学方法。

乙型肝炎病毒（HBV）长期感染超过2.5亿人，每年杀死近一百万，目前的抗病毒药物无法清除感染或充分抑制疾病。病毒通过逆转录进行复制，而主要的抗病毒药物是靶向病毒逆转录酶的核苷类似物。我们正在开发针对其他基本病毒酶活性（核糖核酸酶H（RNaseH））的抗病毒药物。已经在α-羟基麦芽酮和羟基酰亚胺化学型中鉴定出了在低微摩尔至纳摩尔范围内对培养物中的病毒复制具有功效的HBV RNaseH抑制剂。在这里，我们回顾了RNaseH抑制剂的前景，它们目前的构效关系以及优化抑制剂成为临床评估线索的挑战。