Dengue virus (DENV) is the most common mosquito-borne flavivirus, and it affects millions of people globally every year. Currently, there are no approved drugs for the treatment of dengue infection. By screening a natural product library, we identified a novel compound, cyclovirobuxine D (Cvb D), that displays anti-DENV activity. Cvb D inhibits DENV replication in vitro in a dose-dependent manner and protects suckling mice against lethal DENV infection. Mechanistically, Cvb D regulates the expression of genes related to the cellular cholesterol pathway. As a result, Cvb D increases cellular cholesterol synthesis and accumulation, activates mTOR, and inhibits viral-dependent autophagy. Cvb D does not suppress autophagy initiation but impedes the nuclear translocation of the lysosome transcription factor TFEB. In addition, Cvb D restricts the replication of other positive-strand RNA viruses such as Zika virus and Coxsackievirus B3. We speculate that Cvb D could be a broad-spectrum antiviral drug candidate for use against positive-strand RNA viruses that require autophagy for optimal replication.

登革热病毒 (DENV) 是最常见的蚊媒黄病毒，每年影响全球数百万人。目前，尚无批准用于治疗登革热感染的药物。通过筛选天然产物库，我们确定了一种新型化合物环维黄杨星 D (Cvb D)，它具有抗 DENV 活性。Cvb D在体外抑制 DENV 复制以剂量依赖的方式保护乳鼠免受致命的 DENV 感染。从机制上讲，Cvb D 调节与细胞胆固醇通路相关的基因的表达。因此，Cvb D 会增加细胞胆固醇的合成和积累，激活 mTOR，并抑制病毒依赖性自噬。Cvb D 不会抑制自噬启动，但会阻碍溶酶体转录因子 TFEB 的核转位。此外，Cvb D 限制其他正链 RNA 病毒的复制，例如寨卡病毒和柯萨奇病毒 B3。我们推测 Cvb D 可能是一种广谱抗病毒候选药物，用于对抗需要自噬以实现最佳复制的正链 RNA 病毒。