Cyclovirobuxine D inhibits dengue virus replication by impeding the complete autophagy in a cholesterol-dependent manner
Cyclovirobuxine D inhibits dengue virus replication by impeding the complete autophagy in a cholesterol-dependent manner
复制标题
Cyclovirobuxine D 通过胆固醇依赖性方式阻碍完全自噬，从而抑制登革热病毒复制
DOI：
10.1016/j.scib.2020.08.035
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发表时间：
2021-02-10
期刊：
影响因子：
18.9
通讯作者：
Dai, Jianfeng
中科院分区：
文献类型：
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作者：
Wang, Kezhen;Zhang, Jinyu;Dai, Jianfeng
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，还没有批准用于治疗登革热感染的药物。通过筛选天然产物库，我们鉴定了一种新的化合物，环维黄杨星D（Cvb D），其显示出抗DENV活性。Cvb D在体外以剂量依赖性方式抑制DENV复制并保护乳鼠免受致死性DENV感染。在机制上，Cvb D调节与细胞胆固醇途径相关的基因的表达。因此，Cvb D增加细胞胆固醇合成和积累，激活mTOR，并抑制病毒依赖性自噬。Cvb D不抑制自噬起始，但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，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药物候选物，用于对抗需要自噬以实现最佳复制的正链RNA病毒。(C)中国科学出版社.爱思唯尔公司、科学中国出版社出版。All rights reserved.
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. (C) 2020 Science China Press. Published by Elsevier B.V. and Science China Press. All rights reserved.