Cyclovirobuxine D inhibits dengue virus replication by impeding the complete autophagy in a cholesterol-dependent manner

• 来源期刊: 科学通报（英文版）
• 年，卷（期）: 2021,（3）
• 所属期刊栏目: ARTICLES
• 页码范围: 284-296
• 页数: 13页
• 语种: 英文

摘要

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 dis-plays anti-DENV activity.Cvb D inhibits DENV replication in vitro in a dose-dependent manner and pro-tects 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 synthe-sis 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.