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 p...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.展开更多
基金the Priority Academic Program Development of Jiangsu Higher Education InstitutionsProgram for Changjiang Scholars and Innovative Research Team in University(PCSIRT)+4 种基金the National Natural Science Foundation of China(31770933 and 81971917)the Natural Science Foundation of Colleges in Jiangsu Province(17KJA310005)the Open Project Fund from State Key Laboratory of Genetic Engineering,Fudan University(SKLGE1903)the Key Laboratory of Reproduction Regulation of NHC(KF2018-01)a grant from Soochow Securities。
文摘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.
