A human genome-wide loss-of-function screen identifies effective chikungunya antiviral drugs.
A human genome-wide loss-of-function screen identifies effective chikungunya antiviral drugs.
复制标题
人类全基因组的功能丧失屏幕可识别有效的chikungunya抗病毒药物。
DOI：
10.1038/ncomms11320
复制
发表时间：
2016-05-12
影响因子：
16.6
通讯作者：
Lecuit M
中科院分区：
文献类型：
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作者：
Karlas A;Berre S;Couderc T;Varjak M;Braun P;Meyer M;Gangneux N;Karo-Astover L;Weege F;Raftery M;Schönrich G;Klemm U;Wurzlbauer A;Bracher F;Merits A;Meyer TF;Lecuit M
基孔肯雅病毒（CHIKV）是一种全球传播的甲病毒，目前还没有市售的疫苗或治疗方法。在这里，我们使用全基因组siRNA筛选来鉴定影响CHIKV复制的156种前病毒和41种抗病毒宿主因子。我们分析了人类前病毒基因参与的细胞通路，并确定了可药物化的靶点。二十一种小分子抑制剂（其中一些已获得FDA批准）针对六种前病毒因子或途径，在体外具有高抗病毒活性，毒性低。三种已鉴定的抑制剂在基孔肯雅病毒感染的小鼠模型中具有预防性抗病毒作用。其中两种，钙调蛋白抑制剂匹莫齐特和脂肪酸合成抑制剂TOFA，在体内联合使用时具有治疗作用。这些结果证明了功能丧失筛选和途径分析对于合理鉴定具有治疗潜力的小分子的价值，并为开发新的宿主定向抗病毒剂铺平了道路。 基孔肯雅病毒是一种蚊子传播的不可治愈的紧急病原体，导致关节疼痛和发烧。在这里，作者进行了宿主全基因组功能丧失筛选，以确定基孔肯雅病毒抗病毒药物的靶点，并使用基孔肯雅病毒感染的小鼠模型验证命中。
Chikungunya virus (CHIKV) is a globally spreading alphavirus against which there is no commercially available vaccine or therapy. Here we use a genome-wide siRNA screen to identify 156 proviral and 41 antiviral host factors affecting CHIKV replication. We analyse the cellular pathways in which human proviral genes are involved and identify druggable targets. Twenty-one small-molecule inhibitors, some of which are FDA approved, targeting six proviral factors or pathways, have high antiviral activity in vitro, with low toxicity. Three identified inhibitors have prophylactic antiviral effects in mouse models of chikungunya infection. Two of them, the calmodulin inhibitor pimozide and the fatty acid synthesis inhibitor TOFA, have a therapeutic effect in vivo when combined. These results demonstrate the value of loss-of-function screening and pathway analysis for the rational identification of small molecules with therapeutic potential and pave the way for the development of new, host-directed, antiviral agents. Chikungunya virus is a mosquito transmitted untreatable emergent pathogen that causes joint pain and fever. Here the authors perform a host genome-wide loss-of-function screen to identify targets for chikungunya antiviral drugs and validate hits using a mouse model of chikungunya infection.