McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada.
Department of Microbiology and Immunology, Faculty of Medicine, McGill University, Montréal, Québec, Canada.
J Med Virol. 2019 Jul;91(7):1182-1190. doi: 10.1002/jmv.25440. Epub 2019 Mar 4.
Studies aimed at repurposing existing drugs revealed that some antimalarial compounds possess anti-Zika virus (anti-ZIKV) activity. Here, we further tested 14 additional antimalarial drugs and their metabolites or analogs for anti-ZIKV activity using a phenotypic screening approach. We identified four compounds with varying anti-ZIKV activity, including a metabolite of amodiaquine termed desethylamodiaquine (DAQ) and N-desethylchloroquine (DECQ), a metabolite of chloroquine, which both exhibited low micromolar effective concentrations against three different ZIKV strains. Two other compounds termed dihydroartemisinin (DHA) and quinidine (QD) exhibited only partial inhibition of ZIKV replication. Characterization of the inhibitory mechanisms of DAQ and DECQ showed that both drugs target the entry step as well as postentry events of the viral replication cycle. These hits represent attractive starting points for future optimization of new anti-ZIKV drug candidates derived from antimalarial drugs and their analogs.
研究旨在重新利用现有的药物，发现一些抗疟化合物具有抗寨卡病毒（抗 ZIKV）活性。在这里，我们进一步使用表型筛选方法测试了另外 14 种抗疟药物及其代谢物或类似物的抗 ZIKV 活性。我们鉴定了四种具有不同抗 ZIKV 活性的化合物，包括阿莫地喹的代谢物去乙基阿莫地喹（DAQ）和 N-去乙基氯喹（DECQ），氯喹的代谢物，这两种化合物对三种不同的 ZIKV 株均表现出低微摩尔有效浓度。另外两种化合物二氢青蒿素（DHA）和奎宁（QD）仅表现出对 ZIKV 复制的部分抑制作用。对 DAQ 和 DECQ 的抑制机制进行了表征，结果表明这两种药物均靶向病毒复制周期的进入步骤和进入后事件。这些发现为未来从抗疟药物及其类似物中优化新的抗 ZIKV 候选药物提供了有吸引力的起点。
