The Candidate Antimalarial Drug MMV665909 Causes Oxygen-Dependent mRNA Mistranslation and Synergizes with Quinoline-Derived Antimalarials.
The Candidate Antimalarial Drug MMV665909 Causes Oxygen-Dependent mRNA Mistranslation and Synergizes with Quinoline-Derived Antimalarials.
复制标题
候选抗疟药MMV665909导致氧依赖性mRNA误译，并与喹啉衍生的抗疟药协同作用。
DOI：
10.1128/aac.00459-17
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发表时间：
2017-09
影响因子：
4.9
通讯作者：
Avery SV
中科院分区：
文献类型：
--
作者：
Vallières C;Avery SV
为了科普目前抗疟药物日益增强的耐药性，迫切需要具有新作用模式的新药。靶向蛋白质合成的分子似乎是有前途的候选者。我们从候选抗疟药的疟疾新药研发（MMV）疟疾盒中鉴定出一种化合物（MMV665909），该化合物可与氨基糖苷类抗生素巴龙霉素产生协同生长抑制作用，表明该化合物可能在mRNA错误翻译中起作用。这种作用机制得到了证实与酿酒酵母模型，使用现有的记者的误译和其他遗传工具。MMV 665909诱导的误译具有氧依赖性，表明活性氧（ROS）的作用。Rli1（一种在mRNA翻译中必不可少的ROS敏感性保守FeS蛋白）的过表达可挽救MMV665909的抑制作用，这与药物通过Rli1介导的对翻译保真度的作用一致。MMV药物还与主要的喹啉衍生的抗疟药协同作用，这些药物可以干扰氨基酸的可用性或促进ROS应激：氯喹，阿莫地喹和伯氨喹。这些数据共同表明翻译保真度是抗疟疾作用的新靶点，并支持MMV665909作为一种有前途的候选药物。
To cope with growing resistance to current antimalarials, new drugs with novel modes of action are urgently needed. Molecules targeting protein synthesis appear to be promising candidates. We identified a compound (MMV665909) from the Medicines for Malaria Venture (MMV) Malaria Box of candidate antimalarials that could produce synergistic growth inhibition with the aminoglycoside antibiotic paromomycin, suggesting a possible action of the compound in mRNA mistranslation. This mechanism of action was substantiated with a Saccharomyces cerevisiae model using available reporters of mistranslation and other genetic tools. Mistranslation induced by MMV665909 was oxygen dependent, suggesting a role for reactive oxygen species (ROS). Overexpression of Rli1 (a ROS-sensitive, conserved FeS protein essential in mRNA translation) rescued inhibition by MMV665909, consistent with the drug's action on translation fidelity being mediated through Rli1. The MMV drug also synergized with major quinoline-derived antimalarials which can perturb amino acid availability or promote ROS stress: chloroquine, amodiaquine, and primaquine. The data collectively suggest translation fidelity as a novel target of antimalarial action and support MMV665909 as a promising drug candidate.