Application of the automated haematology analyzer XN-30 for discovery and development of anti-malarial drugs
Application of the automated haematology analyzer XN-30 for discovery and development of anti-malarial drugs
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DOI：
10.1186/s12936-019-2642-0
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发表时间：
2019-01-14
期刊：
影响因子：
3
通讯作者：
Horii, Toshihiro
中科院分区：
文献类型：
--
作者：
Tougan, Takahiro;Toya, Yuji;Horii, Toshihiro
背景恶性疟原虫红细胞期在临床上具有重要意义，因为在此生长阶段的疟原虫会引起疟疾症状。目前可用的大多数抗疟疾药物都针对这一阶段，但对抗疟疾药物产生耐药性的寄生虫的出现和传播是全球根除工作的一个重大挑战;因此，迫切需要开发新药。在这项研究中，使用XN-30分析仪表征了五种当前抗疟疾药物（青蒿素、阿托伐醌、氯喹、甲氟喹和乙胺嘧啶）和来自疟疾新药公司提供的病原体盒的400种化合物对恶性疟原虫寄生虫的体外抗疟疾活性。此外，使用分析仪获得的结果进行了分类，根据寄生虫血症的总和每个developmentstages.ResultsThe生长抑制率和半最大（50%）抑制浓度（IC 50）的五个当前抗疟药物计算从寄生虫血症使用XN-30分析仪检测。各菌株和药物呈现出强拟合的S形曲线，所有检测浓度下的中位SD为1.6，表明分析仪测量值的变化对于药物疗效比较而言是可接受的低水平。此外，对病原体盒中的400种化合物进行了抗疟疾活性测试，发现141种药物有效。并将疗效分为4类（Ⅰ型，寄生虫在无DNA复制的情况下被捕获或杀死; Ⅱ型，寄生虫被捕获或杀死，与Ⅰ型相似，寄生虫血症明显减轻; IV型，寄生虫在DNA复制后在滋养体晚期或滋养体晚期被捕获。可重复地并且容易地评价和表征各种化合物的抗疟疾功效。结果表明，XN-30分析仪除了作为重要的诊断工具外，还具有作为药物发现和开发的强大工具的潜力。
BackgroundThe erythrocytic stage of Plasmodium falciparum parasites in humans is clinically important, as the parasites at this growth stage causes malarial symptoms. Most of the currently available anti-malarial drugs target this stage, but the emergence and spread of parasites resistant to anti-malarial drugs are a major challenge to global eradication efforts; therefore, the development of novel medicines is urgently required. In this study, the in vitro anti-malarial activity of five current anti-malarial drugs (artemisinin, atovaquone, chloroquine, mefloquine, and pyrimethamine) and 400 compounds from the Pathogen Box provided by the Medicines for Malaria Venture on P. falciparum parasites was characterized using the XN-30 analyzer. Furthermore, the outcomes obtained using the analyser were classified according to the parasitaemias of total and each developmental stages.ResultsThe growth inhibition rate and the half-maximal (50%) inhibitory concentration (IC50) of the five current anti-malarial drugs were calculated from the parasitaemia detected using the XN-30 analyzer. Respective strains and drugs presented strongly fitted sigmoidal curves, and the median SD at all tested concentrations was 1.6, suggesting that the variation in values measured with the analyser was acceptably low for the comparison of drug efficacy. Furthermore, the anti-malarial activity of the 400 compounds from the Pathogen Box was tested, and 141 drugs were found to be effective. In addition, the efficacy was classified into 4 types (Type I, parasites were arrested or killed without DNA replication; Type II, parasites were arrested or killed similar to Type I, and the parasitaemia was apparently decreased; Type III, parasites progressed to trophozoite without sufficient DNA replication; and Type IV, parasites were arrested at late trophozoite or schizont after DNA replication).ConclusionThe current study demonstrates that the XN-30 analyzer objectively, reproducibly, and easily evaluated and characterized the anti-malarial efficacy of various compounds. The results indicate the potential of the XN-30 analyzer as a powerful tool for drug discovery and development in addition to its use as an important diagnostic tool.