Identification of inhibitors that dually target the new permeability pathway and dihydroorotate dehydrogenase in the blood stage of Plasmodium falciparum
Identification of inhibitors that dually target the new permeability pathway and dihydroorotate dehydrogenase in the blood stage of Plasmodium falciparum
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DOI：
10.1038/srep37502
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发表时间：
2016-11-22
影响因子：
4.6
通讯作者：
Gilson, Paul R.
中科院分区：
文献类型：
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作者：
Dickerman, Benjamin K.;Elsworth, Brendan;Gilson, Paul R.
疟原虫寄生虫是造成毁灭性疾病疟疾的罪魁祸首，每年影响数亿人。血液期寄生虫在受感染的红细胞膜中建立新的渗透性途径（NPP），以促进营养物质的吸收和寄生虫废物的清除。预计NPP的药理学抑制会导致营养饥饿和有毒代谢物的积累，从而导致寄生虫死亡。在这里，我们筛选了一个抗疟疾化合物库，MMV疟疾盒，确定了两种抑制NPP功能的化合物。出乎意料的是，代谢分析表明，这两种化合物还抑制二氢乳清酸脱氢酶（DHODH），这是嘧啶合成所需的，本身就是一种经过验证的药物靶标。酵母DHODH的表达绕过了对寄生虫DHODH的需要，增加了寄生虫对这些化合物的抗性。这些研究确定了两个潜在的候选治疗开发，同时靶向疟原虫，NPP和DHODH的两个基本途径。
Plasmodium parasites are responsible for the devastating disease malaria that affects hundreds of millions of people each year. Blood stage parasites establish new permeability pathways (NPPs) in infected red blood cell membranes to facilitate the uptake of nutrients and removal of parasite waste products. Pharmacological inhibition of the NPPs is expected to lead to nutrient starvation and accumulation of toxic metabolites resulting in parasite death. Here, we have screened a curated library of antimalarial compounds, the MMV Malaria Box, identifying two compounds that inhibit NPP function. Unexpectedly, metabolic profiling suggested that both compounds also inhibit dihydroorotate dehydrogense (DHODH), which is required for pyrimidine synthesis and is a validated drug target in its own right. Expression of yeast DHODH, which bypasses the need for the parasite DHODH, increased parasite resistance to these compounds. These studies identify two potential candidates for therapeutic development that simultaneously target two essential pathways in Plasmodium, NPP and DHODH.