Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7
Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7
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DOI：
10.1073/pnas.1600459113
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发表时间：
2016-02-23
影响因子：
11.1
通讯作者：
Ward, Stephen A.
中科院分区：
文献类型：
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作者：
Ismail, Hanafy M.;Barton, Victoria;Ward, Stephen A.
过去十年，以青蒿素(ART)为基础的抗疟疾药物为减少全球疟疾死亡人数做出了重大贡献，但我们仍然不知道它们是如何杀死寄生虫的。为了更深入地了解ART药物作用的潜在机制，我们开发了一套基于ART活性的蛋白质图谱探针，用于原位识别寄生虫蛋白质药物靶点。为保留恶性疟原虫3D7寄生虫的生物学活性并原位烷化恶性疟原虫3D7寄生虫的分子靶标S，设计了探针。使用这些探针，我们定义了一个ART蛋白质组，它显示了糖酵解、血红蛋白降解、抗氧化防御和蛋白质合成途径中的烷基化靶标，这些过程对寄生虫的生存至关重要。这项工作揭示了这类重要的抗疟疾药物所针对的生物功能的多效性。
The artemisinin (ART)-based antimalarials have contributed significantly to reducing global malaria deaths over the past decade, but we still do not know how they kill parasites. To gain greater insight into the potential mechanisms of ART drug action, we developed a suite of ART activity-based protein profiling probes to identify parasite protein drug targets in situ. Probes were designed to retain biological activity and alkylate the molecular target(s) of Plasmodium falciparum 3D7 parasites in situ. Proteins tagged with the ART probe can then be isolated using click chemistry before identification by liquid chromatography-MS/MS. Using these probes, we define an ART proteome that shows alkylated targets in the glycolytic, hemoglobin degradation, antioxidant defense, and protein synthesis pathways, processes essential for parasite survival. This work reveals the pleiotropic nature of the biological functions targeted by this important class of antimalarial drugs.