Profiling the Antimalarial Mechanism of Artemisinin by Identifying Crucial Target Proteins
Profiling the Antimalarial Mechanism of Artemisinin by Identifying Crucial Target Proteins
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DOI：
10.1016/j.eng.2023.06.001
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发表时间：
2024-04-05
期刊：
影响因子：
12.8
通讯作者：
Wang，Jigang
中科院分区：
文献类型：
--
作者：
Gao，Peng;Wang，Jianyou;Wang，Jigang
青蒿素及其衍生物的广泛使用大大减轻了全球疟疾负担；然而，疟疾仍然对全球健康构成严重威胁。尽管在阐明抗逆转录病毒药物的抗疟疾机制方面取得了重大进展，但抗逆转录病毒药物最关键的靶蛋白和途径仍然未知。迫切需要了解抗逆转录病毒药物的确切抗疟机制，因为在世界一些地区已经观察到出现抗逆转录病毒药物耐药性的迹象。在这里，我们使用了一种包括质谱耦合细胞热移测定（MS-CETSA）和转录组学分析的组合策略来鉴定一组假定的ART抗疟疾靶点。然后，我们对五个潜在的蛋白靶点进行了一系列验证实验，证明ART可能通过干扰氧化还原稳态、脂质代谢和蛋白质合成过程来对抗疟疾寄生虫。总之，这项研究为抗逆转录病毒药物的抗疟疾机制提供了新的视角，并确定了几种参与寄生虫生存的关键蛋白质，这些蛋白质可以作为对抗疟疾的靶标。
The widespread use of artemisinin (ART) and its derivatives has significantly reduced the global burden of malaria; however, malaria still poses a serious threat to global health. Although significant progress has been achieved in elucidating the antimalarial mechanisms of ART, the most crucial target proteins and pathways of ART remain unknown. Knowledge on the exact antimalarial mechanisms of ART is urgently needed, as signs of emerging ART resistance have been observed in some regions of the world. Here, we used a combined strategy involving mass spectrometry-coupled cellular thermal shift assay (MS-CETSA) and transcriptomics profiling to identify a group of putative antimalarial targets of ART. We then conducted a series of validation experiments on five prospective protein targets, demonstrating that ART may function against malaria parasites by interfering with redox homeostasis, lipid metabolism, and protein synthesis processes. Taken together, this study provides fresh perspectives on the antimalarial mechanisms of ART and identifies several crucial proteins involved in parasite survival that can be targeted to combat malaria.