期刊
ACS INFECTIOUS DISEASES
卷 8, 期 1, 页码 210-226出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.1c00550
关键词
Plasmodium falciparum; peroxide antimalarials; ozonides; artemisinins; redox homeostasis; glutathione
资金
- NIH [1160705, APP1128003, APP1185354, APP1148700]
- [AI116723-01]
This study used chemoproteomics to investigate the protein alkylation targets of peroxide antimalarials and found a significant alkylation of proteins involved in redox homeostasis. Disrupted redox processes were confirmed and changes in cellular thiol levels were observed. These findings reveal the mechanism of action of peroxide antimalarials.
: Plasmodium falciparum causes the most lethal form of malaria. Peroxide antimalarials based on artemisinin underpin the frontline treatments for malaria, but artemisinin resistance is rapidly spreading. Synthetic peroxide antimalarials, known as ozonides, are in clinical development and offer a potential alternative. Here, we used chemoproteomics to investigate the protein alkylation targets of artemisinin and ozonide probes, including an analogue of the ozonide clinical candidate, artefenomel. We greatly expanded the list of proteins alkylated by peroxide antimalarials and identified significant enrichment of redox-related proteins for both artemisinins and ozonides. Disrupted redox homeostasis was confirmed by dynamic live imaging of the glutathione redox potential using a genetically encoded redox-sensitive fluorescence-based biosensor. Targeted liquid chromatography-mass spectrometry (LC-MS)-based thiol metabolomics also confirmed changes in cellular thiol levels. This work shows that peroxide antimalarials disproportionately alkylate proteins involved in redox homeostasis and that disrupted redox processes are involved in the mechanism of action of these important antimalarials.
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