Proteomics

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Peroxide antimalarial drugs impact redox homeostasis in Plasmodium falciparum infected red blood cells


ABSTRACT: Plasmodium falciparum causes the most lethal form of malaria. The frontline treatments for this severe disease are combination therapies based on semisynthetic peroxide antimalarials, known as artemisinins. There is growing resistance to artemisinins and new drugs with novel mechanisms of action are urgently required. Synthetic peroxide antimalarials, known as ozonides, exhibit potent antimalarial activity both in vitro and in vivo. Here, we used chemical proteomics to investigate the protein alkylation targets of clickable artemisinin and ozonide probes, including an analogue of the ozonide clinical candidate, OZ439. We greatly expanded the list of protein targets for peroxide antimalarials and identified redox processes as being significantly enriched from the list of protein targets for both artemisinins and ozonides. Disrupted redox homeostasis was confirmed with the use of a genetically encoded fluorescence-based biosensor comprising a redox-sensitive GFP (roGFP) fused to human glutaredoxin 1. This facilitated specific and dynamic live imaging of the glutathione redox potential in the cytosol of peroxide-treated infected red blood cells with high sensitivity and temporal resolution. We also used a targeted LC-MS based thiol metabolomics assay to accurately measure relative changes in cellular thiol levels (including thiol metabolites, glutathione precursors and oxidised and reduced glutathione) within peroxide-treated P. falciparum-infected red blood cells. 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Plasmodium Falciparum Homo Sapiens (human)

TISSUE(S): Blood Cell, Blood

DISEASE(S): Malaria

SUBMITTER: Ghizal Siddiqui  

LAB HEAD: darren creek

PROVIDER: PXD027334 | Pride | 2022-02-17

REPOSITORIES: Pride

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<i>Plasmodium falciparum</i> 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, artefen  ...[more]

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