PXD027334

PXD027334 is an original dataset announced via ProteomeXchange.

Title	Peroxide antimalarial drugs impact redox homeostasis in Plasmodium falciparum infected red blood cells
Description	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.
HostingRepository	PRIDE
AnnounceDate	2022-02-17
AnnouncementXML	Submission_2022-02-17_05:37:33.305.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ghizal Siddiqui
SpeciesList	scientific name: Plasmodium falciparum; NCBI TaxID: 5833; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-07-15 09:29:24	ID requested
⏵ 1	2022-02-17 05:37:34	announced

Siddiqui G, Giannangelo C, De Paoli A, Schuh AK, Heimsch KC, Anderson D, Brown TG, MacRaild CA, Wu J, Wang X, Dong Y, Vennerstrom JL, Becker K, Creek DJ, Infected Red Blood Cells. ACS Infect Dis, 8(1):210-226(2022) [pubmed]

submitter keyword: Plasmodium falciparum, Malaria, Peroxides, Ozonides, Redox homeostasis, Glutathione.

darren creek
contact affiliation	Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
contact email	darren.creek@monash.edu
lab head
Ghizal Siddiqui
contact affiliation	Monash University
contact email	ghizal.siddiqui@monash.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD027334
     1. Label: PRIDE project
     2. Name: Peroxide antimalarial drugs impact redox homeostasis in Plasmodium falciparum infected red blood cells