Peroxide Antimalarial Drugs Target Redox Homeostasis in Plasmodium falciparum Infected Red Blood Cells

Ghizal Siddiqui, Carlo Giannangelo, Amanda De Paoli, Anna Katharina Schuh, Kim C. Heimsch, Dovile Anderson, Timothy G. Brown, Christopher A. Macraild, Jianbo Wu, Xiaofang Wang, Yuxiang Dong, Jonathan L. Vennerstrom, Katja Becker, Darren J. Creek

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)210-226
Number of pages17
JournalACS infectious diseases
Volume8
Issue number1
DOIs
StatePublished - Jan 14 2022

Keywords

  • Plasmodium falciparum
  • artemisinins
  • glutathione
  • ozonides
  • peroxide antimalarials
  • redox homeostasis

ASJC Scopus subject areas

  • Infectious Diseases

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