Journal article

Publication year: 2022

Pages: 210-226

Journal: ACS Infectious Diseases

Volume number: 8

Issue number: 1

ISSN: 2373-8227

Open access status: Hybrid

DOI Link: https://doi.org/10.1021/acsinfecdis.1c00550

Publisher: American Chemical Society

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.

Harvard Citation style: Siddiqui, G., Giannangelo, C., De Paoli, A., Schuh, A., Heimsch, K., Anderson, D., et al. (2022) Peroxide Antimalarial Drugs Target Redox Homeostasis in Plasmodium falciparum Infected Red Blood Cells, ACS Infectious Diseases, 8(1), pp. 210-226. https://doi.org/10.1021/acsinfecdis.1c00550

APA Citation style: Siddiqui, G., Giannangelo, C., De Paoli, A., Schuh, A., Heimsch, K., Anderson, D., Brown, T., MacRaild, C., Wu, J., Wang, X., Dong, Y., Vennerstrom, J., Becker, K., & Creek, D. (2022). Peroxide Antimalarial Drugs Target Redox Homeostasis in Plasmodium falciparum Infected Red Blood Cells. ACS Infectious Diseases. 8(1), 210-226. https://doi.org/10.1021/acsinfecdis.1c00550