Journal article

System-wide biochemical analysis reveals ozonide antimalarials initially act by disruptingPlasmodium falciparumhaemoglobin digestion

Carlo Giannangelo, Ghizal Siddiqui, Amanda De Paoli, Bethany M Anderson, Laura E Edgington-Mitchell, Susan A Charman, Darren J Creek

PLOS PATHOGENS | PUBLIC LIBRARY SCIENCE | Published : 2020

Abstract

Ozonide antimalarials, OZ277 (arterolane) and OZ439 (artefenomel), are synthetic peroxide-based antimalarials with potent activity against the deadliest malaria parasite, Plasmodium falciparum. Here we used a "multi-omics" workflow, in combination with activity-based protein profiling (ABPP), to demonstrate that peroxide antimalarials initially target the haemoglobin (Hb) digestion pathway to kill malaria parasites. Time-dependent metabolomic profiling of ozonide-treated P. falciparum infected red blood cells revealed a rapid depletion of short Hb-derived peptides followed by subsequent alterations in lipid and nucleotide metabolism, while untargeted peptidomics showed accumulation of longer..

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Grants

Awarded by Australian National Health and Medical Research Council (NHMRC)


Awarded by Australian Research Council (ARC) Discovery Early Career Researcher Award (DECRA) Fellowship


Funding Acknowledgements

Funding support was provided by the Australian National Health and Medical Research Council (NHMRC) project grants #APP1128003 to DJC, SAC and LE-M, and #APP1160705 and fellowship #APP1148700 to DJC. LE-M is funded by an Australian Research Council (ARC) Discovery Early Career Researcher Award (DECRA) Fellowship (DE180100418) and the Grimwade Fellowship funded by the Russell and Mab Grimwade Miegunyah Fund at the University of Melbourne. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.