Activity-based protein profiling reveals that secondary-carbon-centered radicals of synthetic 1,2,4-trioxolanes are predominately responsible for modification of protein targets in malaria parasites

Endoperoxide-containing antimalarials, such as artemisinin and the synthetic trioxolane OZ439, are prodrugs activated by heme to generate primary and secondary carbon-centered radicals. We employed activity-based protein profiling (ABPP) to show that the secondary-carbon-centered radical of 1,2,4-trioxolanes is primarily responsible for protein labeling in malaria parasites.