From magic bullet to magic bomb: reductive bioactivation of antiparasitic agents

Paul Ehrlich coined the term "magic bullet" to describe how a drug kills the parasite inside its human host without harming the host itself. Ehrlich concluded that the drug must have a greater affinity to the parasite than to human cells. Today, the specificity of drug action is understood in terms of the drug target. An ideal target is a protein that is essential for the proliferation of the pathogen but absent in human cells. Examples are the enzymes of folate synthesis or of the nonmevalonate pathway in the malaria parasites. However, there are other ways how a drug can kill selectively. Of particular relevance is the specific activation of a prodrug inside the pathogen but not in the host, as this is how the current frontrunners of parasite chemotherapy work. Artemisinins for malaria, fexinidazole for human African trypanosomiasis, benznidazole for Chagas' disease, metronidazole for intestinal protozoa: these molecules are "magic bombs" that are triggered selectively. They are prodrugs that need to be activated by chemical reduction, i.e., the acquisition of an electron, which occurs in the parasite. Such a mode of action is shared by the novel antimalarial peroxides arterolane and artefenomel, which are activated by reduction of the endoperoxide bond with ferrous heme as the likely electron donor, a metabolic end-product of Plasmodium falciparum. Here we provide an overview on the molecular basis of selectivity of antiparasitic drug action with particular reference to the ozonides, the new generation of antimalarial peroxides designed by Jonathan Vennerstrom.