Plasmodium falciparum ATP4 inhibitors to treat malaria: worthy successors to artemisinin?

Progress in controlling malaria has slowed in recent years and the annual death toll remains above 400 000 globally, with most deaths caused by Plasmodium falciparum.1 The joint threats of increasing resistance to insecticides, artemisinin derivatives, and almost all other antimalarials in current use make the development of new classes of antimalarials a high priority. Studies done over the past 10 years have identified the malaria parasite cation ATPase P falciparum ATP4 as a promising target for novel antimalarials by phenotypic screening.2 It plays a role in maintaining low intracellular sodium cation concentrations in P falciparum.3 Inhibition of P falciparum ATP4 disrupts sodium ion homeostasis and is lethal for the parasite. Artefenomel Artesunate before 2008* Artesunate after 2008 Cipargamin Ganaplacide SJ733 (600 mg dose) Drug class Synthetic trioxolane Artemisinin derivative Artemisinin derivative Plasmodium falciparum ATP4 inhibitor Imidazolopiperazine P falciparum ATP4 inhibitor Median parasite clearance half-life (h)† 3·6 3·2 5·3 0·9 3·5 3·6 Mean terminal elimination half-life (h) 62·3 (for 400 mg cohort)