Artemisinin - Mechanism of Action

Mechanism of Action

All artemisinins used today are prodrugs of the biologically active metabolite dihydroartemisinin, which is active during the stage when the parasite is located inside red blood cells. Although there is no consensus regarding the mechanism through which artemisinin derivatives kill the parasites, several lines of evidence indicate that artemisinins exert their antimalarial action by perturbing redox homeostasis in malaria parasites. When the parasite that causes malaria infects a red blood cell, it consumes hemoglobin within its digestive vacuole, a process that generates oxidative stress. In one theory the iron of the heme directly reduces the peroxide bond in artemisinin, generating high-valent iron-oxo species and resulting in a cascade of reactions that produce reactive oxygen radicals which damages the parasite and lead to its death. A more recently described alternative is that artemisinins disrupt cellular redox cycling.

Numerous studies have investigated the type of damage oxygen radicals may induce. For example, Pandey et al. have observed inhibition of digestive vacuole cysteine protease activity of malarial parasites by artemisinin. These observations were supported by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin and inhibition of hemozoin formation by malaria parasites. Electron microscopic evidence linking artemisinin action to the parasite's digestive vacuole has been obtained showing that the digestive vacuole membrane suffers damage soon after parasites are exposed to artemisinin. This would also be consistent with data showing that the digestive vacuole is already established by the mid-ring stage of the parasite's blood cycle, a stage that is sensitive to artemisinins but not other antimalarials.

A commonly cited theory that the parasite's SERCA pump (PfATP6 / PfSERCA) is a target of artemisinins has been increasingly questioned and refuted although this hypothesis continues to be discussed by its original proponents. It is now clear that the original studies claiming specific interactions between SERCAs and artemisinins were undertaken in a Xenopus oocyte system with a poor signal:noise ratio.

A 2005 study investigating the mode of action of artemisinin using a yeast model demonstrated the drug acts on the electron transport chain, generates local reactive oxygen species, and causes the depolarization of the mitochondrial membrane. However, replacement of mitochondrial function in transgenic asexual stage parasites does not alter sensitivity to artemisinins (as would be predicted if mitochondrial targeting was relevant to artemisinin action), whereas atovaquone resistance is observed, which would be consistent with mitochondrial targeting of this antimalarial.