Artemisinin and its derivatives have proven clinical efficacy against drug-resistant malaria. Although many decades have been spent researching this peroxide-containing sesquiterpene, its antimalarial mechanism of action (MOA) is still a topic of debate and requires further exploration. An understanding of its antimalarial MOA may drive the design of novel antimalarials with less structural complexity than artemisinin itself. Recent studies have suggested that both ferrous (Fe2+) ion and the Plasmodium falciparum sarco/endoplasmic reticulum calcium (Ca2+) ion transporter (SERCA) PfATP6 enzyme play roles in artemisinin's antimalarial activity. To find a likely MOA, these roles have been systematically explored by means of homology modeling, metal ion prediction and modeling using the fragment transformation method, and molecular docking studies. A PfATP6 hypothesis for artemisinin's antimalarial MOA will be presented demonstrating the ability of Fe2+ to react irreversibly with artemisinin and nearby residues within the transporter, further explaining the dual requirement of Fe2+ and PfATP6 for the antimalarial activity of artemisinin and its derivatives.

Ferrous ion/PfATP6 dual requirement for antimalarial activity: Making strides towards understanding the MOA of artemisinin

248th National Meeting (2014)

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