<i>Plasmodium falciparum</i> Endoplasmic Reticulum-Resident Calcium Binding Protein Is a Possible Target of Synthetic Antimalarial Endoperoxides, N‑89 and N‑251

The endoperoxide artemisinin is a current first-line antimalarial and a critical component of the artemisinin-based combination therapies (ACT) recommended by WHO for treatment of <i>Plasmodium falciparum</i>, the deadliest of malaria parasites. However, recent emergence of the artemisinin-resistant <i>P. falciparum</i> urged us to develop new antimalarial drugs. We have shown that synthetic endoperoxides N-89 and its hydroxyl derivative N-251 had high antimalarial activities both <i>in vivo</i> and <i>in vitro</i>. However, the mechanisms including the cellular targets of the endoperoxide antimalarials are not well understood. Thus, in this study, we employed chemical proteomics to survey potential molecular targets of endoperoxides by evaluating <i>P. falciparum</i> proteins capable to associate with endoperoxide structure (N-346, a carboxyamino derivative of N-89). We also analyzed the protein expression profiles of malaria parasites treated with N-89 or N-251 to explore possible changes associated with the drug action. From these experiments, we found that <i>P. falciparum</i> endoplasmic reticulum-resident calcium binding protein (<i>Pf</i>ERC) had high affinity to the endoperoxide structure (N-346) and was decreased by treatment with N-89 or N-251. <i>Pf</i>ERC is a member of CREC protein family, a potential disease marker and also a potential target for therapeutic intervention. We propose that the <i>Pf</i>ERC is a strong candidate of the endoperoxide antimalarial’s target.