Interaction of iron(II)-heme and artemisinin with a peptide mimic of Plasmodium falciparum HRP-II.

The interaction of heme or heme-artemisinin adducts (heme-art) with different peptides mimicking repeat sequences of the Histidine-Rich-Protein-II of Plasmodium falciparum (PfHRP-II) was investigated. The pseudo-first order rate constants of the coordination of heme or heme-art onto a histidine rich peptide, used as a mimic of PfHRP-II putative heme binding sequence, are of the same order of magnitude, namely 42 and 14 s(-1), respectively. Despite the intrinsic reactivity of the carbonyl at C10 of heme-art toward a hydroxyl function, a peptide containing a serine or threonine residue does not readily react with heme-art adducts.

Heme alkylation by artesunic acid and trioxaquine DU1301, two antimalarial trioxanes.

The sesquiterpene Artemisinin, an antimalarial drug that is effective against multidrug-resistant Plasmodium falciparum strains, contains a 1,2,4-trioxane, and the endoperoxide function plays a key role in its biological activity. However, its poor solubility means that hemisynthetic derivatives, such as artesunic acid, are preferred for drugs. The reductive activation of the peroxide function of artemisinin by iron(II)-heme produces heme derivatives that are alkylated at meso positions by a C-centered radical derived from artemisinin.