Abstract:
The malaria parasite, along with other hematophagous organisms face the problem of disposing of overwhelming quantities of heme released when they digest host hemoglobin. Plasmodium and several other organisms deal with this problem by crystalizing heme in the form of hemozoin, a cyclic dimer of Fe(III) protoporphyrin IX. A number of key past and present antimalarial drugs are believed to act by inhibiting this process, resulting in free heme that kills the parasite. The first report of heme-antimalarial complex formation dates to 1965, but no crystal structures of such complexes were available until 2008 when we obtained single crystals of heme-halofantrine. Since then several complexes of quinoline methanols have been crystallized, but recent studies on the effects of these drugs in parasites have cast doubt on the hemozoin inhibition hypothesis for this class. In an effort to further investigate this question, we have made fluorescent analogues to study their uptake into parasite cells by super-resolution fluorescence microscopy. On the other hand, the 4-aminoquinolines, including chloroquine clearly inhibit hemozoin formation in the parasite, but no crystal structures of the heme complexes of this drug class have been obtained. Use of molecular dynamics simulations with magnetic measurements together EXAFS spectroscopy has shed some light on their structures. Recent evidence, however, suggests that these drugs may in fact act by poisoning crystal growth, rather than forming solution complexes with heme. In silico modeling of surface interactions of novel compounds with heme may provide a method for discovering new hemozoin-inhibiting antimalarial scaffolds.