US EPA

8319925 

Journal Article 

Interplay between malaria, crystalline hemozoin formation, and antimalarial drug action and design 

Weissbuch, I; Leiserowitz, L 

2008 

Yes 

Chemical Reviews
ISSN: 0009-2665
EISSN: 1520-6890 

108 

11 

4899-4914 

English 

10.1021/cr078274t 

We review the interplay between malaria, the formation of synthetic β-hematin and natural crystalline hemozoin, and antimalarial drug action and design. The crystal morphology of β-hematin and natural hemozoin is described, including a simple analysis of why only very few types of stable crystal faces may be expected in keeping with observation. Drug action of various types of antimalarials, such as quinolines, phenanthrene derivatives, and diethylamino-alkoxyxanthones is postulated as a result of stereospecific binding thereof to specific hemozoin crystal faces and subsequent inhibition of crystal growth. The experimental evidence indicating adsorption of the quinoline type drugs to particular crystal faces is reviewed in terms of possible binding sites on those faces, the functional groups of the drug, change in crystal (β-hematin) morphology, and various methods, suggesting that the quinoline drugs were occluded within the growing crystals. The drugs may be described as hemozoin crystal capping agents (CMOLs) in view of their proposed ability to bind stereospecifically to particular faces of the crystal, despite being completely different in molecular structure from that of the β-hematin cyclic molecular dimer, and thus inhibit growth along two principal directions. In concert with pure drug, halofantrine or quinoline methanol-Fe3+-PPIX complexes would act as TMAs binding stereo-selctively to the third principal face and inhibiting its growth. On the other hand, artemisinin drug action is described as a result of binding of artemisinin-β-hematin cyclic dimer adducts to all of the principal faces of hemozoin, resulting in effective crystal growth inhibition. Such proposed adducts may be considered as tailor-made crystal growth inhibitors since their molecular structures are the same as that of the β-hematin cyclic dimer but for an added (artemisinin) moiety bound to various sites on the periphery of the porphyrin rings and thus tailored for adsorption to specific faces. A detailed description of the various hemozoin surface binding sites with a focus on their spatial arrangement is given, to best design effective inhibitors of hemozoin nucleation and growth. Finally, nucleation of hemozoin crystals is reviewed in view of very recent findings that acyl-glycerols within lipid bodies promote the- nucleation process. Future work would have to provide evidence whether there is any crystal alignment within the lipid bodies including the crystallographic nature thereof and develop methods to map the distribution of antimalarial drugs occluded within hemozoin crystals. © 2008 American Chemical Society.