No abstract

Malaria, resulting from the parasites of the genus Plasmodium, places an untold burden on the global population. As recently as 40 years ago, only 10% of the world's population was at risk from malaria. Today, over 40% of the world's population is at risk. Due to increased parasite resistance to traditional drugs and vector resistance to insecticides, malaria is once again resurgent. An emergent theme from current strategies for the development of new antimalarials is that metal homeostasis within the parasite represents an important drug target. During the intra-erythrocytic phase of its life cycle, the malaria parasite can degrade up to 75% of an infected cell's hemoglobin. While hemoglobin proteolysis yields requisite amino acids, it also releases toxic free heme (Fe(III)PPIX). To balance the metabolic requirements for amino acids against the toxic effects of heme, malaria parasites have evolved a detoxification mechanism which involves the formation of a crystalline heme aggregate known as hemozoin. An overview of the biochemistry of the critical detoxification process will place it in the appropriate context with regards to drug targeting and design. Quinoline-ring antimalarial drugs are effective against the intraerythrocytic stages of pigment-producing parasites. Recent work on the mechanism of these compounds suggests that they prevent the formation of hemozoin. Evidence for such a mechanism is reviewed, especially in the context of the newly reported crystal structure of hemozoin. Additionally, novel drugs, such as the hydroxyxanthones, which have many of the characteristics of the quinolines are currently being investigated. Recent work has also highlighted two classes of inorganic complexes that have interesting antimalarial activity: (1) metal-N(4)O(2) Schiff base complexes and (2) porphyrins. The mechanism of action for these complexes is discussed. The use of these complexes as probes for the elucidation of structure-activity relationships in heme polymerization inhibitor design and the loci of drug resistance is also detailed. As the biochemistry of the complicated interactions between host, parasite, and vector become better understood, the rationale for new antimalarial drug treatments will continue to improve. Clearly, the homeostasis of metal ions is a complicated biochemical process and is not completely understood. For the immediate future, it does, however, provide a clear target for the development of new and improved treatments for malaria.

A critical target for the development of new antimalarial treatments is the detoxification pathway of free heme released during the catabolism of host hemoglobin in the digestive vacuole of the malaria parasite Plasmodium falciparum. We have examined a family of peptide dendrimers (BNT I and II) based on the tandem repeat motif of HRP II from P. falciparum for their abilities both to bind heme substrates and to form the critical detoxification polymer hemozoin. Each template was capable of binding significant amounts of the natural substrate, Fe(III)PPIX. Binding of the metal-free base protoporphyrin IX to the templates suggests, however, that substrate recognition is based on the porphyrin moiety rather than specific metal recognition. Such a supposition is further supported by the fact that Zn(II)PPIX, as well as the structurally related metal-free and metallophthalocyanines, can bind to the templates. Further, it was shown that the dendrimeric BNT I and BNT II were capable of supporting the polymerization of hemozoin. In light of previously reported binding studies of linear sequences derived from HRP II and the polymer polyhistidine, the results suggest that the tandem organization of the tripeptide binding sites promotes the formation of hemozoin for these model templates.

No abstract

Schiff base N4O2 complexes offer a flexible template on which to develop novel antimalarial drug complexes that inhibit the aggregation of hemozoin, a detoxification product of the malaria parasite Plasmodium falciparum. The efficacies of these complexes are dependent on the charges of the complexes. Further evidence suggests that these complexes inhibit hemozoin formation via a specific drug/heme propionate salt that prevents the formation of the requisite axial propionato linkage in the repeating dimeric unit of the hemozoin aggregate.