Heme Aggregation Inhibitors Antimalarial Drugs Targeting an Essential Biomineralization Process
During the intra-erythrocytic phase of its life cycle, the malaria parasite can degrade up to 75 percent of an infected cell 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-N4O2 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.
Keywords: Biomineralization process; Biotransportation and Localization; Heme Aggregation Inhibitors; Hemoglobin Proteolysis; Hemoglobin tetramer; Hemozoin Inhibition; High spine monomeric; Metalloporphyrin Complexes; Schiff Based Metallodrugs; Surrogate oxyanions
Document Type: Review Article
Publication date: 01 February 2001
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