Malarial hemozoin: From target to tool

Abstract

Background Malaria is an extremely devastating disease that continues to affect millions of people each year. A distinctive attribute of malaria infected red blood cells is the presence of malarial pigment or so-called hemozoin. Hemozoin is a biocrystal synthesized by Plasmodium and other blood-feeding parasites to avoid the toxicity of free heme derived from the digestion of hemoglobin during invasion of the erythrocytes. Scope of Review Hemozoin is involved in several aspects of the pathology of the disease as well as in important processes such as the immunogenicity elicited. It is known that the once best antimalarial drug, chloroquine, exerted its effect through interference with the process of hemozoin formation. In the present review we explore what is known about hemozoin, from hemoglobin digestion, to its final structural analysis, to its physicochemical properties, its role in the disease and notions of the possible mechanisms that could kill the parasite by disrupting the synthesis or integrity of this remarkable crystal. Major Conclusions The importance and peculiarities of this biocrystal have given researchers cause to consider it as a target for new antimalarials and to use it through unconventional approaches for diagnostics and therapeutics against the disease. General Significance Hemozoin plays an essential role in the biology of malarial disease. Innovative ideas could use all the existing data on the unique chemical and biophysical properties of this macromolecule to come up with new ways of combating malaria.

Antimalarials inhibit hematin crystallization by unique drug–surface site interactions

“…It is generally accepted that the quinoline class of antimalarials (quinine, chloroquine, amodiaquine, and others) work by suppressing hematin crystallization (8,13,21,25,26,28,29). The prevailing hypothesis is that drugs decrease the activity of soluble hematin by forming noncrystallizable complexes (13,30).…”

“…The released heme rapidly oxidizes to Fe(III) hematin, which is toxic to the parasite in its free state (6). The main mechanism of heme detoxification (8) implemented by the parasite is sequestration as nontoxic hemozoin crystals (9)(10)(11)(12) (Fig. 1C).…”

Evaluation of naphthoquinones identified the acetylated isolapachol as a potent and selective antiplasmodium agent

“…In agreement to this, it was observed that compound 1 but not lapachol, inhibits the b-hematin formation and this may explain the enhanced antimalarial activity of compound 1 versus lapachol. Hemozoin is vital for parasite maintenance 28 . In fact, we observed that most parasite cells were destroyed under compound 1 treatment, suggesting this is a parasiticidal agent.…”

Antimalarial Activity of Small-Molecule Benzothiazole Hydrazones

“…Heme-interacting molecule may inhibit hemozoin formation (39,40). Thus, to check the effect of these molecules on hemozoin formation, we measured hemozoin formation in vitro by parasite lysate in presence or absence of different BHs.…”