Hemozoin aggregation inhibition

As is often the case in multidisciplinary research, a number of different assays have been developed to monitor the inhibition of hemozoin aggregation (Table 1). Consequently, a great deal of confusion has arisen in the literature concerning the exact efficacy of a particular hemozoin inhibitor. For this reason, it is worthwhile to discuss the principal assays employed in the evaluation of antimalarial compounds and those assays specifically designed to evaluate heme aggregation inhibition. 

Scheme 1 Potential inhibition pathways to hemozoin aggregation...

Fig. (3). Hemozoin Production Mediated by Bionucleating Templates. Representative polymerization assay with 50 pM of hemin in 2 ml acetate buffer (500 mM, pH 4.8) at 37° C. BNTI and BNTII were used in 1 and 2 nmol amounts. Chloroquine (CQ, 100 pM) was included with BNT I and BNT n in inhibition reactions. Polyhistidine and bovine serum albumin in approximately 1 and 2 nmol amounts were used in protein control experiments. The blank control was the acetate buffer above. Base line amounts of insoluble aggregate are consistent with those previously reported under similar conditions.

For over 300 years, the quinoline family of drugs, and chloroquine in particular, has been used as the primary treatment for malaria. Recent studies have demonstrated that this drug inhibits the aggregation of free heme into hemozoin, allowing levels of monomeric heme to rise until cell lysis occurs. Although the determined structure of hemozoin makes the polymer termination scheme proposed by Sullivan et al. unlikely, hemozoin drug heme interactions appear critical in the inhibition mechanism. Thus, researchers have identified the characteristics of... 

Figure 2 Modes of hemozoin inhibition. On a neutrai iipid dropiet tempiate (T), heme can aggregate to form the biomineral HZ. Antimalarials may inhibit this aggregation by binding heme substrate, interacting with the iipid tempiate or trapping heme bound to the template. All actions serve to prevent the formation of HZ.

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