Inhibition of hemozoin

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. 

FQ might thus strike the parasite not only via direct inhibition of hemozoin formation but also by production of lethal hydroxyl radicals. These radicals are known to be particularly aggressive toward unsaturated fatty acids present in... 

In conclusion, the activity of FQ is due to more than one route (Fig. 31). Due to its physicochemical properties, FQ could specifically target the lipid site of hemozoin formation. Its mechanism of action should be in part similar to that of CQ, based on the inhibition of hemozoin formation. Upon the specific (acidic and oxidizing) DV conditions, production of radical oxygen species (ROS) by FQ should be sufficient to promote significant damage on membranes of the parasite DV. The strong activity of FQ on CQ-resistant clones and isolates of P. falciparum suggests a fundamental difference in interaction with resistance mechanisms of the parasite. 

The binding of heme-artemisinin adducts to H -n with high affinity constants may result in the inhibition of hemozoin fonnation leading to the building-up of the concentration of free heme within the parasite. 

Loup C, Lelievre J, Benoit-Vical F, Meunier B. (2007) Trioxaquines and heme-artemisinin adducts inhibit the in vitro formation of hemozoin better than chloroquine. Antimicrob Agents Chemother 51 3768-3770. 

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... 

The antimalarial activity of FQ was initially compared with that of the purely organic CQ in an effort to understand how the presence of the ferrocene contributes to the antiplasmodial property. Over the years, the mechanism of CQ has been (and is still) the subject of many discussions and arguments. Nevertheless, there is strong evidence that the action of CQ is linked to its localization in the DV of the parasite and to the inhibition of the formation of hemozoin ([37], see [155-157]). 

The hydrophobic ferrocene moiety should establish favorable van der Waals interactions with lipid structures involved at the interface with aqueous content of the DV, positioning FQ in the same catalytic site as hematin [157]. This preferential location of FQ should cause inhibition of formation of hemozoin more efficiently than CQ does. 

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.

Inhibition of the nucleation and/or growth of the hemozoin crystals induced by FQ may be explained by the stereoselective binding of FQ with faces thereof. Generally, the two forms, biogenic (hemozoin) and synthetic (P-hematin), of the malaria pigment present three dominant crystal feces [h k 1 of the [100] side surfaces, 010 face that is perpendicular to each other, and the 011 fece that is inclined relative to the c-axis, ending at each end of crystal [85]. Sometimes, the biogenic hemozoin crystals have a face 001, which is perpendicular to the c-axis and that does not develop properly. The 001 face is exposed to the... 

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