The role of haem in the activity of chloroquine and related antimalarial drugs
Introduction
Malaria is the most serious parasitic disease in man, both from the point of view of mortality and morbidity and from its world-wide occurrence in tropical and subtropical regions. It is estimated that 300 million people are infected annually, with one to two million deaths [1], [2]. The problem has been exacerbated by the appearance of drug resistant strains in the last three decades [3]. Since this resistance appears to be drug specific, rather than the result of a change in the biochemical target of these drugs, a thorough understanding of the mechanism of action of known drugs is an important priority [4] and may realistically afford the opportunity to develop new and effective substitutes.
Historically, chloroquine was the most effective drug for treatment and prophylaxis because of its strong therapeutic activity, low toxicity and low cost [5]. The mechanism of activity of chloroquine and a number of related antimalarials has been the subject of ongoing debate in the literature for many years [6], but advances since 1990 have contributed greatly to our understanding of the antimalarial activity of these drugs and may offer the opportunity for new breakthroughs in the development of novel and effective compounds. Current evidence suggests that the mechanism of action involves a unique bioinorganic process.
Fig. 1 illustrates the life cycle of Plasmodium falciparum, one of the four species of parasite which are pathogenic in man (and also the most dangerous). As can be seen, a portion of the life cycle occurs within the erythrocyte (red blood cell) of the human host. During this stage of the cycle, the parasite utilises host haemoglobin as a food source [7]. Haemoglobin is imported into a specialised acidic compartment in the parasite, known as a food vacuole and broken down by proteolytic enzymes called plasmepsins [8] to peptides which are subsequently degraded to amino acids. In the process four equivalents of haem (ferroprotoporphyrin IX, or Fe(II)PPIX) are released and oxidised (Fig. 2). Ferriprotoporphyrin IX (Fe(III)PPIX) is toxic to microorganisms in its free form (as discussed below) [9] and, in the parasite, is detoxified by conversion to an insoluble compound known as malaria pigment or haemozoin. As will be seen below, recent evidence suggests that it is this detoxification process which is the target of chloroquine and related drugs.
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Composition and structure of haemozoin
Haemozoin, or malaria pigment has been known since the eighteenth century, when discolouration of the internal organs of deceased chronic malaria suffers was first noticed [10]. This pigment was believed to be melanin until, in 1911, Brown first showed that it was constituted of haem [11]. Over the subsequent eight decades it was believed that haemozoin was either a specific haemoprotein (e.g. Ref. [12]) or else consisted of partially degraded haemoglobin [13]. In 1987, however, Fitch and
Mechanism of haemozoin and β-haematin formation
There is still substantial uncertainty over the mechanism of haemozoin formation in vivo. Originally Slater and Cerami [28] suggested that the reaction is enzyme-catalysed. This conclusion was based on the extreme conditions apparently required for synthetic β-haematin formation [16], and observations that an extract of plasmodial membranes apparently catalyses β-haematin formation. This so-called haem polymerase was reported to be heat-labile, supporting its identification as an enzyme. This
Mechanism of action of chloroquine and related antimalarials
Many hypotheses have been advanced over the last three to four decades to account for the mechanism of action of chloroquine. The literature dealing with this question up to 1993 has been critically discussed by Slater [6] and will not be detailed further here.
Hypotheses for the mode of action of chloroquine essentially fall into two broad categories: those in which the drug exerts its action outside the food vacuole of the parasite and those in which the activity is located inside the food
The interaction of antimalarial drugs with Fe(III)PPIX; thermodynamics and structure
There is a large body of literature reporting various types of spectroscopic evidence for complex formation between antimalarial drugs and Fe(III)PPIX [24], [57], [69], [70], [71], [77], [85], [86], [87], [88], [89], [90], [91], [92], [93], including among others chloroquine, amodiaquine, quinine, quinidine, halofantrine and mefloquine, but quantitative data is much sparser. Chou et al. [57] reported association constants for several antimalarial drug complexes of Fe(III)PPIX in aqueous
Additional requirements for antimalarial activity and prospects for rational design
Based on current evidence presented above a hierarchical set of requirements for rational design of a novel antimalarial compound can be envisaged [108]. It should:
- 1.
form a relatively strong complex with Fe(III)PPIX which should persist around pH 5;
- 2.
inhibit β-haematin formation;
- 3.
accumulate in the food vacuole of the parasite;
- 4.
be relatively non-toxic;
- 5.
be bio-available and be sufficiently water soluble.
Conclusions
Considerable progress towards understanding the mechanism of action of chloroquine and related antimalarials has been made over the last seven years. A combination of bioinorganic chemistry, organic synthesis, pharmacology and basic biology have provided a great deal of new information on the unique processes occurring in the food vacuole of the parasite and it may be hoped that their continued application will lead to the rational design of new drugs in the foreseeable future. In this respect,
Acknowledgements
The authors would like to thank the Foundation for Research Development, Pretoria, the Medical Research Council of South Africa, the University of Cape Town, the Nellie Atkinson Bequest and the University of the Witwatersrand for financial support.
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