The role of haem in the activity of chloroquine and related antimalarial drugs

Abstract

Advances made over the last decade indicate that the mechanism of action of important antimalarial agents, such as chloroquine, involves formation of π–π complexes between drugs and ferriprotoporphyrin IX. This process is believed to block the detoxification of host haemoglobin-derived haem in the food vacuole of the parasite. Detoxification of haem occurs via conversion to a coordination polymer involving the formation of an Fe(III)-carboxylate bond between the propionate group of one ferriprotoporphyrin IX molecule and the Fe(III) centre of the next. This compound is known as malaria pigment or haemozoin in vivo, but can also be prepared synthetically, in which case it is referred to as β-haematin. Literature relating to the structure and mechanism of formation of haemozoin/β-haematin, the mechanism of action of the drugs and thermodynamics and structures of ferriprotoporphyrin IX-drug complexes is reviewed.

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.