Recent Advances in the Discovery of Haem-Targeting Drugs for Malaria and Schistosomiasis

Katherine A De Villiers,Timothy J Egan

doi:10.3390/molecules14082868

Katherine A De Villiers, Timothy J Egan

Open Access

https://doi.org/10.3390/molecules14082868

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Abstract

Haem is believed to be the target of some of the historically most important antimalarial drugs, most notably chloroquine. This target is almost ideal as haem is host-derived and the process targeted, haemozoin formation, is a physico-chemical process with no equivalent in the host. The result is that the target remains viable despite resistance to current drugs, which arises from mutations in parasite membrane transport proteins. Recent advances in high-throughput screening methods, together with a better understanding of the interaction of existing drugs with this target, have created new prospects for discovering novel haem-targeting chemotypes and for target-based structural design of new drugs. Finally, the discovery that Schistosoma mansoni also produces haemozoin suggests that new drugs of this type may be chemotherapeutic not only for malaria, but also for schistosomiasis. These recent developments in the literature are reviewed.

Highlights

During development inside the red blood cell, the malaria parasite P. falciparum digests between 60 and 80% [1] of the available haemoglobin in an acidic food vacuole [2,3]
Notions that the formation of this crystalline material is an autocatalytic or protein-mediated process have been largely dispelled in light of compelling evidence that natural haemozoin exists enveloped inside neutral lipid bodies within the digestive vacuole of P
Coupled with the favourable fact that the process of haemozoin formation is unique to the parasite, this mechanistic insight renders the pathway of haem disposal an invaluable target for rational drug design

Summary

Introduction

During development inside the red blood cell, the malaria parasite P. falciparum digests between 60 and 80% [1] of the available haemoglobin in an acidic food vacuole [2,3]. In what appears to be a detoxification mechanism, malaria parasites sequester free Fe(III)PPIX into a micro-crystalline form known as haemozoin or malaria pigment [7]. While Plasmodium haemozoin comprises well-defined, micron-sized rectangular crystals, the crystalline material recovered from S. mansoni and R. prolixus is less homogenous and differs markedly in overall morphology [11]. Despite these differences in external appearance, it has been shown that all haemozoin crystals are isostructural and share the same unit cell. Pisciotta et al have shown that crystals of Plasmodium haemozoin occur within nanospheres predominantly formed of neutral lipids inside the food vacuole [12]. While the compounds discussed have their intended use as antimalarial agents, they could eventually be of chemotherapeutic value to treat schistosomiasis given a common means of haem disposal

Chemotherapy of Human Malaria and Schistosomiasis

Interactions of Existing Antimalarials with Haem

Findings

Conclusions