Recent Advances in the Discovery of Haem-Targeting Drugs for Malaria and Schistosomiasis 英文参考文献.docVIP

Molecules 2009, 14, 2868-2887; doi:10.3390/moleculeOPEN ACCESS molecules ISSN 1420-3049 /journal/molecules Review Recent Advances in the Discovery of Haem-Targeting Drugs for Malaria and Schistosomiasis Katherine A. de Villiers 1,* and Timothy J. Egan 2 1 University of Stellenbosch, Private Bag X1, Matieland 7602, South Africa 2 University of Cape Town, Private Bag, Rondebosch 7701, South Africa; E-mail: timothy.egan@uct.ac.za (T.J.E.) * Author to whom correspondence should be addressed; E-mail: kchen@sun.ac.za Received: 30 June 2009; in revised form: 20 July 2009 / Accepted: 22 July 2009 / Published: 4 August 2009 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. Keywords: haem; haemozoin; high-throughput screening; rational drug design 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]. As a consequence of the proteolytic breakdown of haemoglobin, iron (II)