Malaria remains the most prevalent and devastating parasitic disease of the tropics. It is indigenous in over one hundred countries or areas of the world; over 50 % of the world's human population reside in areas endemic for this disease. Over the last 30 years the battle to contain malaria has swung towards the parasite with the emergence and gradual spread of drug-resistant organisms. Multi-drug resistant Plasmodium falciparum, the most deadly species of malaria infection, has been identified throughout Africa, Asia and South America and is spreading rapidly. There is a desperate need for new therapies. This project is directed towards a fundamental understanding of a key area of P. falciparum biochemistry - the process of intraerythrocytic hemoglobin catabolism, which is shown to be an excellent but largely uncharacterized target for chemotherapy. The long term objective of the research is to design novel and specific chemotherapeutic agents which perturb this area of parasite metabolism. The primary aims of this project are: Firstly, to carry out mechanistic and structural characterization of a novel aspartic hemoglobin protease which is present in the lysosomal vacuole of P. falciparum and to develop specific inhibitors of its function. Secondly, to determine the mechanism of biosynthesis of malaria pigment (hemozoin) which is the end product of parasite induced hemoglobin catabolism. These problems are tackled in a multidisciplinary approach which includes the technology of physical and structural chemistry, biochemistry and molecular biology.
|Martiney, J A; Ferrer, A S; Cerami, A et al. (1999) Chloroquine uptake, altered partitioning and the basis of drug resistance: evidence for chloride-dependent ionic regulation. Novartis Found Symp 226:265-77;discussion 277-80|
|Roepe, P D; Martiney, J A (1999) Are ion-exchange processes central to understanding drug-resistance phenomena? Trends Pharmacol Sci 20:62-5|
|Paciorkowski, A; Dai, W W; Cerami, A et al. (1997) Synergism of cimetidine with anti-malarial agents. J Parasitol 83:960-3|
|Martiney, J A; Cerami, A; Slater, A F (1996) Inhibition of hemozoin formation in Plasmodium falciparum trophozoite extracts by heme analogs: possible implication in the resistance to malaria conferred by the beta-thalassemia trait. Mol Med 2:236-46|
|Berger, B J; Martiney, J; Slater, A F et al. (1995) Chloroquine resistance is not associated with drug metabolism in Plasmodium falciparum. J Parasitol 81:1004-8|
|Martiney, J A; Cerami, A; Slater, A F (1995) Verapamil reversal of chloroquine resistance in the malaria parasite Plasmodium falciparum is specific for resistant parasites and independent of the weak base effect. J Biol Chem 270:22393-8|