Pathogenesis of Malaria
Human malaria infects ~400,000,000 individuals a year and because of increasing drug resistance and the widespread failure of mosquito control programs is an increasing world health problem. Malaria, primarily that caused by P. falciparum, results in 2-3 million deaths a year and places a great economic burden upon developing nations. We are currently engaged in several areas of malaria-related research:
In collaboration with Dr. Walter Szarek and Dr. Bob Kisilevsky of Queen’s University we are developing agents that inhibit the invasion of red cells, an essential part of the life cycle of Plasmodium (3). This avenue of research is promising because these compounds are cheap to synthesise, and appear to have limited toxicity in mice. These agents represent a novel group of antimalarials since they interfere with the initial adhesion and recognition process that malaria parasites require to invade a red cell and thereby escape from the host’s immune system.
We are developing synthetic surfactants as quinilone sensitizing agents for drug resistant malaria (1). This work builds on our initial observation that common synthetic surfactants are substrates of P-glycoproteins and that their presence can inhibit quinoline efflux from parasites. Plasmodium P-glycoproteins interact with different classes of surfactants than do mammalian cells, and therefore we believe we can develop sensitizing agents that are economically attractive to developing countries.
We are investigating the multiple ligand/receptor interactions that the receptor CD36 participates in. CD36 is a 88kDa glycoprotein that is found on platelets, macrophages and the vascular endothelium that is related to known scavenger receptors. Our primary interest is the ligand/receptor interaction of CD36 with the most deadly form of malaria, Plasmodium falciparum, however we are also attempting to characterise the binding domains on CD36 for oxidised low density lipoprotein (oxLDL) and oxidized HDL(2).
1. Ciach, M., K. Zong, K. C. Kain, and I. Crandall. 2003. Reversal of mefloquine and quinine resistance in Plasmodium falciparum with NP30. Antimicrob Agents Chemother 47:2393-6.
2. Guy, R. A., G. F. Maguire, I. Crandall, P. W. Connelly, and K. C. Kain. 2001. Characterization of peroxynitrite-oxidized low density lipoprotein binding to human CD36. Atherosclerosis 155:19-28.
3. Kisilevsky, R., I. Crandall, W. A. Szarek, S. Bhat, C. Tan, L. Boudreau, and K. C. Kain. 2002. Short-chain aliphatic polysulfonates inhibit the entry of Plasmodium into red blood cells. Antimicrob Agents Chemother 46:2619-26.
Leslie Dan Faculty of Pharmacy
University of Toronto
# 639 – 144 College Street
Toronto, Ontario, M5S 3M2