Intraerythrocytic plasmodia are highly vulnerable to oxidant stress and oxidant drugs. However, neither the etiology of this vulnerability nor the mechanisms and targets of oxidant damage are known. We have not shown that qinghaosu is an oxidant antimalarial drug, and will use it as a prototype for our investigations. We hope to determine why qinghaosu and other oxidants are selectively toxic to malarial parasites and elucidate their mechanism and targets of oxidant damage. In order to determine the causes of this oxidant susceptibility, we will attempt to better understand the parasite's enzymes of peroxide metabolism (catalase and glutathione peroxidase), following up on our earlier work on superoxide dismutase. We will also determine whether parasites contain soluble or insoluble pools of iron which are capable of acting as intracellular catalysts for the production of activated oxygen. In order to full understand the antimalarial activity of qinghaosu and other oxidant drugs, we will attempt to identify the specific activated oxygen species generated by the drug in situ and locate the most important intracellular targets of oxidant damage. New antimalarial drugs are greatly needed now and, because of the parasite's genetic sophistication, will be needed for the foreseeable future. We are now close to understanding exactly why malarial parasites are sensitive to oxidant drugs such as qinghaosu. Such an understanding will aid in the development of new antimalarial agents.
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