Malaria, which affects over 200 million people per year, is becoming increasingly resistant to all of the currently available antimalarial drugs, making the development of new antimalarial agents imperative. One of the most promising new classes of drugs in development are the endoperoxides, derivatives of artemisinin (qinghaosu). We have been attempting to elucidate the mode of action of artemisinin. We propose that it has a two-step mechanism, in which the drug is first activated by intraparasitic heme/iron into an electrophilic compound, which then kills the parasite by alkylating important parasite protein(s). Evidence for the activation step includes our observations that heme and iron catalyze the decomposition of artemisinin into free radicals, and that iron chelators antagonize the drug's action. Evidence for the alkylation step includes our observations that artemisinin alkylates albumin in vitro, and that [3H] -dihydroartemisinin-treated parasites contain specific radiolabeled parasite-associated proteins. In order to both fully prove and better understand this mechanism, we will attempt to identify and characterize the alkylated malaria proteins. In addition, an attempt will be made to determine the chemical mechanisms for artemisinin's reactions with amino acids and heme, and carry out structure-activity relationship studies. We will also elucidate the mechanism by which the drug is taken up, determine where the intracellular drug targets are, and attempt to obtain artemisinin-resistant mutants. The results of these studies should have a direct application to the design of second-generation endoperoxides.
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