Schistosomiasis is an important tropical parasitic disease with more than two hundred million human infections in more than 70 countries (Engels et al., 2002). In spite of the widespread use of chemotherapy and other control strategies transmission rates of schistosomiasis have changed little over the past 50 years. Currently a single drug is in widespread use and there is concern that drug resistant parasites will appear (Doenhoff et al., 2002; Cioli and Pica-Mattoccia, 2003). Laboratory results indicate that in vitro selection can lead to drug resistant parasites (Fallen and Doenhoff, 1994). Therefore, there is an urgent need for the development of new chemotherapies for the control of schistosomiasis. The goal of this Exploratory/Developmental Research proposal (i.e. R21) is to identify individual proteins or pathways that can be targeted for chemotherapeutic treatment of schistosomiasis. Artemisinins are a new class of antimalarial and antischistosomal compounds that are thought to function via artemisinin radical derivatives. These artemisinin radicals are thought to then alkylate free amino and thiol groups of specific amino acid residues of proteins. Very little is known about mechanisms of action of artemisinins against schistosomes and no schistosome proteins that react with artemisinin have been identified. Therefore, our first specific aim is to 1 ) Determine schistosome proteins labeled by artemisinins after in vivo and in vitro labeling of parasites using proteomic approaches. Because artemisinins are active against schistosomes and schistosomes produce heme derivatives similar to Plasmodium, we hypothesize that similar killing mechanisms will be involved in the action of artemisinins against schistosomes. Therefore, the two additional aims of this proposal are designed to test if artemisinin protein targets in Schistosoma mansoni are homologous to the identified protein targets in Plasmodium. Our further specific aims are to 2.) Determine the pharmacological effect of artemisinin on S. mansoni Ca-ATPases; 3.) Determine whether artemisinins block the histamine releasing ability of S. mansoni translationally controlled tumor protein. The critical conclusions of this study will direct subsequent future experiments into the molecular mechanism of artemisinin's anti-parasitic activity.