Chagas' disease is a serious public health problem in Latin America, and no treatment is available for the prevalent chronic stage. Its causative agent, Trypanosoma cruzi, requires specific endogenous sterols for survival, and we have recently demonstrated that squalene synthase (SQS) is a promising target for antiparasitic chemotherapy. E5700 and ER-119884 are quinuclidine-based inhibitors of mammalian SQS that are currently in development as cholesterol-and triglyceride-lowering agents in humans. These compounds were found to be potent noncompetitive or mixed-type inhibitors of T. cruzi SQS with K i values in the low nanomolar to subnanomolar range in the absence or presence of 20 M inorganic pyrophosphate. The antiproliferative 50% inhibitory concentrations of the compounds against extracellular epimastigotes and intracellular amastigotes were ca. 10 nM and 0.4 to 1.6 nM, respectively, with no effects on host cells. When treated with these compounds at the MIC, all of the parasite's sterols disappeared from the parasite cells. In vivo studies indicated that E5700 was able to provide full protection against death and completely arrested the development of parasitemia when given at a concentration of 50 mg/kg of body weight/day for 30 days, while ER-119884 provided only partial protection. This is the first report of an orally active SQS inhibitor that is capable of providing complete protection against fulminant, acute Chagas' disease.Chagas' disease, a parasitic disease caused by the kinetoplastid protozoan Trypanosoma (Schizotrypanum) cruzi, is still one of the most serious public health problems in Latin America, despite recent advances in the control of the vectorial and transfusional transmission of the parasite (36). There are ca. 18 million people currently infected with T. cruzi, most of them in the chronic phase, which can lead to severe heart and gastrointestinal lesions (36). Current chemotherapy, based on the nitrofuran nifurtimox (Bayer) and the nitroimidazole benznidazole (Roche), is unsatisfactory as these compounds are effective only for recent infections and have frequent toxic side effects (21,24,28). Studies have shown that T. cruzi has a strict requirement for specific endogenous sterols (ergosterol and analogs) for survival and growth and cannot use the abundant supply of cholesterol present in its mammalian host (21)(22)(23)25). Ergosterol biosynthesis inhibitors with potent in vitro activity and special pharmacokinetic properties in mammals (large volumes of distribution and long half-lives) can induce the radical cure of parasitic infection in experimental animal models of both acute and chronic 25). Squalene synthase (SQS; EC 2.5.1.21) catalyzes a head-to-head reductive dimerization of two molecules of farnesyl pyrophosphate (FPP) in a two-step reaction to form squalene (Fig.

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