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Summary: Dr. Urbina is studying the biochemistry and molecular biology of Trypanosoma cruzi.

We have reported before the specific in vitro activity of squalene synthase (SQS) and farnesyl-pyrophosphate synthase (FPPS), which are inhibitors against Trypanosoma cruzi, the causative agent of Chagas disease in Latin America. We have investigated in detail the in vitro and in vivo activity of risedronate (2-(3-pyridyl)-1-hydroxy-ethane-1,1-bisphosphonic acid), one of the most potent T. cruzi FPPS inhibitors known. We found that the selective antiparasitic activity of this compound is associated with the depletion of sterols and other essential poly-isoprenoids and involves drastic ultrastructural alterations of the intracellular parasites with no biochemical or ultrastructural effects on the host cells, which fully retained their normal structure and activity upon treatment. In a murine model of acute Chagas disease, risedronate, given i.v. at doses as low as 1 mg/kg.d for 7 days, induced a greater than 90 percent reduction in parasitemia and increased significantly the survival of treated animals. There was no relapse of parasitemia after treatment was discontinued, suggesting trypanocidal, rather that trypanostatic, activity. More recently, we studied the antiparasitic activity of E5700 and ER-119884, two novel quinuclidine SQS inhibitors, currently in development as cholesterol-lowering agents by Eisai Co. Ltd. These compounds were potent non-competitive or mixed-type inhibitors of T. cruzi SQS with K_i values in the low nanomolar/subnanomolar range in the absence or presence of 20 microM inorganic pyrophosphate. Their antiproliferative IC₅₀ against extracellular epimastigotes and intracellular amastigotes was about 10 nM and 0.4-1.6 nM, respectively, with no effects on host cells. At the MIC, all parasites' sterols disappeared in treated cells. In vivo studies indicated that E5700 was able to provide full protection against death and completely arrested development of parasitemia when given at 50 mg/Kg.d for 30 days, while ER-119884 provided only partial protection. This is the first report of an orally active SQS inhibitor capable of providing complete protection against fulminant acute Chagas disease.