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Antimicrobial Agents and Chemotherapy, July 2004, p. 2379-2387, Vol. 48, No. 7
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.7.2379-2387.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

In Vitro and In Vivo Activities of E5700 and ER-119884, Two Novel Orally Active Squalene Synthase Inhibitors, against Trypanosoma cruzi

Laboratorio de Quimica Biológica, Centro de Bioquimica y Biofisica, Instituto Venezolano de Investigaciones Cientificas, Altos de Pipe, Caracas 1020,¹ Laboratorio de Enzimología de Parásitos, Departamento de Biologia, Facultad de Ciencias, Universidad de Los Andes, La Hechicera, Merida,² Laboratorio de Quimioterapia e Inmunologia, Instituto de Biologia Experimental, Facultad de Ciencias, Universidad Central de Venezuela, Caracas 1040, Venezuela,³ Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki 300-2635, Japan⁴

Received 3 December 2003/ Returned for modification 15 January 2004/ Accepted 2 March 2004

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 µM 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.

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