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BIOGRAPHY:
Dr. Urbina earned his Ph.D. in physical chemistry from the Massachusetts Institute of Technology in 1975. He subsequently held positions at the Universidad Central de Venezuela, where he is still Professor of Physical Chemistry and Biophysics at the Escuela de Biologia, Facultad de Ciencias and at the Instituto Venezolano de Investigaciones Cientificas, where he is currently Head of the Research Group of Biological Chemistry. He has received a Simon Guggenheim Fellowship and a Lorenzo Mendoza Fleury Prize. His HHMI project is entitled "In vivo Anti-Trypanosoma cruzi Activity of New Isoprenoid and
Sterol Biosynthesis Inhibitors."
RESEARCH ABSTRACT SUMMARY:
In vivo Anti-Trypanosoma cruzi Activity of New Isoprenoid and Sterol Biosynthesis Inhibitors
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 Ki 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.
Photo: Kent Kallberg, Kallberg Studios
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