Squalene synthase as a chemotherapeutic target in Trypanosoma cruzi and Leishmania mexicana.
Trypanosoma cruzi and Leishmania parasites have a strict requirement for specific endogenous sterols (ergosterol and analogs) for survival and growth and cannot use the abundant supply of cholesterol present in their mammalian hosts. Squalene synthase ( SQS, E.C. 2.5.1.21) catalyzes the first committed step in sterol biosynthesis and is currently under intense study as a possible target for cholesterol-lowering agents in humans, but it has not been investigated as a target for anti-parasitic chemotherapy. SQS is a membrane-bound enzyme in both T. cruzi epimastigotes and Leishmania mexicana promastigotes with a dual subcellular localization, being almost evenly distributed between glycosomes and mitochondrial/microsomal vesicles. Kinetic studies showed that the parasite enzymes display normal Michaelis-Menten kinetics and the values of the kinetic constants are comparable to those of the mammalian enzyme. We synthesized and purified 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (BPQ-OH), a potent and specific inhibitor of mammalian SQS and found that it is also a powerful non-competitive inhibitor of T. cruzi and L. mexicana SQS, with K(i)'s in the range of 12-62 nM. BPQ-OH induced a dose-dependent reduction of proliferation the extracellular stages of these parasites with minimal growth inhibitory concentrations (MIC) of 10-30 microM. Growth inhibition and cell lysis induced by BPQ-OH in both parasites was associated with complete depletion of endogenous squalene and sterols, consistent with a blockade of de novo sterol synthesis at the level of SQS. BPQ-OH was able to eradicate intracellular T. cruzi amastigotes from Vero cells cultured at 37 degrees C, with a MIC of 30 microM with no deleterious effects on host cells. Taken together, these results support the notion that SQS inhibitors could be developed as selective anti-trypanosomatid agents.[1]References
- Squalene synthase as a chemotherapeutic target in Trypanosoma cruzi and Leishmania mexicana. Urbina, J.A., Concepcion, J.L., Rangel, S., Visbal, G., Lira, R. Mol. Biochem. Parasitol. (2002) [Pubmed]
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