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. 2001 Apr;45(4):1210-5.
doi: 10.1128/AAC.45.4.1210-1215.2001.

Potent anti-Trypanosoma cruzi activities of oxidosqualene cyclase inhibitors

F S Buckner  1 , J H Griffin, A J Wilson, W C Van Voorhis
Affiliations

Potent anti-Trypanosoma cruzi activities of oxidosqualene cyclase inhibitors

F S Buckner et al. Antimicrob Agents Chemother. 2001 Apr.

Abstract

Trypanosoma cruzi is the protozoan agent that causes Chagas' disease, a major health problem in Latin America. Better drugs are needed to treat infected individuals. The sterol biosynthesis pathway is a potentially excellent target for drug therapy against T. cruzi. In this study, we investigated the antitrypanosomal activities of a series of compounds designed to inhibit a key enzyme in sterol biosynthesis, oxidosqualene cyclase. This enzyme converts 2,3-oxidosqualene to the tetracyclic product, lanosterol. The lead compound, N-(4E,8E)-5,9, 13-trimethyl-4,8, 12-tetradecatrien-1-ylpyridinium, is an electron-poor aromatic mimic of a monocyclized transition state or high-energy intermediate formed from oxidosqualene. This compound and 27 related compounds were tested against mammalian-stage T. cruzi, and 12 inhibited growth by 50% at concentrations below 25 nM. The lead compound was shown to cause an accumulation of oxidosqualene and decreased production of lanosterol and ergosterol, consistent with specific inhibition of the oxidosqualene cyclase. The data demonstrate potent anti-T. cruzi activity associated with inhibition of oxidosqualene cyclase.

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Figures

FIG. 1
FIG. 1
Biosynthesis of ergosterol as characterized in yeast. The pathway shows the major intermediates (bold characters) and enzymes by their yeast designations (ERG1, squalene epoxidase; ERG7, oxidosqualene cyclase; ERG11, C14-demethylase). Drug classes that act on selected sites in the pathway are shown in italics.
FIG. 2
FIG. 2
Conversion of 2,3-oxidosqualene to lanosterol.
FIG. 3
FIG. 3
Structures of OSC inhibitors and the monocyclized cationic intermediate formed in the cyclization of oxidosqualene to lanosterol. OTS, tosylate.
FIG. 4
FIG. 4
TLC of cellular sterols from T. cruzi epimastigotes grown without drugs (lane 1) or with 5 μM OSC inhibitor no. 1 (lane 2) or with 25 μM ketoconazole (lane 3). The parasites were grown for 24 h in the presence of [3H]mevalonalactone and the indicated drugs. Sterols from a Candida albicans extract and their identification are shown for comparison (lane 4). (Lane 4 was separated from lane 3 by three intervening lanes that were removed from the figure for simpler display.) Note the reduction in ergosterol in parasites treated with the OSC inhibitor or ketoconazole. S, squalene; OS, 2,3-oxidosqualene; DOS, dioxidosqualene; L, lanosterol; E, ergosterol. The digital image was produced with Adobe Photoshop 5.0.
FIG. 5
FIG. 5
Isobologram of OSC inhibitor no. 1 and ketoconazole or terbinafine against mammalian-stage T. cruzi. CI, cyclase inhibitor.
See this image and copyright information in PMC

References

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