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Antimicrobial Agents and Chemotherapy, April 2001, p. 1210-1215, Vol. 45, No. 4
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.4.1210-1215.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Potent Anti-Trypanosoma cruzi Activities of Oxidosqualene Cyclase Inhibitors

Frederick S. Buckner,1,* John H. Griffin,2,dagger Aaron J. Wilson,1 and Wesley C. Van Voorhis1

Department of Medicine, University of Washington, Seattle, Washington 98195,1 and Department of Chemistry, Stanford University, Stanford, California 943052

Received 8 November 2000/Returned for modification 8 January 2001/Accepted 22 January 2001

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.

* Corresponding author. Mailing address: University of Washington, Infectious Diseases, Box 357185, Seattle, WA 98195-7185. Phone: (206) 543-0821. Fax: (206) 685-8681. E-mail: fbuckner{at}u.washington.edu.

dagger Present address: Advanced Medicine, Inc., South San Francisco, CA 94080.

Antimicrobial Agents and Chemotherapy, April 2001, p. 1210-1215, Vol. 45, No. 4
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.4.1210-1215.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Lepesheva, G. I., Zaitseva, N. G., Nes, W. D., Zhou, W., Arase, M., Liu, J., Hill, G. C., Waterman, M. R. (2006). CYP51 from Trypanosoma cruzi: A PHYLA-SPECIFIC RESIDUE IN THE B' HELIX DEFINES SUBSTRATE PREFERENCES OF STEROL 14{alpha}-DEMETHYLASE. J. Biol. Chem. 281: 3577-3585 [Abstract] [Full Text]  


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