A class of sterol 14-demethylase inhibitors as anti-Trypanosoma cruzi agents

Frederick Buckner, Kohei Yokoyama, Jeffrey Lockman, Kendra Aikenhead, Junko Ohkanda, Martin Sadilek, Saïd Sebti, Wesley Van Voorhis, Andrew Hamilton, Michael H. Gelb

Research output: Contribution to journalArticle

Abstract

Chronic infection with the protozoan parasite Trypanosoma cruzi is a major cause of morbidity and mortality in Latin America. Drug treatments for the associated illness, Chagas disease, are toxic and frequently unsuccessful. In a screening effort against the drug target protein farnesyltransferase, we identified a series of disubstituted imidazoles with highly potent anti-T. cruzi activity that apparently acted through a mechanism independent of protein farnesylation. Metabolic labeling studies of T. cruzi suggested that sterol biosynthesis was inhibited. Combined GC/MS analysis confirmed depletion of cellular sterols and suggested that the site of action was sterol 14-demethylase, a cytochrome P450 enzyme. Spectral studies with recombinant T. cruzi sterol 14-demethylase demonstrated that the compounds bind directly to this enzyme. Two of the compounds were well absorbed when given orally to mice, gave sustained plasma levels, and were well tolerated. The compounds were administered orally to mice with acute T. cruzi infection and caused dramatic decrease in parasitemia and led to 100% survival. These disubstituted imidazole compounds can be prepared by a relatively short synthetic route and represent a structural class with potent anti-T. cruzi activity.

Original languageEnglish (US)
Pages (from-to)15149-15153
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number25
DOIs
StatePublished - Dec 9 2003

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Sterol 14-Demethylase
Trypanosoma cruzi
Sterols
Cytochrome P-450 Enzyme System
Protein Prenylation
Protozoan Infections
Imidazoles
Parasitemia
Chagas Disease
Latin America
Poisons
Pharmaceutical Preparations
Parasites
Morbidity
Mortality
Enzymes
Infection

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Buckner, F., Yokoyama, K., Lockman, J., Aikenhead, K., Ohkanda, J., Sadilek, M., ... Gelb, M. H. (2003). A class of sterol 14-demethylase inhibitors as anti-Trypanosoma cruzi agents. Proceedings of the National Academy of Sciences of the United States of America, 100(25), 15149-15153. https://doi.org/10.1073/pnas.2535442100

A class of sterol 14-demethylase inhibitors as anti-Trypanosoma cruzi agents. / Buckner, Frederick; Yokoyama, Kohei; Lockman, Jeffrey; Aikenhead, Kendra; Ohkanda, Junko; Sadilek, Martin; Sebti, Saïd; Van Voorhis, Wesley; Hamilton, Andrew; Gelb, Michael H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 25, 09.12.2003, p. 15149-15153.

Research output: Contribution to journalArticle

Buckner, F, Yokoyama, K, Lockman, J, Aikenhead, K, Ohkanda, J, Sadilek, M, Sebti, S, Van Voorhis, W, Hamilton, A & Gelb, MH 2003, 'A class of sterol 14-demethylase inhibitors as anti-Trypanosoma cruzi agents', Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 25, pp. 15149-15153. https://doi.org/10.1073/pnas.2535442100
Buckner, Frederick ; Yokoyama, Kohei ; Lockman, Jeffrey ; Aikenhead, Kendra ; Ohkanda, Junko ; Sadilek, Martin ; Sebti, Saïd ; Van Voorhis, Wesley ; Hamilton, Andrew ; Gelb, Michael H. / A class of sterol 14-demethylase inhibitors as anti-Trypanosoma cruzi agents. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 25. pp. 15149-15153.
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