Sterol 14α-Demethylase as a Potential Target for Antitrypanosomal Therapy: Enzyme Inhibition and Parasite Cell Growth

Galina I. Lepesheva, Robert D. Ott, Tatiana Y. Hargrove, Yuliya Y. Kleshchenko, Inge Schuster, W. David Nes, George C. Hill, Fernando Villalta, Michael R. Waterman

Research output: Contribution to journalArticle

106 Scopus citations

Abstract

Sterol 14α-demethylases (CYP51) serve as primary targets for antifungal drugs, and specific inhibition of CYP51s in protozoan parasites Trypanosoma brucei (TB) and Trypanosoma cruzi (TC) might provide an effective treatment strategy for human trypanosomiases. Primary inhibitor selection is based initially on the cytochrome P450 spectral response to ligand binding. Ligands that demonstrate strongest binding parameters were examined as inhibitors of reconstituted TB and TC CYP51 activity in vitro. Direct correlation between potency of the compounds as CYP51 inhibitors and their antiparasitic effect in TB and TC cells implies essential requirements for endogenous sterol production in both trypanosomes and suggests a lead structure with a defined region most promising for further modifications. The approach developed here can be used for further large-scale search for new CYP51 inhibitors.

Original languageEnglish
Pages (from-to)1283-1293
Number of pages11
JournalChemistry and Biology
Volume14
Issue number11
DOIs
StatePublished - Nov 26 2007

Keywords

  • CHEMBIO
  • MICROBIO

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    Lepesheva, G. I., Ott, R. D., Hargrove, T. Y., Kleshchenko, Y. Y., Schuster, I., Nes, W. D., Hill, G. C., Villalta, F., & Waterman, M. R. (2007). Sterol 14α-Demethylase as a Potential Target for Antitrypanosomal Therapy: Enzyme Inhibition and Parasite Cell Growth. Chemistry and Biology, 14(11), 1283-1293. https://doi.org/10.1016/j.chembiol.2007.10.011