title: Sterol 14alpha-demethylase as a potential target for antitrypanosomal therapy: enzyme inhibition and parasite cell growth.
abstract: Sterol 14alpha-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.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA. galina.i.lepesheva@vanderbilt.edu
authors.forename: Galina I
authors.initials: GI
authors.lastname: Lepesheva
authors.forename: Robert D
authors.initials: RD
authors.lastname: Ott
authors.forename: Tatiana Y
authors.initials: TY
authors.lastname: Hargrove
authors.forename: Yuliya Y
authors.initials: YY
authors.lastname: Kleshchenko
authors.forename: Inge
authors.initials: I
authors.lastname: Schuster
authors.forename: W David
authors.initials: WD
authors.lastname: Nes
authors.forename: George C
authors.initials: GC
authors.lastname: Hill
authors.forename: Fernando
authors.initials: F
authors.lastname: Villalta
authors.forename: Michael R
authors.initials: MR
authors.lastname: Waterman
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D065607:Cytochrome P-450 Enzyme Inhibitors; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D058886:Sterol 14-Demethylase; D013379:Substrate Specificity; D014346:Trypanosoma brucei brucei / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D014349:Trypanosoma cruzi / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D014352:Trypanosomiasis / Q000188:drug therapy*
chemical_list: D000981:Antiprotozoal Agents; C548418:CYP51A1 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase