title: Targeting Trypanosoma cruzi sterol 14α-demethylase (CYP51).
abstract: There are at least two obvious features that must be considered upon targeting specific metabolic pathways/enzymes for drug development: the pathway must be essential and the enzyme must allow the design of pharmacologically useful inhibitors. Here, we describe Trypanosoma cruzi sterol 14α-demethylase as a promising target for anti-Chagasic chemotherapy. The use of anti-fungal azoles, which block sterol biosynthesis and therefore membrane formation in fungi, against the protozoan parasite has turned out to be highly successful: a broad spectrum anti-fungal drug, the triazole compound posaconazole, is now entering phase II clinical trials for treatment of Chagas disease. This review summarizes comparative information on anti-fungal azoles and novel inhibitory scaffolds selective for Trypanosomatidae sterol 14α-demethylase through the lens of recent structure/functional characterization of the target enzyme. We believe our studies open wide opportunities for rational design of novel, pathogen-specific and therefore more potent and efficient anti-trypanosomal drugs.
authors.affiliation: Department of Biochemistry School of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Galina I
authors.initials: GI
authors.lastname: Lepesheva
authors.forename: Fernando
authors.initials: F
authors.lastname: Villalta
authors.forename: Michael R
authors.initials: MR
authors.lastname: Waterman
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology; D001393:Azoles / Q000494:pharmacology; D020134:Catalytic Domain; D014355:Chagas Disease / Q000469:parasitology / Q000628:therapy; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D055808:Drug Discovery; D006801:Humans; D011487:Protein Conformation; D013379:Substrate Specificity; D014230:Triazoles / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology*
chemical_list: D058888:14-alpha Demethylase Inhibitors; D000935:Antifungal Agents; D001393:Azoles; C509352:CYP51 protein, Trypanosoma cruzi; D065607:Cytochrome P-450 Enzyme Inhibitors; D014230:Triazoles; D014344:Trypanocidal Agents; C101425:posaconazole; D003577:Cytochrome P-450 Enzyme System