Michael Waterman
Faculty Member
Last active: 2/12/2015

Targeting Trypanosoma cruzi sterol 14α-demethylase (CYP51).

Lepesheva GI, Villalta F, Waterman MR
Adv Parasitol. 2011 75: 65-87

PMID: 21820552 · PMCID: PMC3488290 · DOI:10.1016/B978-0-12-385863-4.00004-6

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.

Copyright © 2011 Elsevier Ltd. All rights reserved.

MeSH Terms (14)

14-alpha Demethylase Inhibitors Antifungal Agents Azoles Catalytic Domain Chagas Disease Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System Drug Discovery Humans Protein Conformation Substrate Specificity Triazoles Trypanocidal Agents Trypanosoma cruzi

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