Journal
FEBS LETTERS
Volume 588, Issue 21, Pages 3878-3885Publisher
WILEY
DOI: 10.1016/j.febslet.2014.08.030
Keywords
Sterol 14 alpha-demethylase; CYP51 sequence variation; Drug resistance; Structure-based drug design; Trypanosoma cruzi
Funding
- National Institutes of Health [R01 GM067871]
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CYP51 (sterol 14 alpha-demethylase) is an efficient target for clinical and agricultural antifungals and an emerging target for treatment of Chagas disease, the infection that is caused by multiple strains of a protozoan pathogen Trypanosoma cruzi. Here, we analyze CYP51A from the Y strain T. cruzi. In this protein, proline 355, a residue highly conserved across the CYP51 family, is replaced with serine. The purified enzyme retains its catalytic activity, yet has been found less susceptible to inhibition. These biochemical data are consistent with cellular experiments, both in insect and human stages of the pathogen. Comparative structural analysis of CYP51 complexes with VNI and two derivatives suggests that broad-spectrum CYP51 inhibitors are likely to be preferable as antichagasic drug candidates. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.
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