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

Structural insights into inhibition of sterol 14alpha-demethylase in the human pathogen Trypanosoma cruzi.

Lepesheva GI, Hargrove TY, Anderson S, Kleshchenko Y, Furtak V, Wawrzak Z, Villalta F, Waterman MR
J Biol Chem. 2010 285 (33): 25582-90

PMID: 20530488 · PMCID: PMC2919122 · DOI:10.1074/jbc.M110.133215

Trypanosoma cruzi causes Chagas disease (American trypanosomiasis), which threatens the lives of millions of people and remains incurable in its chronic stage. The antifungal drug posaconazole that blocks sterol biosynthesis in the parasite is the only compound entering clinical trials for the chronic form of this infection. Crystal structures of the drug target enzyme, Trypanosoma cruzi sterol 14alpha-demethylase (CYP51), complexed with posaconazole, another antifungal agent fluconazole and an experimental inhibitor, (R)-4'-chloro-N-(1-(2,4-dichlorophenyl)-2-(1H-imid-azol-1-yl)ethyl)biphenyl-4-carboxamide (VNF), allow prediction of important chemical features that enhance the drug potencies. Combined with comparative analysis of inhibitor binding parameters, influence on the catalytic activity of the trypanosomal enzyme and its human counterpart, and their cellular effects at different stages of the Trypanosoma cruzi life cycle, the structural data provide a molecular background to CYP51 inhibition and azole resistance and enlighten the path for directed design of new, more potent and selective drugs to develop an efficient treatment for Chagas disease.

MeSH Terms (13)

Animals Antifungal Agents Chagas Disease Crystallography, X-Ray Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System Humans Immunoblotting Molecular Structure Myocytes, Cardiac Protein Structure, Secondary Triazoles Trypanosoma cruzi

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