Structural insights into inhibition of sterol 14alpha-demethylase in the human pathogen Trypanosoma cruzi.
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.
Lepesheva
Galina I
GI
Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA. i.lepesheva@vanderbilt.edu
Hargrove
Tatiana Y
TY
Anderson
Spencer
S
Kleshchenko
Yuliya
Y
Furtak
Vyacheslav
V
Wawrzak
Zdzislaw
Z
Villalta
Fernando
F
Waterman
Michael R
MR
D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D014355:Chagas Disease / Q000188:drug therapy; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry*; D006801:Humans; D015151:Immunoblotting; D015394:Molecular Structure; D032383:Myocytes, Cardiac / Q000469:parasitology; D017433:Protein Structure, Secondary; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology* / Q000472:pathogenicity
D000935:Antifungal Agents; C509352:CYP51 protein, Trypanosoma cruzi; D065607:Cytochrome P-450 Enzyme Inhibitors; D014230:Triazoles; C101425:posaconazole; D003577:Cytochrome P-450 Enzyme System