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

Galina I. Lepesheva, Tatiana Y. Hargrove, Spencer Anderson, Yuliya Kleshchenko, Vyacheslav Furtak, Zdzislaw Wawrzak, Fernando Villalta, Michael R. Waterman

Research output: Contribution to journalArticlepeer-review

126 Scopus citations

Abstract

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 14α-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.

Original languageEnglish (US)
Pages (from-to)25582-25590
Number of pages9
JournalJournal of Biological Chemistry
Volume285
Issue number33
DOIs
StatePublished - Aug 13 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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