G I Lepesheva


Affiliation: Vanderbilt University
Country: USA


  1. Lepesheva G, Waterman M. Sterol 14alpha-demethylase (CYP51) as a therapeutic target for human trypanosomiasis and leishmaniasis. Curr Top Med Chem. 2011;11:2060-71 pubmed
  2. Hargrove T, Wawrzak Z, Fisher P, Child S, Nes W, Guengerich F, et al. Binding of a physiological substrate causes large-scale conformational reorganization in cytochrome P450 51. J Biol Chem. 2018;293:19344-19353 pubmed publisher
  3. Cherkesova T, Hargrove T, Vanrell M, Ges I, Usanov S, Romano P, et al. Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition. FEBS Lett. 2014;588:3878-85 pubmed publisher
    ..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. ..
  4. Lepesheva G, Park H, Hargrove T, Vanhollebeke B, Wawrzak Z, Harp J, et al. Crystal structures of Trypanosoma brucei sterol 14alpha-demethylase and implications for selective treatment of human infections. J Biol Chem. 2010;285:1773-80 pubmed publisher
    ..The structures shed new light on 14DM functional conservation and open an excellent opportunity for directed design of novel antiparasitic drugs. ..
  5. request reprint
    Lepesheva G, Hargrove T, Ott R, Nes W, Waterman M. Biodiversity of CYP51 in trypanosomes. Biochem Soc Trans. 2006;34:1161-4 pubmed
  6. Lepesheva G, Ott R, Hargrove T, Kleshchenko Y, Schuster I, Nes W, et al. Sterol 14alpha-demethylase as a potential target for antitrypanosomal therapy: enzyme inhibition and parasite cell growth. Chem Biol. 2007;14:1283-93 pubmed
    ..The approach developed here can be used for further large-scale search for new CYP51 inhibitors. ..
  7. Lepesheva G, Hargrove T, Kleshchenko Y, Nes W, Villalta F, Waterman M. CYP51: A major drug target in the cytochrome P450 superfamily. Lipids. 2008;43:1117-25 pubmed publisher
    ..32-Methylene cyclopropyl lanost-7-enol exhibited selectivity toward TC with 50% cell growth inhibition at 3 microM. ..
  8. Hoekstra W, Hargrove T, Wawrzak Z, da Gama Jaen Batista D, Da Silva C, Nefertiti A, et al. Clinical Candidate VT-1161's Antiparasitic Effect In Vitro, Activity in a Murine Model of Chagas Disease, and Structural Characterization in Complex with the Target Enzyme CYP51 from Trypanosoma cruzi. Antimicrob Agents Chemother. 2016;60:1058-66 pubmed publisher
  9. request reprint
    Lepesheva G, Nes W, Zhou W, Hill G, Waterman M. CYP51 from Trypanosoma brucei is obtusifoliol-specific. Biochemistry. 2004;43:10789-99 pubmed

More Information


  1. Hargrove T, Friggeri L, Wawrzak Z, Qi A, Hoekstra W, Schotzinger R, et al. Structural analyses of Candida albicans sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis. J Biol Chem. 2017;292:6728-6743 pubmed publisher
    ..Our comparative structural analysis outlines phylum-specific CYP51 features that could direct future rational development of more efficient broad-spectrum antifungals. ..
  2. Hargrove T, Garvey E, Hoekstra W, Yates C, Wawrzak Z, Rachakonda G, et al. Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14?-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity. Antimicrob Agents Chemother. 2017;61: pubmed publisher
    ..fumigatus potency of VT-1598 and confirming its promise as a broad-spectrum antifungal agent. ..
  3. Lepesheva G, Waterman M. Structural basis for conservation in the CYP51 family. Biochim Biophys Acta. 2011;1814:88-93 pubmed publisher
  4. Hargrove T, Wawrzak Z, Lamb D, Guengerich F, Lepesheva G. Structure-Functional Characterization of Cytochrome P450 Sterol 14α-Demethylase (CYP51B) from Aspergillus fumigatus and Molecular Basis for the Development of Antifungal Drugs. J Biol Chem. 2015;290:23916-34 pubmed publisher
  5. Hargrove T, Friggeri L, Wawrzak Z, Sivakumaran S, Yazlovitskaya E, Hiebert S, et al. Human sterol 14α-demethylase as a target for anticancer chemotherapy: towards structure-aided drug design. J Lipid Res. 2016;57:1552-63 pubmed publisher