G I Lepesheva
Affiliation: Vanderbilt University
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
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. ..
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. ..
Lepesheva G, Hargrove T, Ott R, Nes W, Waterman M. Biodiversity of CYP51 in trypanosomes. Biochem Soc Trans. 2006;34:1161-4 pubmed
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. ..
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. ..
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
Lepesheva G, Nes W, Zhou W, Hill G, Waterman M. CYP51 from Trypanosoma brucei is obtusifoliol-specific. Biochemistry. 2004;43:10789-99 pubmed
Hargrove T, Friggeri L, Wawrzak Z, Qi A, Hoekstra W, Schotzinger R, et al
. Structural analyses of Candida albicans sterol 14Î±-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. ..