TY - JOUR
T1 - Sterol 14α-Demethylase as a Potential Target for Antitrypanosomal Therapy
T2 - Enzyme Inhibition and Parasite Cell Growth
AU - Lepesheva, Galina I.
AU - Ott, Robert D.
AU - Hargrove, Tatiana Y.
AU - Kleshchenko, Yuliya Y.
AU - Schuster, Inge
AU - Nes, W. David
AU - Hill, George C.
AU - Villalta, Fernando
AU - Waterman, Michael R.
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health (GM067871 to M.R.W., GM63477 to W.D.N., SC1GM 081168 and GM 008037 to F.V.), from the American Heart Association (0535121N to G.I.L.), and from Welch Foundation (D-1276 to W.D.N.).
PY - 2007/11/26
Y1 - 2007/11/26
N2 - Sterol 14α-demethylases (CYP51) serve as primary targets for antifungal drugs, and specific inhibition of CYP51s in protozoan parasites Trypanosoma brucei (TB) and Trypanosoma cruzi (TC) might provide an effective treatment strategy for human trypanosomiases. Primary inhibitor selection is based initially on the cytochrome P450 spectral response to ligand binding. Ligands that demonstrate strongest binding parameters were examined as inhibitors of reconstituted TB and TC CYP51 activity in vitro. Direct correlation between potency of the compounds as CYP51 inhibitors and their antiparasitic effect in TB and TC cells implies essential requirements for endogenous sterol production in both trypanosomes and suggests a lead structure with a defined region most promising for further modifications. The approach developed here can be used for further large-scale search for new CYP51 inhibitors.
AB - Sterol 14α-demethylases (CYP51) serve as primary targets for antifungal drugs, and specific inhibition of CYP51s in protozoan parasites Trypanosoma brucei (TB) and Trypanosoma cruzi (TC) might provide an effective treatment strategy for human trypanosomiases. Primary inhibitor selection is based initially on the cytochrome P450 spectral response to ligand binding. Ligands that demonstrate strongest binding parameters were examined as inhibitors of reconstituted TB and TC CYP51 activity in vitro. Direct correlation between potency of the compounds as CYP51 inhibitors and their antiparasitic effect in TB and TC cells implies essential requirements for endogenous sterol production in both trypanosomes and suggests a lead structure with a defined region most promising for further modifications. The approach developed here can be used for further large-scale search for new CYP51 inhibitors.
KW - CHEMBIO
KW - MICROBIO
UR - http://www.scopus.com/inward/record.url?scp=36049032778&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2007.10.011
DO - 10.1016/j.chembiol.2007.10.011
M3 - Article
C2 - 18022567
AN - SCOPUS:36049032778
SN - 1074-5521
VL - 14
SP - 1283
EP - 1293
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 11
ER -