TY - JOUR
T1 - Validation of Human Sterol 14α-Demethylase (CYP51) Druggability
T2 - Structure-Guided Design, Synthesis, and Evaluation of Stoichiometric, Functionally Irreversible Inhibitors
AU - Friggeri, Laura
AU - Hargrove, Tatiana Y.
AU - Wawrzak, Zdzislaw
AU - Guengerich, F. Peter
AU - Lepesheva, Galina I.
N1 - Funding Information:
We thank Dr. John D. York (Vanderbilt University) for the helpful discussion. The research was supported by funding from the National Institutes of Health (no. GM067871, G.I.L.). Vanderbilt University is a member institution of the Life Sciences Collaborative Access Team at Sector 21 of the Advanced Photon Source (Argonne, IL). Use of the Advanced Photon Source at the Argonne National Laboratory was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-06CH11357.
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/11/27
Y1 - 2019/11/27
N2 - Sterol 14α-demethylases (CYP51) are the cytochrome P450 enzymes required for biosynthesis of sterols in eukaryotes, the major targets for antifungal agents and prospective targets for treatment of protozoan infections. Human CYP51 could be and, for a while, was considered as a potential target for cholesterol-lowering drugs (the role that is now played by statins, which are also in clinical trials for cancer) but revealed high intrinsic resistance to inhibition. While microbial CYP51 enzymes are often inhibited stoichiometrically and functionally irreversibly, no strong inhibitors have been identified for human CYP51. In this study, we used comparative structure/functional analysis of CYP51 orthologs from different biological kingdoms and employed site-directed mutagenesis to elucidate the molecular basis for the resistance of the human enzyme to inhibition and also designed, synthesized, and characterized new compounds. Two of them inhibit human CYP51 functionally irreversibly with their potency approaching the potencies of azole drugs currently used to inhibit microbial CYP51.
AB - Sterol 14α-demethylases (CYP51) are the cytochrome P450 enzymes required for biosynthesis of sterols in eukaryotes, the major targets for antifungal agents and prospective targets for treatment of protozoan infections. Human CYP51 could be and, for a while, was considered as a potential target for cholesterol-lowering drugs (the role that is now played by statins, which are also in clinical trials for cancer) but revealed high intrinsic resistance to inhibition. While microbial CYP51 enzymes are often inhibited stoichiometrically and functionally irreversibly, no strong inhibitors have been identified for human CYP51. In this study, we used comparative structure/functional analysis of CYP51 orthologs from different biological kingdoms and employed site-directed mutagenesis to elucidate the molecular basis for the resistance of the human enzyme to inhibition and also designed, synthesized, and characterized new compounds. Two of them inhibit human CYP51 functionally irreversibly with their potency approaching the potencies of azole drugs currently used to inhibit microbial CYP51.
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U2 - 10.1021/acs.jmedchem.9b01485
DO - 10.1021/acs.jmedchem.9b01485
M3 - Article
C2 - 31663733
AN - SCOPUS:85074979447
SN - 0022-2623
VL - 62
SP - 10391
EP - 10401
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 22
ER -
