Validation of Human Sterol 14α-Demethylase (CYP51) Druggability: Structure-Guided Design, Synthesis, and Evaluation of Stoichiometric, Functionally Irreversible Inhibitors

Laura Friggeri, Tatiana Y. Hargrove, Zdzislaw Wawrzak, F. Peter Guengerich, Galina I. Lepesheva*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)10391-10401
Number of pages11
JournalJournal of Medicinal Chemistry
Volume62
Issue number22
DOIs
StatePublished - Nov 27 2019

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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