Rational Design of Potent and Selective Inhibitors of an Epoxide Hydrolase Virulence Factor from Pseudomonas aeruginosa

Seiya Kitamura, Kelli L. Hvorecny, Jun Niu, Bruce D. Hammock, Dean R. Madden, Christophe Morisseau

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

The virulence factor cystic fibrosis transmembrane conductance regulator (CFTR) inhibitory factor (Cif) is secreted by Pseudomonas aeruginosa and is the founding member of a distinct class of epoxide hydrolases (EHs) that triggers the catalysis-dependent degradation of the CFTR. We describe here the development of a series of potent and selective Cif inhibitors by structure-based drug design. Initial screening revealed 1a (KB2115), a thyroid hormone analog, as a lead compound with low micromolar potency. Structural requirements for potency were systematically probed, and interactions between Cif and 1a were characterized by X-ray crystallography. On the basis of these data, new compounds were designed to yield additional hydrogen bonding with residues of the Cif active site. From this effort, three compounds were identified that are 10-fold more potent toward Cif than our first-generation inhibitors and have no detectable thyroid hormone-like activity. These inhibitors will be useful tools to study the pathological role of Cif and have the potential for clinical application.

Original languageEnglish (US)
Pages (from-to)4790-4799
Number of pages10
JournalJournal of Medicinal Chemistry
Volume59
Issue number10
DOIs
StatePublished - May 26 2016

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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