Rational Design of Potent and Selective Inhibitors of an Epoxide Hydrolase Virulence Factor from Pseudomonas aeruginosa.
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.
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis , One Shields Avenue, Davis, California 95616, United States.
Seiya
S
Kitamura
Department of Biochemistry, Geisel School of Medicine at Dartmouth , 7200 Vail Building, Hanover, New Hampshire 03755, United States.
Kelli L
KL
Hvorecny
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis , One Shields Avenue, Davis, California 95616, United States.
Jun
J
Niu
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis , One Shields Avenue, Davis, California 95616, United States.
Bruce D
BD
Hammock
Department of Biochemistry, Geisel School of Medicine at Dartmouth , 7200 Vail Building, Hanover, New Hampshire 03755, United States.
Dean R
DR
Madden
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis , One Shields Avenue, Davis, California 95616, United States.
Christophe
C
Morisseau
D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D011550:Pseudomonas aeruginosa / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014284:Triiodothyronine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D037521:Virulence Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
D037521:Virulence Factors; D014284:Triiodothyronine; C010642:3,3',5-triiodothyroacetic acid; D004851:Epoxide Hydrolases