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Research ArticleArticle

Benzopyrimido-pyrrolo-oxazine-dione (R)-BPO-27 Inhibits CFTR Chloride Channel Gating by Competition with ATP

Yonjung Kim, Marc O. Anderson, Jinhong Park, Min Goo Lee, Wan Namkung and A. S. Verkman
Molecular Pharmacology October 2015, 88 (4) 689-696; DOI: https://doi.org/10.1124/mol.115.098368
Yonjung Kim
Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea (Y.K., M.G.L.); Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California (M.O.A.); College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea (J.P., W.N.); and Departments of Medicine and Physiology, University of California, San Francisco, California (A.S.V.)
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Marc O. Anderson
Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea (Y.K., M.G.L.); Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California (M.O.A.); College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea (J.P., W.N.); and Departments of Medicine and Physiology, University of California, San Francisco, California (A.S.V.)
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Jinhong Park
Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea (Y.K., M.G.L.); Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California (M.O.A.); College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea (J.P., W.N.); and Departments of Medicine and Physiology, University of California, San Francisco, California (A.S.V.)
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Min Goo Lee
Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea (Y.K., M.G.L.); Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California (M.O.A.); College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea (J.P., W.N.); and Departments of Medicine and Physiology, University of California, San Francisco, California (A.S.V.)
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Wan Namkung
Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea (Y.K., M.G.L.); Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California (M.O.A.); College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea (J.P., W.N.); and Departments of Medicine and Physiology, University of California, San Francisco, California (A.S.V.)
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A. S. Verkman
Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea (Y.K., M.G.L.); Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California (M.O.A.); College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea (J.P., W.N.); and Departments of Medicine and Physiology, University of California, San Francisco, California (A.S.V.)
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Abstract

We previously reported that benzopyrimido-pyrrolo-oxazinedione BPO-27 [6-(5-bromofuran-2-yl)-7,9-dimethyl-8,10-dioxo-11-phenyl-7,8,9,10-tetrahydro-6H-benzo[b]pyrimido [4′,5′:3,4]pyrrolo [1,2-d][1,4]oxazine-2-carboxylic acid] inhibits the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel with low nanomolar potency and reduces cystogenesis in a model of polycystic kidney disease. We used computational chemistry and patch-clamp to show that enantiomerically pure (R)-BPO-27 inhibits CFTR by competition with ATP, whereas (S)-BPO-27 is inactive. Docking computations using a homology model of CFTR structure suggested that (R)-BPO-27 binds near the canonical ATP binding site, and these findings were supported by molecular dynamics simulations showing a lower binding energy for the (R) versus (S) stereoisomers. Three additional lower-potency BPO-27 analogs were modeled in a similar fashion, with the binding energies predicted in the correct order. Whole-cell patch-clamp studies showed linear CFTR currents with a voltage-independent (R)-BPO-27 block mechanism. Single-channel recordings in inside-out patches showed reduced CFTR channel open probability and increased channel closed time by (R)-BPO-27 without altered unitary channel conductance. At a concentration of (R)-BPO-27 that inhibited CFTR chloride current by ∼50%, the EC50 for ATP activation of CFTR increased from 0.27 to 1.77 mM but was not changed by CFTRinh-172 [4-[[4-oxo-2-thioxo-3-[3-trifluoromethyl)phenyl]-5-thiazolidinylidene]methyl]benzoic acid], a thiazolidinone CFTR inhibitor that acts at a site distinct from the ATP binding site. Our results suggest that (R)-BPO-27 inhibition of CFTR involves competition with ATP.

Footnotes

    • Received February 10, 2015.
    • Accepted July 13, 2015.
  • Yonjung Kim and Marc O. Anderson contributed equally to this work.

  • This work was supported by National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants DK75302, DK72517, DK35124]; National Institutes of Health National Institute of Biomedical Imaging and Bioengineering [EB00415]; National Institutes of Health National Eye Institute [EY135740]; the Cystic Fibrosis Foundation [R613]; and the National Research Foundation, the Ministry of Science, ICT & Future Planning, Republic of Korea [2013R1A3A2042197].

  • dx.doi.org/10.1124/mol.115.098368.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 88 (4)
Molecular Pharmacology
Vol. 88, Issue 4
1 Oct 2015
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Research ArticleArticle

CFTR Inhibition by (R)-BPO-27

Yonjung Kim, Marc O. Anderson, Jinhong Park, Min Goo Lee, Wan Namkung and A. S. Verkman
Molecular Pharmacology October 1, 2015, 88 (4) 689-696; DOI: https://doi.org/10.1124/mol.115.098368

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Research ArticleArticle

CFTR Inhibition by (R)-BPO-27

Yonjung Kim, Marc O. Anderson, Jinhong Park, Min Goo Lee, Wan Namkung and A. S. Verkman
Molecular Pharmacology October 1, 2015, 88 (4) 689-696; DOI: https://doi.org/10.1124/mol.115.098368
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