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

Authors
 Yonjung Kim  ;  Marc O. Anderson  ;  Jinhong Park  ;  Min Goo Lee  ;  Wan Namkung  ;  A. S. Verkman 
Citation
 Molecular Pharmacology, Vol.88(4) : 689-696, 2015 
Journal Title
 Molecular Pharmacology 
ISSN
 0026-895X 
Issue Date
2015
MeSH
Adenosine Triphosphate/metabolism* ; Binding Sites/physiology ; Binding, Competitive/drug effects ; Binding, Competitive/physiology* ; Cystic Fibrosis Transmembrane Conductance Regulator/antagonists & inhibitors* ; Cystic Fibrosis Transmembrane Conductance Regulator/physiology* ; Dose-Response Relationship, Drug ; HEK293 Cells ; Humans ; Ion Channel Gating/drug effects ; Ion Channel Gating/physiology ; Oxazines/chemistry ; Oxazines/metabolism ; Oxazines/pharmacology ; Protein Structure, Secondary ; Pyrimidines/chemistry ; Pyrimidines/metabolism* ; Pyrimidines/pharmacology
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.
Full Text
http://molpharm.aspetjournals.org/content/88/4/689.abstract
DOI
10.1124/mol.115.098368
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Yon Jung(김연정) ORCID logo https://orcid.org/0000-0003-0251-8711
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/140998
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