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

DC FieldValueLanguage
dc.contributor.author김연정-
dc.contributor.author이민구-
dc.date.accessioned2016-02-04T11:41:53Z-
dc.date.available2016-02-04T11:41:53Z-
dc.date.issued2015-
dc.identifier.issn0026-895X-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/140998-
dc.description.abstractWe 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.-
dc.description.statementOfResponsibilityopen-
dc.format.extent689~696-
dc.relation.isPartOfMOLECULAR PHARMACOLOGY-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.subject.MESHAdenosine Triphosphate/metabolism*-
dc.subject.MESHBinding Sites/physiology-
dc.subject.MESHBinding, Competitive/drug effects-
dc.subject.MESHBinding, Competitive/physiology*-
dc.subject.MESHCystic Fibrosis Transmembrane Conductance Regulator/antagonists & inhibitors*-
dc.subject.MESHCystic Fibrosis Transmembrane Conductance Regulator/physiology*-
dc.subject.MESHDose-Response Relationship, Drug-
dc.subject.MESHHEK293 Cells-
dc.subject.MESHHumans-
dc.subject.MESHIon Channel Gating/drug effects-
dc.subject.MESHIon Channel Gating/physiology-
dc.subject.MESHOxazines/chemistry-
dc.subject.MESHOxazines/metabolism-
dc.subject.MESHOxazines/pharmacology-
dc.subject.MESHProtein Structure, Secondary-
dc.subject.MESHPyrimidines/chemistry-
dc.subject.MESHPyrimidines/metabolism*-
dc.subject.MESHPyrimidines/pharmacology-
dc.titleBenzopyrimido-pyrrolo-oxazine-dione (R)-BPO-27 Inhibits CFTR Chloride Channel Gating by Competition with ATP-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Pharmacology (약리학)-
dc.contributor.googleauthorYonjung Kim-
dc.contributor.googleauthorMarc O. Anderson-
dc.contributor.googleauthorJinhong Park-
dc.contributor.googleauthorMin Goo Lee-
dc.contributor.googleauthorWan Namkung-
dc.contributor.googleauthorA. S. Verkman-
dc.identifier.doi10.1124/mol.115.098368-
dc.admin.authorfalse-
dc.admin.mappingfalse-
dc.contributor.localIdA00695-
dc.contributor.localIdA02781-
dc.relation.journalcodeJ02267-
dc.identifier.eissn1521-0111-
dc.identifier.pmid26174774-
dc.identifier.urlhttp://molpharm.aspetjournals.org/content/88/4/689.abstract-
dc.contributor.alternativeNameKim, Yon Jung-
dc.contributor.alternativeNameLee, Min Goo-
dc.contributor.affiliatedAuthorKim, Yon Jung-
dc.contributor.affiliatedAuthorLee, Min Goo-
dc.rights.accessRightsnot free-
dc.citation.volume88-
dc.citation.number4-
dc.citation.startPage689-
dc.citation.endPage696-
dc.identifier.bibliographicCitationMOLECULAR PHARMACOLOGY, Vol.88(4) : 689-696, 2015-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers

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