title: Discovery of novel potent ΔF508-CFTR correctors that target the nucleotide binding domain.
abstract: The deletion of Phe508 (ΔF508) in the first nucleotide binding domain (NBD1) of CFTR is the most common mutation associated with cystic fibrosis. The ΔF508-CFTR mutant is recognized as improperly folded and targeted for proteasomal degradation. Based on molecular dynamics simulation results, we hypothesized that interaction between ΔF508-NBD1 and housekeeping proteins prevents ΔF508-CFTR delivery to the plasma membrane. Based on this assumption we applied structure-based virtual screening to identify new low-molecular-weight compounds that should bind to ΔF508-NBD1 and act as protein-protein interaction inhibitors. Using different functional assays for CFTR activity, we demonstrated that in silico-selected compounds induced functional expression of ΔF508-CFTR in transfected HeLa cells, human bronchial CF cells in primary culture, and in the nasal epithelium of homozygous ΔF508-CFTR mice. The proposed compounds disrupt keratin8-ΔF508-CFTR interaction in ΔF508-CFTR HeLa cells. Structural analysis of ΔF508-NBD1 in the presence of these compounds suggests their binding to NBD1. We conclude that our strategy leads to the discovery of new compounds that are among the most potent correctors of ΔF508-CFTR trafficking defect known to date.
authors: Department of Bioinformatics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warszawa, Poland.
authors: Norbert
authors: N
authors: Odolczyk
authors: Janine
authors: J
authors: Fritsch
authors: Caroline
authors: C
authors: Norez
authors: Nathalie
authors: N
authors: Servel
authors: Melanie Faria
authors: MF
authors: da Cunha
authors: Sara
authors: S
authors: Bitam
authors: Anna
authors: A
authors: Kupniewska
authors: Ludovic
authors: L
authors: Wiszniewski
authors: Julien
authors: J
authors: Colas
authors: Krzysztof
authors: K
authors: Tarnowski
authors: Danielle
authors: D
authors: Tondelier
authors: Ariel
authors: A
authors: Roldan
authors: Emilie L
authors: EL
authors: Saussereau
authors: Patricia
authors: P
authors: Melin-Heschel
authors: Grzegorz
authors: G
authors: Wieczorek
authors: Gergely L
authors: GL
authors: Lukacs
authors: Michal
authors: M
authors: Dadlez
authors: Grazyna
authors: G
authors: Faure
authors: Harald
authors: H
authors: Herrmann
authors: Mario
authors: M
authors: Ollero
authors: Frédéric
authors: F
authors: Becq
authors: Piotr
authors: P
authors: Zielenkiewicz
authors: Aleksander
authors: A
authors: Edelman
mesh_terms: D000818:Animals; D001665:Binding Sites; D001980:Bronchi / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018118:Chloride Channels / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006720:Homozygote; D006801:Humans; D053533:Keratin-8 / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D060066:Protein Interaction Maps / Q000187:drug effects; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D018118:Chloride Channels; D053533:Keratin-8; D054852:Small Molecule Libraries; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: CFTR; chloride channel; cystic fibrosis; drug discovery; ΔF508-CFTR correctors
references: Mol Pharmacol. 2009 Jun;75(6):1430-8
references: 19339490
references: J Cyst Fibros. 2012 May;11(3):237-45
references: 22293084
references: J Chem Inf Model. 2009 Jun;49(6):1568-80
references: 19445499
references: J Cyst Fibros. 2008 Jul;7(4):295-300
references: 18234567
references: Cell. 2006 Aug 11;126(3):571-82
references: 16901789
references: Thorax. 2005 Jan;60(1):55-9
references: 15618584
references: J Comput Aided Mol Des. 2010 Dec;24(12):971-91
references: 20976528
references: Chem Biol. 2011 Feb 25;18(2):231-42
references: 21338920
references: FEBS Lett. 2006 Apr 3;580(8):2081-6
references: 16546175
references: PLoS Biol. 2009 Jul;7(7):e1000155
references: 19621064
references: Nat Chem Biol. 2010 Jan;6(1):25-33
references: 19966789
references: Biochim Biophys Acta. 2008 Jun;1783(6):1189-99
references: 18267124
references: Chembiochem. 2007 Jun 18;8(9):1012-20
references: 17497613
references: Hum Mol Genet. 2012 Feb 1;21(3):623-34
references: 22038833
references: Science. 1989 Sep 8;245(4922):1066-73
references: 2475911
references: J Comput Aided Mol Des. 2006 Oct-Nov;20(10-11):601-19
references: 17149653
references: J Clin Invest. 2005 Sep;115(9):2564-71
references: 16127463
references: Mol Pharmacol. 2007 Mar;71(3):751-8
references: 17132688
references: Cell. 1995 Oct 6;83(1):129-35
references: 7553864
references: Proteins. 2006 Jun 1;63(4):892-906
references: 16477622
references: Nat Cell Biol. 2004 Apr;6(4):343-50
references: 15048129
references: Nature. 1992 Aug 27;358(6389):761-4
references: 1380673
references: Proteomics. 2006 Jul;6(14):4084-99
references: 16791827
references: Mol Pharmacol. 2010 Sep;78(3):411-8
references: 20501743
references: Mol Pharmacol. 2005 Dec;68(6):1736-46
references: 16150931
references: Cell Mol Life Sci. 2005 Feb;62(4):446-60
references: 15719171
references: Cell Mol Life Sci. 2008 Aug;65(16):2594-612
references: 18597042
references: J Pharmacol Exp Ther. 2006 May;317(2):500-5
references: 16424149
references: N Engl J Med. 2011 Nov 3;365(18):1663-72
references: 22047557
references: Am J Physiol Cell Physiol. 2011 Oct;301(4):C872-85
references: 21753184
references: J Med Chem. 2004 Feb 12;47(4):962-72
references: 14761197
references: Thorax. 2010 Jun;65(6):539-44
references: 20522854
references: FASEB J. 2013 Feb;27(2):536-45
references: 23104983
references: Mol Pharmacol. 2010 Jun;77(6):922-30
references: 20200141
references: Cell. 2012 Jan 20;148(1-2):164-74
references: 22265409
references: Cell. 2012 Jan 20;148(1-2):150-63
references: 22265408
references: J Med Chem. 2006 Oct 5;49(20):5851-5
references: 17004700
references: Br J Pharmacol. 2011 Jun;163(4):876-86
references: 21366549
references: Mol Biosyst. 2009 Feb;5(2):123-7
references: 19156256
references: J Cyst Fibros. 2011 Jun;10 Suppl 2:S129-45
references: 21658632
references: Hum Mol Genet. 2012 Mar 15;21(6):1287-98
references: 22121115
references: Mol Pharm. 2005 Sep-Oct;2(5):407-13
references: 16196493
references: Nature. 1991 Dec 19-26;354(6354):526-8
references: 1722027
references: Proc Natl Acad Sci U S A. 2011 Nov 15;108(46):18843-8
references: 21976485
references: Am J Physiol Cell Physiol. 2006 Jan;290(1):C45-56
references: 16049054
references: Mol Pharmacol. 2008 Feb;73(2):478-89
references: 17975008
references: J Biol Chem. 2012 Nov 23;287(48):40547-59
references: 23045527
references: Am J Physiol Lung Cell Mol Physiol. 2006 Jun;290(6):L1117-30
references: 16443646
references: Cell. 1995 Oct 6;83(1):121-7
references: 7553863
references: Cell. 1991 Sep 6;66(5):1027-36
references: 1716180
references: Lancet. 2003 May 17;361(9370):1671-6
references: 12767731
references: Annu Rev Biochem. 2008;77:701-26
references: 18304008