Abstract
CFTR protein is an ion channel regulated by cAMP-dependent phosphorylation and expressed in many types of epithelial cells. CFTR-mediated chloride and bicarbonate secretion play an important role in the respiratory and gastrointestinal systems. Pharmacological modulators of CFTR represent promising drugs for a variety of diseases. In particular, correctors and potentiators may restore the activity of CFTR in cystic fibrosis patients. Potentiators are also potentially useful to improve mucociliary clearance in patients with chronic obstructive pulmonary disease. On the other hand, CFTR inhibitors may be useful to block fluid and electrolyte loss in secretory diarrhea and slow down the progression of polycystic kidney disease.
Similar content being viewed by others
References
Riordan JR (2008) CFTR function and prospects for therapy. Annu Rev Biochem 77:701–726
Mornon JP, Hoffmann B, Jonic S, Lehn P (2015) Callebaut I (2015) Full-open and closed CFTR channels, with lateral tunnels from the cytoplasm and an alternative position of the F508 region, as revealed by molecular dynamics. Cell Mol Life Sci 72:1377–1403
Elborn JS (2016) Cystic fibrosis. Lancet. doi:10.1016/S0140-6736(16)00576-6
Rogers CS, Stoltz DA, Meyerholz DK, Ostedgaard LS, Rokhlina T, Taft PJ, Rogan MP, Pezzulo AA, Karp PH, Itani OA, Kabel AC, Wohlford-Lenane CL, Davis GJ, Hanfland RA, Smith TL, Samuel M, Wax D, Murphy CN, Rieke A, Whitworth K, Uc A, Starner TD, Brogden KA, Shilyansky J, McCray PB Jr, Zabner J, Prather RS, Welsh MJ (2008) Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science 321:1837–1841
Stoltz DA, Meyerholz DK, Pezzulo AA, Ramachandran S, Rogan MP, Davis GJ, Hanfland RA, Wohlford-Lenane C, Dohrn CL, Bartlett JA, Nelson GA 4th, Chang EH, Taft PJ, Ludwig PS, Estin M, Hornick EE, Launspach JL, Samuel M, Rokhlina T, Karp PH, Ostedgaard LS, Uc A, Starner TD, Horswill AR, Brogden KA, Prather RS, Richter SS, Shilyansky J, McCray PB Jr, Zabner J, Welsh MJ (2010) Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth. Sci Transl Med 2:29ra31
Sun X, Sui H, Fisher JT, Yan Z, Liu X, Cho HJ, Joo NS, Zhang Y, Zhou W, Yi Y, Kinyon JM, Lei-Butters DC, Griffin MA, Naumann P, Luo M, Ascher J, Wang K, Frana T, Wine JJ, Meyerholz DK, Engelhardt JF (2010) Disease phenotype of a ferret CFTR-knockout model of cystic fibrosis. J Clin Invest 120:3149–3160
Olivier AK, Yi Y, Sun X, Sui H, Liang B, Hu S, Xie W, Fisher JT, Keiser NW, Lei D, Zhou W, Yan Z, Li G, Evans TI, Meyerholz DK, Wang K, Stewart ZA, Norris AW, Engelhardt JF (2012) Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets. J Clin Invest 122:3755–3768
Cook DP, Rector MV, Bouzek DC, Michalski AS, Gansemer ND, Reznikov LR, Li X, Stroik MR, Ostedgaard LS, Abou Alaiwa MH, Thompson MA, Prakash YS, Krishnan R, Meyerholz DK, Seow CY, Stoltz DA (2016) Cystic fibrosis transmembrane conductance regulator in sarcoplasmic reticulum of airway smooth muscle. Implications for airway contractility. Am J Respir Crit Care Med 193:417–426
Brill SR, Ross KE, Davidow CJ, Ye M, Grantham JJ, Caplan MJ (1996) Immunolocalization of ion transport proteins in human autosomal dominant polycystic kidney epithelial cells. Proc Natl Acad Sci USA 93:10206–10211
Scott-Ward TS, Li H, Schmidt A, Cai Z, Sheppard DN (2004) Direct block of the cystic fibrosis transmembrane conductance regulator Cl− channel by niflumic acid. Mol Membr Biol 21:27–38
Sheppard DN, Robinson KA (1997) Mechanism of glibenclamide inhibition of cystic fibrosis transmembrane conductance regulator Cl− channels expressed in a murine cell line. J Physiol 503:333–346
Walsh KB, Long KJ, Shen X (1999) Structural and ionic determinants of 5-nitro-2-(3-phenylprophyl-amino)-benzoic acid block of the CFTR chloride channel. Br J Pharmacol 127:369–376
Zhang ZR, Zeltwanger S, McCarty NA (2000) Direct comparison of NPPB and DPC as probes of CFTR expressed in Xenopus oocytes. J Membr Biol 175:35–52
Zhou Z, Hu S, Hwang TC (2002) Probing an open CFTR pore with organic anion blockers. J Gen Physiol 120:647–662
Jayaraman S, Haggie P, Wachter RM, Remington SJ, Verkman AS (2000) Mechanism and cellular applications of a green fluorescent protein-based halide sensor. J Biol Chem 275:6047–6050
Galietta LV, Jayaraman S, Verkman AS (2001) Cell-based assay for high-throughput quantitative screening of CFTR chloride transport agonists. Am J Physiol 281:C1734–C1742
Ma T, Thiagarajah JR, Yang H, Sonawane ND, Folli C, Galietta LJ, Verkman AS (2002) Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion. J Clin Invest 110:1651–1658
Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, Pfeffer U, Ravazzolo R, Zegarra-Moran O, Galietta LJ (2008) TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity. Science 322:590–594
Pedemonte N, Caci E, Sondo E, Caputo A, Rhoden K, Pfeffer U, Di Candia M, Bandettini R, Ravazzolo R, Zegarra-Moran O, Galietta LJ (2007) Thiocyanate transport in resting and IL-4-stimulated human bronchial epithelial cells: role of pendrin and anion channels. J Immunol 178:5144–5153
Taddei A, Folli C, Zegarra-Moran O, Fanen P, Verkman AS, Galietta LJ (2004) Altered channel gating mechanism for CFTR inhibition by a high-affinity thiazolidinone blocker. FEBS Lett 558:52–56
Kopeikin Z, Sohma Y, Li M, Hwang TC (2010) On the mechanism of CFTR inhibition by a thiazolidinone derivative. J Gen Physiol 136:659–671
Caci E, Caputo A, Hinzpeter A, Arous N, Fanen P, Sonawane N, Verkman AS, Ravazzolo R, Zegarra-Moran O, Galietta LJ (2008) Evidence for direct CFTR inhibition by CFTRinh-172 based on Arg347 mutagenesis. Biochem J 413:135–142
Sonawane ND, Verkman AS (2008) Thiazolidinone CFTR inhibitors with improved water solubility identified by structure-activity analysis. Bioorg Med Chem 16:8187–8195
Muanprasat C, Sonawane ND, Salinas D, Taddei A, Galietta LJ, Verkman AS (2004) Discovery of glycine hydrazide pore-occluding CFTR inhibitors: mechanism, structure-activity analysis, and in vivo efficacy. J Gen Physiol 124:125–137
Norimatsu Y, Ivetac A, Alexander C, O’Donnell N, Frye L, Sansom MS, Dawson DC (2012) Locating a plausible binding site for an open-channel blocker, GlyH-101, in the pore of the cystic fibrosis transmembrane conductance regulator. Mol Pharmacol 82:1042–1055
Sonawane ND, Zhao D, Zegarra-Moran O, Galietta LJ, Verkman AS (2008) Nanomolar CFTR inhibition by pore-occluding divalent polyethylene glycol-malonic acid hydrazides. Chem Biol 15:718–728
Sonawane ND, Zhao D, Zegarra-Moran O, Galietta LJ, Verkman AS (2007) Lectin conjugates as potent, nonabsorbable CFTR inhibitors for reducing intestinal fluid secretion in cholera. Gastroenterology 132:1234–1244
Tradtrantip L, Sonawane ND, Namkung W, Verkman AS (2009) Nanomolar potency pyrimido-pyrrolo-quinoxalinedione CFTR inhibitor reduces cyst size in a polycystic kidney disease model. J Med Chem 52:6447–6455
Snyder DS, Tradtrantip L, Yao C, Kurth MJ, Verkman AS (2011) Potent, metabolically stable benzopyrimido-pyrrolo-oxazine-dione (BPO) CFTR inhibitors for polycystic kidney disease. J Med Chem 54:5468–5477
Stutts MJ, Henke DC, Boucher RC (1990) Diphenylamine-2-carboxylate (DPC) inhibits both Cl− conductance and cyclooxygenase of canine tracheal epithelium. Pflugers Arch 415:611–616
Kelly M, Trudel S, Brouillard F, Bouillaud F, Colas J, Nguyen-Khoa T, Ollero M, Edelman A, Fritsch J (2010) Cystic fibrosis transmembrane regulator inhibitors CFTRinh-172 and GlyH-101 target mitochondrial functions, independently of chloride channel inhibition. J Pharmacol Exp Ther 333:60–69
Perez A, Issler AC, Cotton CU, Kelley TJ, Verkman AS, Davis PB (2007) CFTR inhibition mimics the cystic fibrosis inflammatory profile. Am J Physiol 292:L383–L395
Thiagarajah JR, Verkman AS (2013) Chloride channel-targeted therapy for secretory diarrheas. Curr Opin Pharmacol 13:888–894
Davidow CJ, Maser RL, Rome LA, Calvet JP, Grantham JJ (1996) The cystic fibrosis transmembrane conductance regulator mediates transepithelial fluid secretion by human autosomal dominant polycystic kidney disease epithelium in vitro. Kidney Int 50:208–218
Li H, Findlay IA, Sheppard DN (2004) The relationship between cell proliferation, Cl− secretion, and renal cyst growth: a study using CFTR inhibitors. Kidney Int 66:1926–1938
Yang B, Sonawane ND, Zhao D, Somlo S, Verkman AS (2008) Small-molecule CFTR inhibitors slow cyst growth in polycystic kidney disease. J Am Soc Nephrol 19:1300–1310
Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T, Turnbull A, Singh A, Joubran J, Hazlewood A, Zhou J, McCartney J, Arumugam V, Decker C, Yang J, Young C, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu P (2009) Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci USA 106:18825–18830
Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, Sagel SD, Hornick DB, Konstan MW, Donaldson SH, Moss RB, Pilewski JM, Rubenstein RC, Uluer AZ, Aitken ML, Freedman SD, Rose LM, Mayer-Hamblett N, Dong Q, Zha J, Stone AJ, Olson ER, Ordoñez CL, Campbell PW, Ashlock MA, Ramsey BW (2010) Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med 363:1991–2003
Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordoñez C, Elborn JS, VX08-770-102 Study Group (2011) A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 365:1663–1672
Veit G, Avramescu RG, Chiang AN, Houck SA, Cai Z, Peters KW, Hong JS, Pollard HB, Guggino WB, Balch WE, Skach WR, Cutting GR, Frizzell RA, Sheppard DN, Cyr DM, Sorscher EJ, Brodsky JL, Lukacs GL (2016) From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol Biol Cell 27:424–433
Lukacs GL, Verkman AS (2012) CFTR: folding, misfolding and correcting the ΔF508 conformational defect. Trends Mol Med 18:81–91
Drumm ML, Wilkinson DJ, Smit LS, Worrell RT, Strong TV, Frizzell RA, Dawson DC, Collins FS (1991) Chloride conductance expressed by delta F508 and other mutant CFTRs in Xenopus oocytes. Science 254:1797–1799
Arispe N, Ma J, Jacobson KA, Pollard HB (1998) Direct activation of cystic fibrosis transmembrane conductance regulator channels by 8-cyclopentyl-1,3-dipropylxanthine (CPX) and 1,3-diallyl-8-cyclohexylxanthine (DAX). J Biol Chem 273:5727–5734
Al-Nakkash L, Hwang TC (1999) Activation of wild-type and deltaF508-CFTR by phosphodiesterase inhibitors through cAMP-dependent and -independent mechanisms. Pflugers Arch 437:553–561
French PJ, Bijman J, Bot AG, Boomaars WE, Scholte BJ, de Jonge HR (1997) Genistein activates CFTR Cl− channels via a tyrosine kinase- and protein phosphatase-independent mechanism. Am J Physiol 273:C747–C753
Illek B, Zhang L, Lewis NC, Moss RB, Dong JY, Fischer H (1999) Defective function of the cystic fibrosis-causing missense mutation G551D is recovered by genistein. Am J Physiol 277:C833–C839
He Z, Raman S, Guo Y, Reenstra WW (1998) Cystic fibrosis transmembrane conductance regulator activation by cAMP-independent mechanisms. Am J Physiol 275:C958–C966
Smit LS, Wilkinson DJ, Mansoura MK, Collins FS, Dawson DC (1993) Functional roles of the nucleotide-binding folds in the activation of the cystic fibrosis transmembrane conductance regulator. Proc Natl Acad Sci USA 90:9963–9967
Weinreich F, Wood PG, Riordan JR, Nagel G (1997) Direct action of genistein on CFTR. Pflugers Arch 434:484–491
Al-Nakkash L, Hu S, Li M, Hwang TC (2001) A common mechanism for cystic fibrosis transmembrane conductance regulator protein activation by genistein and benzimidazolone analogs. J Pharmacol Exp Ther 296:464–472
Cai Z, Sheppard DN (2002) Phloxine B interacts with the cystic fibrosis transmembrane conductance regulator at multiple sites to modulate channel activity. J Biol Chem 277:19546–19553
Becq F, Mettey Y, Gray MA, Galietta LJ, Dormer RL, Merten M, Métayé T, Chappe V, Marvingt-Mounir C, Zegarra-Moran O, Tarran R, Bulteau L, Dérand R, Pereira MM, McPherson MA, Rogier C, Joffre M, Argent BE, Sarrouilhe D, Kammouni W, Figarella C, Verrier B, Gola M, Vierfond JM (1999) Development of substituted Benzo[c]quinolizinium compounds as novel activators of the cystic fibrosis chloride channel. J Biol Chem 274:27415–27425
Zegarra-Moran O, Romio L, Folli C, Caci E, Becq F, Vierfond JM, Mettey Y, Cabrini G, Fanen P, Galietta LJ (2002) Correction of G551D-CFTR transport defect in epithelial monolayers by genistein but not by CPX or MPB-07. Br J Pharmacol 137:504–512
McCarty NA, Standaert TA, Teresi M, Tuthill C, Launspach J, Kelley TJ, Milgram LJ, Hilliard KA, Regelmann WE, Weatherly MR, Aitken ML, Konstan MW, Ahrens RC (2002) A phase I randomized, multicenter trial of CPX in adult subjects with mild cystic fibrosis. Pediatr Pulmonol 33:90–98
Ahrens RC, Standaert TA, Launspach J, Han SH, Teresi ME, Aitken ML, Kelley TJ, Hilliard KA, Milgram LJ, Konstan MW, Weatherly MR, McCarty NA (2002) Use of nasal potential difference and sweat chloride as outcome measures in multicenter clinical trials in subjects with cystic fibrosis. Pediatr Pulmonol 33:142–150
Galietta LJ, Haggie PM, Verkman AS (2001) Green fluorescent protein-based halide indicators with improved chloride and iodide affinities. FEBS Lett 499:220–224
Galietta LJ, Springsteel MF, Eda M, Niedzinski EJ, By K, Haddadin MJ, Kurth MJ, Nantz MH, Verkman AS (2001) Novel CFTR chloride channel activators identified by screening of combinatorial libraries based on flavone and benzoquinolizinium lead compounds. J Biol Chem 276:19723–19728
Sammelson RE, Ma T, Galietta LJ, Verkman AS, Kurth MJ (2003) 3-(2-Benzyloxyphenyl)isoxazoles and isoxazolines: synthesis and evaluation as CFTR activators. Bioorg Med Chem Lett 13:2509–2512
Ma T, Vetrivel L, Yang H, Pedemonte N, Zegarra-Moran O, Galietta LJ, Verkman AS (2002) High-affinity activators of cystic fibrosis transmembrane conductance regulator (CFTR) chloride conductance identified by high-throughput screening. J Biol Chem 277:37235–37241
Yang H, Shelat AA, Guy RK, Gopinath VS, Ma T, Du K, Lukacs GL, Taddei A, Folli C, Pedemonte N, Galietta LJ, Verkman AS (2003) Nanomolar affinity small molecule correctors of defective Delta F508-CFTR chloride channel gating. J Biol Chem 278:35079–35085
Pedemonte N, Sonawane ND, Taddei A, Hu J, Zegarra-Moran O, Suen YF, Robins LI, Dicus CW, Willenbring D, Nantz MH, Kurth MJ, Galietta LJ, Verkman AS (2005) Phenylglycine and sulfonamide correctors of defective ∆F508 and G551D cystic fibrosis transmembrane conductance regulator chloride-channel gating. Mol Pharmacol 67:1797–1807
Pedemonte N, Diena T, Caci E, Nieddu E, Mazzei M, Ravazzolo R, Zegarra-Moran O, Galietta LJ (2005) Antihypertensive 1,4-dihydropyridines as correctors of the cystic fibrosis transmembrane conductance regulator channel gating defect caused by cystic fibrosis mutations. Mol Pharmacol 68:1736–1746
Pedemonte N, Boido D, Moran O, Giampieri M, Mazzei M, Ravazzolo R, Galietta LJ (2007) Structure-activity relationship of 1,4-dihydropyridines as potentiators of the cystic fibrosis transmembrane conductance regulator chloride channel. Mol Pharmacol 72:197–207
Van Goor F, Straley KS, Cao D, González J, Hadida S, Hazlewood A, Joubran J, Knapp T, Makings LR, Miller M, Neuberger T, Olson E, Panchenko V, Rader J, Singh A, Stack JH, Tung R, Grootenhuis PD, Negulescu P (2006) Rescue of ∆F508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules. Am J Physiol 290:L1117–L1130
Hadida S, Van Goor F, Zhou J, Arumugam V, McCartney J, Hazlewood A, Decker C, Negulescu P, Grootenhuis PD (2014) Discovery of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, ivacaftor), a potent and orally bioavailable CFTR potentiator. J Med Chem 57:9776–9795
Van Goor F, Yu H, Burton B, Hoffman B (2014) Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros 13:29–36
Moran O, Galietta LJ, Zegarra-Moran O (2005) Binding site of activators of the cystic fibrosis transmembrane conductance regulator in the nucleotide binding domains. Cell Mol Life Sci 62:446–460
Lewis HA, Buchanan SG, Burley SK, Conners K, Dickey M, Dorwart M, Fowler R, Gao X, Guggino WB, Hendrickson WA, Hunt JF, Kearins MC, Lorimer D, Maloney PC, Post KW, Rajashankar KR, Rutter ME, Sauder JM, Shriver S, Thibodeau PH, Thomas PJ, Zhang M, Zhao X, Emtage S (2004) Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator. EMBO J 23:282–293
Zegarra-Moran O, Monteverde M, Galietta LJ, Moran O (2007) Functional analysis of mutations in the putative binding site for cystic fibrosis transmembrane conductance regulator potentiators. Interaction between activation and inhibition. J Biol Chem 282:9098–9104
Li MS, Cowley EA, Linsdell P (2012) Pseudohalide anions reveal a novel extracellular site for potentiators to increase CFTR function. Br J Pharmacol 167:1062–1075
Wellhauser L, Kim Chiaw P, Pasyk S, Li C, Ramjeesingh M, Bear CE (2009) A small-molecule modulator interacts directly with deltaPhe508-CFTR to modify its ATPase activity and conformational stability. Mol Pharmacol 75:1430–1438
Galfrè E, Galeno L, Moran O (2012) A potentiator induces conformational changes on the recombinant CFTR nucleotide binding domains in solution. Cell Mol Life Sci 69:3701–3713
Eckford PD, Li C, Ramjeesingh M, Bear CE (2012) Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner. J Biol Chem 287:36639–36649
Jih KY, Hwang TC (2013) Vx-770 potentiates CFTR function by promoting decoupling between the gating cycle and ATP hydrolysis cycle. Proc Natl Acad Sci USA 110:4404–4409
Sloane PA, Shastry S, Wilhelm A, Courville C, Tang LP, Backer K, Levin E, Raju SV, Li Y, Mazur M, Byan-Parker S, Grizzle W, Sorscher EJ, Dransfield MT, Rowe SM (2012) A pharmacologic approach to acquired cystic fibrosis transmembrane conductance regulator dysfunction in smoking related lung disease. PLoS One 7:e39809
Dransfield MT, Wilhelm AM, Flanagan B, Courville C, Tidwell SL, Raju SV, Gaggar A, Steele C, Tang LP, Liu B, Rowe SM (2013) Acquired cystic fibrosis transmembrane conductance regulator dysfunction in the lower airways in COPD. Chest 144:498–506
Pedemonte N, Zegarra-Moran O, Galietta LJ (2011) High-throughput screening of libraries of compounds to identify CFTR modulators. Methods Mol Biol 741:13–21
Carlile GW, Robert R, Zhang D, Teske KA, Luo Y, Hanrahan JW, Thomas DY (2007) Correctors of protein trafficking defects identified by a novel high-throughput screening assay. ChemBioChem 8:1012–1020
Pedemonte N, Lukacs GL, Du K, Caci E, Zegarra-Moran O, Galietta LJ, Verkman AS (2005) Small-molecule correctors of defective DeltaF508-CFTR cellular processing identified by high-throughput screening. J Clin Invest 115:2564–2571
Yoo CL, Yu GJ, Yang B, Robins LI, Verkman AS, Kurth MJ (2008) 4′-Methyl-4,5′-bithiazole-based correctors of defective delta F508-CFTR cellular processing. Bioorg Med Chem Lett 18:2610–2614
Yu GJ, Yoo CL, Yang B, Lodewyk MW, Meng L, El-Idreesy TT, Fettinger JC, Tantillo DJ, Verkman AS, Kurth MJ (2008) Potent s-cis-locked bithiazole correctors of ∆F508 cystic fibrosis transmembrane conductance regulator cellular processing for cystic fibrosis therapy. J Med Chem 51:6044–6054
Coffman KC, Nguyen HH, Phuan PW, Hudson BM, Yu GJ, Bagdasarian AL, Montgomery D, Lodewyk MW, Yang B, Yoo CL, Verkman AS, Tantillo DJ, Kurth MJ (2014) Constrained bithiazoles: small molecule correctors of defective ΔF508-CFTR protein trafficking. J Med Chem 57:6729–6738
Van Goor F, Hadida S, Grootenhuis PD, Burton B, Stack JH, Straley KS, Decker CJ, Miller M, McCartney J, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu PA (2011) Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci USA 108:18843–18848
Robert R, Carlile GW, Pavel C, Liu N, Anjos SM, Liao J, Luo Y, Zhang D, Thomas DY, Hanrahan JW (2008) Structural analog of sildenafil identified as a novel corrector of the F508del-CFTR trafficking defect. Mol Pharmacol 73:478–489
Robert R, Carlile GW, Liao J, Balghi H, Lesimple P, Liu N, Kus B, Rotin D, Wilke M, de Jonge HR, Scholte BJ, Thomas DY, Hanrahan JW (2010) Correction of the ∆phe508 cystic fibrosis transmembrane conductance regulator trafficking defect by the bioavailable compound glafenine. Mol Pharmacol 77:922–930
Carlile GW, Keyzers RA, Teske KA, Robert R, Williams DE, Linington RG, Gray CA, Centko RM, Yan L, Anjos SM, Sampson HM, Zhang D, Liao J, Hanrahan JW, Andersen RJ, Thomas DY (2012) Correction of F508del-CFTR trafficking by the sponge alkaloid latonduine is modulated by interaction with PARP. Chem Biol 19:1288–1299
Hutt DM, Herman D, Rodrigues AP, Noel S, Pilewski JM, Matteson J, Hoch B, Kellner W, Kelly JW, Schmidt A, Thomas PJ, Matsumura Y, Skach WR, Gentzsch M, Riordan JR, Sorscher EJ, Okiyoneda T, Yates JR 3rd, Lukacs GL, Frizzell RA, Manning G, Gottesfeld JM, Balch WE (2010) Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis. Nat Chem Biol 6:25–33
Trzcinska-Daneluti AM, Nguyen L, Jiang C, Fladd C, Uehling D, Prakesch M, Al-awar R, Rotin D (2012) Use of kinase inhibitors to correct ΔF508-CFTR function. Mol Cell Proteomics 11:745–757
Norez C, Vandebrouck C, Bertrand J, Noel S, Durieu E, Oumata N, Galons H, Antigny F, Chatelier A, Bois P, Meijer L, Becq F (2014) Roscovitine is a proteostasis regulator that corrects the trafficking defect of F508del-CFTR by a CDK-independent mechanism. Br J Pharmacol 171:4831–4849
Luciani A, Villella VR, Esposito S, Brunetti-Pierri N, Medina D, Settembre C, Gavina M, Pulze L, Giardino I, Pettoello-Mantovani M, D’Apolito M, Guido S, Masliah E, Spencer B, Quaratino S, Raia V, Ballabio A, Maiuri L (2010) Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. Nat Cell Biol 12:863–875
De Stefano D, Villella VR, Esposito S, Tosco A, Sepe A, De Gregorio F, Salvadori L, Grassia R, Leone CA, De Rosa G, Maiuri MC, Pettoello-Mantovani M, Guido S, Bossi A, Zolin A, Venerando A, Pinna LA, Mehta A, Bona G, Kroemer G, Maiuri L, Raia V (2014) Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation. Autophagy 10:2053–2074
Odolczyk N, Fritsch J, Norez C, Servel N, da Cunha MF, Bitam S, Kupniewska A, Wiszniewski L, Colas J, Tarnowski K, Tondelier D, Roldan A, Saussereau EL, Melin-Heschel P, Wieczorek G, Lukacs GL, Dadlez M, Faure G, Herrmann H, Ollero M, Becq F, Zielenkiewicz P, Edelman A (2013) Discovery of novel potent ΔF508-CFTR correctors that target the nucleotide binding domain. EMBO Mol Med 5:1484–1501
Hegde RN, Parashuraman S, Iorio F, Ciciriello F, Capuani F, Carissimo A, Carrella D, Belcastro V, Subramanian A, Bounti L, Persico M, Carlile G, Galietta L, Thomas DY, Di Bernardo D, Luini A (2015) Unravelling druggable signalling networks that control F508del-CFTR proteostasis. Elife 4:e10365
Pankow S, Bamberger C, Calzolari D, Martínez-Bartolomé S, Lavallée-Adam M, Balch WE, Yates JR 3rd (2015) ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature 528:510–516
Veit G, Avramescu RG, Perdomo D, Phuan PW, Bagdany M, Apaja PM, Borot F, Szollosi D, Wu YS, Finkbeiner WE, Hegedus T, Verkman AS, Lukacs GL (2014) Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression. Sci Transl Med 6:246ra97
Cholon DM, Quinney NL, Fulcher ML, Esther CR Jr, Das J, Dokholyan NV, Randell SH, Boucher RC, Gentzsch M (2014) Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis. Sci Transl Med 6:246ra96
Favia M, Mancini MT, Bezzerri V, Guerra L, Laselva O, Abbattiscianni AC, Debellis L, Reshkin SJ, Gambari R, Cabrini G, Casavola V (2014) Trimethylangelicin promotes the functional rescue of mutant F508del CFTR protein in cystic fibrosis airway cells. Am J Physiol 307:L48–L61
Pedemonte N, Tomati V, Sondo E, Caci E, Millo E, Armirotti A, Damonte G, Zegarra-Moran O, Galietta LJ (2011) Dual activity of aminoarylthiazoles on the trafficking and gating defects of the cystic fibrosis transmembrane conductance regulator chloride channel caused by cystic fibrosis mutations. J Biol Chem 286:15215–15226
Pesce E, Bellotti M, Liessi N, Guariento S, Damonte G, Cichero E, Galatini A, Salis A, Gianotti A, Pedemonte N, Zegarra-Moran O, Fossa P, Galietta LJ, Millo E (2015) Synthesis and structure-activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis. Eur J Med Chem 99:14–35
Carlile GW, Robert R, Matthes E, Yang Q, Solari R, Hatley R, Edge CM, Hanrahan JW, Andersen R, Thomas DY, Birault V (2016) Latonduine analogs restore F508del-cystic fibrosis transmembrane conductance regulator trafficking through the modulation of poly-ADP ribose polymerase 3 and poly-ADP ribose polymerase 16 activity. Mol Pharmacol 90:65–79
Okiyoneda T, Veit G, Dekkers JF, Bagdany M, Soya N, Xu H, Roldan A, Verkman AS, Kurth M, Simon A, Hegedus T, Beekman JM, Lukacs GL (2013) Mechanism-based corrector combination restores ΔF508-CFTR folding and function. Nat Chem Biol 9:444–454
Farinha CM, King-Underwood J, Sousa M, Correia AR, Henriques BJ, Roxo-Rosa M, Da Paula AC, Williams J, Hirst S, Gomes CM, Amaral MD (2013) Revertants, low temperature, and correctors reveal the mechanism of F508del-CFTR rescue by VX-809 and suggest multiple agents for full correction. Chem Biol 20:943–955
Grove DE, Rosser MF, Ren HY, Naren AP, Cyr DM (2009) Mechanisms for rescue of correctable folding defects in CFTR∆F508. Mol Biol Cell 20:4059–4069
Clancy JP, Rowe SM, Accurso FJ, Aitken ML, Amin RS, Ashlock MA, Ballmann M, Boyle MP, Bronsveld I, Campbell PW, De Boeck K, Donaldson SH, Dorkin HL, Dunitz JM, Durie PR, Jain M, Leonard A, McCoy KS, Moss RB, Pilewski JM, Rosenbluth DB, Rubenstein RC, Schechter MS, Botfield M, Ordoñez CL, Spencer-Green GT, Vernillet L, Wisseh S, Yen K, Konstan MW (2012) Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax 67:12–18
Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, Colombo C, Davies JC, De Boeck K, Flume PA, Konstan MW, McColley SA, McCoy K, McKone EF, Munck A, Ratjen F, Rowe SM, Waltz D, Boyle MP, TRAFFIC Study Group; TRANSPORT Study Group (2015) Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med 373:220–231
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zegarra-Moran, O., Galietta, L.J.V. CFTR pharmacology. Cell. Mol. Life Sci. 74, 117–128 (2017). https://doi.org/10.1007/s00018-016-2392-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00018-016-2392-x