ABCMdb

PMID: 21658632

Becq F, Mall MA, Sheppard DN, Conese M, Zegarra-Moran O
Pharmacological therapy for cystic fibrosis: from bench to bedside.
J Cyst Fibros. 2011 Jun;10 Suppl 2:S129-45., [PubMed]

Sentences

No. Mutations Sentence Comment

31 ABCC7 p.Trp1282* Class I mutations: defective protein production Some CF mutations (e.g. W1282X) are nonsense mutations that introduce stop signals known as premature termination codons (PTCs) into the CFTR gene. Login to comment 42 ABCC7 p.Gly551Asp Class III mutations (e.g. G551D) disrupt channel regulation by affecting the pattern of channel opening and closing (termed gating) [12]. Login to comment 44 ABCC7 p.Gly551Asp By contrast, for G551D channel openings occur very infrequently and are separated by prolonged periods of channel closure (e.g. [12, fig. 4B]). Login to comment 49 ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro For example, the conductance of an open wild-type CFTR Cl-channel is ~8 pS, whereas that of R347P is only 2 pS [13]. Login to comment 50 ABCC7 p.Arg347His An explanation for why mutations at R347 decrease Cl- flow through CFTR was provided by Tabcharani et al. [14], who demonstrated that the CF mutant R347H converts CFTR from a multi-ion pore to a single-ion pore. Login to comment 56 ABCC7 p.Pro574His ABCC7 p.Ala455Glu Interestingly, Zielenski and Tsui [10] assigned A455E and P574H, two CF mutations associated with a milder clinical phenotype (pancreatic sufficiency) to Class V. Login to comment 58 ABCC7 p.Pro574His ABCC7 p.Pro574His ABCC7 p.Ala455Glu Moreover, on reaching the cell surface A455E forms Cl-channels with open probability (Po), a measure of channel activity, similar to that of wild-type CFTR, whereas the Po of P574H exceeds that of wild-type CFTR [15]. Login to comment 100 ABCC7 p.Arg258Gly ABCC7 p.Ser945Leu ABCC7 p.His949Tyr [29] BHK cells F508del, R258G, S945L, H949Y cAMP-stimulated iodide efflux, biochemistry VRT-325 (1-10 μM) rescued F508del-CFTR and other mutants after 48 h incubation of BHK cells at 37°C. VRT-325 also rescues misprocessed P-gp mutants and acts as P-gp inhibitor. Login to comment 116 ABCC7 p.Gly622Asp MPB-07, MPB-91, analogues [104] human CF nasal epithelial cells, CF15 F508del, G622D Biochemistry, iodide efflux, degradation assay MPB compounds protect a proteolytic cleavage site by directly binding to the NBD1 domain of F508del-CFTR. Login to comment 118 ABCC7 p.Arg1283Met PDE5 inhibitors Sidenafil (Viagra) [106] human CF nasal epithelial cells, CF15 F508del, R1283M Biochemistry, immunofluorescence, iodide efflux Sildenafil restored F508del-CFTR activity by preventing F508del-CFTR/calnexin interaction in the ER. Login to comment 128 ABCC7 p.Trp1282* For further information, see the text. *Cellular model used: Primary cells/tissues: HBE, human bronchial epithelial cells from normal subjects; HBEC-CF primary, human bronchial epithelial cells from CF patients. Cell-lines (immortalized) expressing endogeneous CFTR: CF15 cells (human nasal airway, F508del/F508del); CFBE41o- (human bronchial origin, F508del/F508del); CFPAC-1 (human pancreatic duct origin, F508del/F508del); CFT1 (human tracheal origin, F508del/F508del); CuFi-1 (human bronchial origin, F508del/F508del); NuLi-1 (human bronchial origin, wild-type CFTR); IB3-1 (human bronchial origin, F508del/W1282X); LLC-PK1 (pig kidney epithelial cell line, wild-type CFTR). Login to comment 175 ABCC7 p.Gly551Asp Moreover, treatment of CF airway epithelia (genotype F508del/G551D) with VX-770 (10 μM) increased airway surface liquid (ASL) volume and ciliary beat frequency to levels about half those of normal airway epithelia [33]. Login to comment 177 ABCC7 p.Gly551Asp The drug was first tested in 39 adult CF patients with the class III mutation G551D, who took the drug orally in a randomized, double-blind, placebo-controlled trial [34]. Login to comment 180 ABCC7 p.Gly551Asp Following the success of this clinical trial, VX-770 is now being tested in Phase III clinical trials in the USA and Europe, including studies of children and adults with the G551D mutation as well as a study of adults carrying the F508del mutation (www.vrtx.com/current-projects/drug-candidates/vx-770.html). Login to comment 213 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp [120] HeLa cells expressing CFTRs F508del, G551D Electrophysiology, NPD assay Genistein strongly increased G551D-CFTR Cl- currents. Login to comment 215 ABCC7 p.Gly551Asp Genistein stimulated the NPD of CF patients bearing the G551D mutation. Login to comment 216 ABCC7 p.Lys1250Ala [121] NIH3T3 cells F508del, K1250A Electrophysiology Genistein and benzimidazolones shared the same mechanism of action. Login to comment 217 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp [122] FRT, HNEC-CF (G551D) primary WT, G551D Electrophysiology Genistein, but neither CPX nor MPB-07, rescued transepithelial Cl-transport in G551D epithelia. Login to comment 219 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp [124] CHO WT, G551D Electrophysiology, iodide efflux The CF mutation G551D disrupts the inhibition of CFTR activity by elevated concentrations of genistein. Login to comment 223 ABCC7 p.Gly551Asp Benzo[c]quinolizinium and benzo[f]indolo [2,3-a]quinolizinium salts [128] CHO WT, G551D Iodide efflux Structure-activity relationships to identify the structural basis for CFTR activation. Login to comment 225 ABCC7 p.Gly551Asp 7,8 benzoflavones [129] FRT, HBEC primary WT, G551D YFP cell-based assay and electrophysiology Screening of a combinatorial library based on flavone and benzoquinolizinium structures yielded a new family of active compounds, 7,8 benzoflavones. Login to comment 226 ABCC7 p.Gly551Asp Some agents also activated G551D-CFTR. Login to comment 230 ABCC7 p.Gly551Asp Table 3 (continued) Compound Ref. Cell system * CFTR isoform Method Results Benzoflavones analogues [132] FRT WT, G551D YFP cell-based assay Analysis of a panel of benzoflavones analogues to analyse structure-activity relationships and to model a pharmacophore. Login to comment 231 ABCC7 p.Gly551Asp CFTRact-01 to CFTRact-17 [133] FRT, HBEC-CF (F508del) primary WT, G551D, temperature-corrected F508del YFP cell-based assay and electrophysiology HTS of a 60,000 compound library yielded 14 active compounds from different chemical families. Login to comment 237 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp ABCC7 p.Gly1349Asp [136] COS-7 G551D, G1349D, G551D/G1349D Electrophysiology, iodide efflux Study explores the contribution of G551 and G1349 to CFTR modulation (potentiation and inhibition) by phloxine B. Login to comment 238 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp ABCC7 p.Gly1349Asp [137] C127, FRT WT, G551D, G1349D Electrophysiology Phloxine B has distinct effects on G551D and G1349D-CFTR, suggesting that drug therapy for CF is mutation-specific. Login to comment 242 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Phenylglycine and sulfonamide [140] FRT, HBEC-CF (F508del) Temperature-corrected F508del YFP cell-based assay, electrophysiology HTS of a library containing 50,000 diverse small molecules yielded two novel classes of potentiators that were active with nanomolar potency on F508del- and G551D-CFTR. Login to comment 243 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp ABCC7 p.Glu193Lys [141] COS-7, HEK293, FRT G551D, G1349D, E193K, G970R YFP cell-based assay, electrophysiology Study demonstrates that potentiators are active on mutations residing in different CFTR domains and that potencies are mutation-specific. Login to comment 244 ABCC7 p.Ser660Ala 5-nitro-2-(3-phenyl propylamino)benzoate (NPPB) analogues [142] BHK, HEK293, CFBE41o- transfected WT, F508del, R-S660A-CFTR Electrophysiology NPPB analogues stimulate WT and F508del-CFTR channel activity at submicromolar concentrations without blocking the channel pore. Login to comment 245 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Dihydropyridines (DHP) [143] FRT, HBEC-CF (F508del) G551D, temperature-corrected F508del YFP cell-based assay, electrophysiology Screening of an approved drugs library identified some antihypertensive 1,4-dihydropyridines as submicromolar potentiators of F508del-CFTR and, with less potency, of G551D CFTR. Login to comment 246 ABCC7 p.Gly551Asp ABCC7 p.Gly1349Asp [144] FRT G551D, G1349D, temperature-corrected F508del YFP cell-based assay, electrophysiology Structure-activity relationships for CFTR potentiation and Ca2+-channel inhibition leading to identification of compounds that more potently potentiate CFTR than block Ca2+-channels. Login to comment 253 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp N-(2,4-di-tert-butyl- 5-hydroxyphenyl)- 4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770) [33] FRT, NIH3T3, HBEC primary WT, G551D and F508del Electrophysiology, ASL height and ciliary beat frequency VX-770 increases the open probability of G551D-CFTR Cl-channels and hence, stimulates Cl-secretion, apical surface hydration and ciliary beat frequency of human bronchial epithelia expressing G551D-CFTR. Login to comment 255 ABCC7 p.Gly551Asp Pyrrolo[2,3-b] pyrazines derivatives (RP) [147] CHO, Calu-3, mice colon WT, G551D, temperature-corrected F508del Iodide efflux, electrophysiology The synthesis and screening of a small library of 6 RP derivatives identified RP107 as a submicromolar activator of wild-type and mutant CFTR. Login to comment 271 ABCC7 p.Gly551Asp VX-770 [34] Phase 1 and 2 completed Phase 3 This randomized, double-blind, placebo-controlled trial evaluated the safety and tolerability of VX-770 in adult CF patients with at least one copy of the G551D mutation. Login to comment 275 ABCC7 p.Gly551Asp Thus, VX-770 improved CFTR and lung function in adult CF patients with the G551D mutation. Login to comment