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Vx-809

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https://www.readbyqxmd.com/read/28546419/direct-binding-of-the-corrector-vx-809-to-human-cftr-nbd1-evidence-of-an-allosteric-coupling-between-the-binding-site-and-the-nbd1-cl4-interface
#1
Rhea P Hudson, Jennifer E Dawson, P Andrew Chong, Zhengrong Yang, Linda Millen, Philip J Thomas, Christie G Brouillette, Julie D Forman-Kay
Understanding the mechanism of action of modulator compounds for the cystic fibrosis transmembrane conductance regulator (CFTR) is key for the optimization of therapeutics as well as obtaining insights into the molecular mechanisms of CFTR function. We demonstrate the direct binding of VX-809 to the first nucleotide-binding domain (NBD1) of human CFTR. Disruption of the interaction between C-terminal helices and the NBD1 core upon VX-809 binding is observed from chemical shift changes in the NMR spectra of residues in the helices and on the surface of β-strands S3, S9, and S10...
August 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28366727/corrector-vx-809-promotes-interactions-between-cytoplasmic-loop-one-and-the-first-nucleotide-binding-domain-of-cftr
#2
Tip W Loo, David M Clarke
A large number of correctors have been identified that can partially repair defects in folding, stability and trafficking of CFTR processing mutants that cause cystic fibrosis (CF). The best corrector, VX-809 (Lumacaftor), has shown some promise when used in combination with a potentiator (Ivacaftor). Understanding the mechanism of VX-809 is essential for development of better correctors. Here, we tested our prediction that VX-809 repairs folding and processing defects of CFTR by promoting interactions between the first cytoplasmic loop (CL1) of transmembrane domain 1 (TMD1) and the first nucleotide-binding domain (NBD1)...
July 15, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28360110/the-cftr-trafficking-mutation-f508del-inhibits-the-constitutive-activity-of-slc26a9
#3
Carol A Bertrand, Shalini Mitra, Sanjay K Mishra, Xiaohui Wang, Yu Zhao, Joseph M Pilewski, Dean R Madden, Raymond A Frizzell
Several members of the SLC26A family of anion transporters associate with CFTR, forming complexes in which CFTR and SLC26A functions are reciprocally regulated. These associations are thought to be facilitated by PDZ scaffolding interactions. CFTR has been shown to be positively regulated by NHERF-1, and negatively regulated by CAL in airway epithelia. However, it is unclear which PDZ-domain protein(s) interact with SLC26A9, a SLC26A family member found in airway epithelia. We have previously shown that primary, human bronchial epithelia (HBE) from non-CF donors exhibit constitutive anion secretion attributable to SLC26A9...
June 1, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28346090/identifying-inhibitors-of-the-hsp90-aha1-protein-complex-a-potential-target-to-drug-cystic-fibrosis-by-alpha-technology
#4
Verena Ihrig, Wolfgang M J Obermann
Deletion of a single phenylalanine residue at position 508 of the protein CFTR (cystic fibrosis transmembrane conductance regulator), a chloride channel in lung epithelium, is the most common cause for cystic fibrosis. As a consequence, folding of the CFTRΔF508 protein and delivery to the cell surface are compromised, resulting in degradation of the polypeptide. Accordingly, decreased surface presence of CFTRΔF508 causes impaired chloride ion conductivity and is associated with mucus accumulation, a hallmark of cystic fibrosis...
August 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28001373/direct-measurement-of-trafficking-of-the-cystic-fibrosis-transmembrane-conductance-regulator-to-the-cell-surface-and-binding-to-a-chemical-chaperone
#5
Zhihui Zhang, Michael M Baksh, M G Finn, David K Heidary, Christopher I Richards
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) result in the disease cystic fibrosis. Deletion of Phe508, the most prevalent mutation associated with this disease, disrupts trafficking of the protein. Small molecule correctors yield moderate improvements in the trafficking of ΔF508-CFTR to the plasma membrane. It is currently not known if correctors increase the level of trafficking through improved cargo loading of transport vesicles or through direct binding to CFTR. Real-time measurements of trafficking were utilized to identify the mechanistic details of chemical, biochemical, and thermal factors that impact CFTR correction, using the corrector molecule VX-809, a secondary mutation (I539T), and low-temperature conditions...
January 10, 2017: Biochemistry
https://www.readbyqxmd.com/read/27983869/pharmacological-rescue-of-conditionally-reprogrammed-cystic-fibrosis-bronchial-epithelial-cells
#6
Martina Gentzsch, Susan E Boyles, Chaitra Cheluvaraju, Imron G Chaudhry, Nancy L Quinney, Crescentia Cho, Hong Dang, Xuefeng Liu, Richard Schlegel, Scott H Randell
Well-differentiated primary human bronchial epithelial (HBE) cell cultures are vital for cystic fibrosis (CF) research, particularly for the development of cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs. Culturing of epithelial cells with irradiated 3T3 fibroblast feeder cells plus the RhoA kinase inhibitor Y-27632 (Y), termed conditionally reprogrammed cell (CRC) technology, enhances cell growth and lifespan while preserving cell-of-origin functionality. We initially determined the electrophysiological and morphological characteristics of conventional versus CRC-expanded non-CF HBE cells...
May 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/27895116/correctors-and-potentiators-rescue-function-of-the-truncated-w1282x-cystic-fibrosis-transmembrane-regulator-cftr-translation-product
#7
Peter M Haggie, Puay-Wah Phuan, Joseph-Anthony Tan, Haijin Xu, Radu G Avramescu, Doranda Perdomo, Lorna Zlock, Dennis W Nielson, Walter E Finkbeiner, Gergely L Lukacs, Alan S Verkman
W1282X is the fifth most common cystic fibrosis transmembrane regulator (CFTR) mutation that causes cystic fibrosis. Here, we investigated the utility of a small molecule corrector/potentiator strategy, as used for ΔF508-CFTR, to produce functional rescue of the truncated translation product of the W1282X mutation, CFTR1281, without the need for read-through. In transfected cell systems, certain potentiators and correctors, including VX-809 and VX-770, increased CFTR1281 activity. To identify novel correctors and potentiators with potentially greater efficacy on CFTR1281, functional screens were done of ∼30,000 synthetic small molecules and drugs/nutraceuticals in CFTR1281-transfected cells...
January 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27614011/the-investigational-cystic-fibrosis-drug-trimethylangelicin-directly-modulates-cftr-by-stabilizing-the-first-membrane-spanning-domain
#8
Onofrio Laselva, Steven Molinski, Valeria Casavola, Christine E Bear
Cystic Fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The most common mutation, deletion of phenylalanine 508 (F508del), disrupts tertiary assembly, causing protein misprocessing and loss of CFTR function in epithelial tissues. Lumacaftor (VX-809) is a Class 1 corrector molecule shown to partially rescue misprocessing of F508del and together with the potentiator of channel activity: ivacaftor (VX-770) has been approved for treatment of CF patients homozygous for the F508del mutation...
November 1, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27571970/generation-of-%C3%AE-f508-cftr-t84-cell-lines-by-crispr-cas9-mediated-genome-editing
#9
Woo Young Chung, Myungjae Song, Jinhong Park, Wan Namkung, Jinu Lee, Hyongbum Kim, Min Goo Lee, Joo Young Kim
OBJECTIVES: To provide a simple method to make a stable ΔF508-CFTR-expressing T84 cell line that can be used as an efficient screening model system for ΔF508-CFTR rescue. RESULTS: CFTR knockout cell lines were generated by Cas9 with a single-guide RNA (sgRNA) targeting exon 1 of the CFTR genome, which produced indels that abolished CFTR protein expressions. Next, stable ΔF508-CFTR expression was achieved by genome integration of ΔF508-CFTR via the lentivirus infection system...
December 2016: Biotechnology Letters
https://www.readbyqxmd.com/read/27402691/restoration-of-r117h-cftr-folding-and-function-in-human-airway-cells-through-combination-treatment-with-vx-809-and-vx-770
#10
Martina Gentzsch, Hong Y Ren, Scott A Houck, Nancy L Quinney, Deborah M Cholon, Pattarawut Sopha, Imron G Chaudhry, Jhuma Das, Nikolay V Dokholyan, Scott H Randell, Douglas M Cyr
Cystic fibrosis (CF) is a lethal recessive genetic disease caused primarily by the F508del mutation in the CF transmembrane conductance regulator (CFTR). The potentiator VX-770 was the first CFTR modulator approved by the FDA for treatment of CF patients with the gating mutation G551D. Orkambi is a drug containing VX-770 and corrector VX809 and is approved for treatment of CF patients homozygous for F508del, which has folding and gating defects. At least 30% of CF patients are heterozygous for the F508del mutation with the other allele encoding for one of many different rare CFTR mutations...
September 1, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/27334259/characterizing-responses-to-cftr-modulating-drugs-using-rectal-organoids-derived-from-subjects-with-cystic-fibrosis
#11
Johanna F Dekkers, Gitte Berkers, Evelien Kruisselbrink, Annelotte Vonk, Hugo R de Jonge, Hettie M Janssens, Inez Bronsveld, Eduard A van de Graaf, Edward E S Nieuwenhuis, Roderick H J Houwen, Frank P Vleggaar, Johanna C Escher, Yolanda B de Rijke, Christof J Majoor, Harry G M Heijerman, Karin M de Winter-de Groot, Hans Clevers, Cornelis K van der Ent, Jeffrey M Beekman
Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations...
June 22, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27298017/efficacy-and-safety-of-lumacaftor-ivacaftor-combination-therapy-in-patients-with-cystic-fibrosis-homozygous-for-phe508del-cftr-by-pulmonary-function-subgroup-a-pooled-analysis
#12
J Stuart Elborn, Bonnie W Ramsey, Michael P Boyle, Michael W Konstan, Xiaohong Huang, Gautham Marigowda, David Waltz, Claire E Wainwright
BACKGROUND: Lumacaftor/ivacaftor combination therapy has shown clinical benefits in patients with cystic fibrosis homozygous for the Phe508del CFTR mutation; however, pretreatment lung function is a confounding factor that potentially affects the efficacy and safety of this therapy. We aimed to assess the efficacy and safety of lumacaftor/ivacaftor therapy in these patients, defined by specific categories of lung function. METHODS: Both trials (TRAFFIC and TRANSPORT) included in this pooled analysis were multinational, randomised, double-blind, placebo-controlled, parallel-group, phase 3 studies...
August 2016: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/27214033/mechanistic-approaches-to-improve-correction-of-the-most-common-disease-causing-mutation-in-cystic-fibrosis
#13
Vedrana Bali, Ahmed Lazrak, Purushotham Guroji, Sadis Matalon, Zsuzsanna Bebok
The most common mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene leads to deletion of the phenylalanine at position 508 (ΔF508) in the CFTR protein and causes multiple folding and functional defects. Contrary to large-scale efforts by industry and academia, no significant therapeutic benefit has been achieved with a single "corrector". Therefore, investigations concentrate on drug combinations. Orkambi (Vertex Pharmaceuticals), the first FDA-approved drug for treatment of cystic fibrosis (CF) caused by this mutation, is a combination of a corrector (VX-809) that facilitates ΔF508 CFTR biogenesis and a potentiator (VX-770), which improves its function...
2016: PloS One
https://www.readbyqxmd.com/read/27168400/ribosomal-stalk-protein-silencing-partially-corrects-the-%C3%AE-f508-cftr-functional-expression-defect
#14
Guido Veit, Kathryn Oliver, Pirjo M Apaja, Doranda Perdomo, Aurélien Bidaud-Meynard, Sheng-Ting Lin, Jingyu Guo, Mert Icyuz, Eric J Sorscher, John L Hartman, Gergely L Lukacs
The most common cystic fibrosis (CF) causing mutation, deletion of phenylalanine 508 (ΔF508 or Phe508del), results in functional expression defect of the CF transmembrane conductance regulator (CFTR) at the apical plasma membrane (PM) of secretory epithelia, which is attributed to the degradation of the misfolded channel at the endoplasmic reticulum (ER). Deletion of phenylalanine 670 (ΔF670) in the yeast oligomycin resistance 1 gene (YOR1, an ABC transporter) of Saccharomyces cerevisiae phenocopies the ΔF508-CFTR folding and trafficking defects...
May 2016: PLoS Biology
https://www.readbyqxmd.com/read/27160424/potentiator-synergy-in-rectal-organoids-carrying-s1251n-g551d-or-f508del-cftr-mutations
#15
Johanna F Dekkers, Peter Van Mourik, Annelotte M Vonk, Evelien Kruisselbrink, Gitte Berkers, Karin M de Winter-de Groot, Hettie M Janssens, Inez Bronsveld, Cornelis K van der Ent, Hugo R de Jonge, Jeffrey M Beekman
The potentiator VX-770 (ivacaftor/KALYDECO™) targets defective gating of CFTR and has been approved for treatment of cystic fibrosis (CF) subjects carrying G551D, S1251N or one of 8 other mutations. Still, the current potentiator treatment does not normalize CFTR-dependent biomarkers, indicating the need for development of more effective potentiator strategies. We have recently pioneered a functional CFTR assay in primary rectal organoids and used this model to characterize interactions between VX-770, genistein and curcumin, the latter 2 being natural food components with established CFTR potentiation capacities...
September 2016: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/27146408/characterization-of-mitochondrial-function-in-cells-with-impaired-cystic-fibrosis-transmembrane-conductance-regulator-cftr-function
#16
Anna Atlante, Maria Favia, Antonella Bobba, Lorenzo Guerra, Valeria Casavola, Stephan Joel Reshkin
Evidence supporting the occurrence of oxidative stress in Cystic Fibrosis (CF) is well established and the literature suggests that oxidative stress is inseparably linked to mitochondrial dysfunction. Here, we have characterized mitochondrial function, in particular as it regards the steps of oxidative phosphorylation and ROS production, in airway cells either homozygous for the F508del-CFTR allele or stably expressing wt-CFTR. We find that oxygen consumption, ΔΨ generation, adenine nucleotide translocator-dependent ADP/ATP exchange and both mitochondrial Complex I and IV activities are impaired in CF cells, while both mitochondrial ROS production and membrane lipid peroxidation increase...
June 2016: Journal of Bioenergetics and Biomembranes
https://www.readbyqxmd.com/read/27103391/optimal-correction-of-distinct-cftr-folding-mutants-in-rectal-cystic-fibrosis-organoids
#17
Johanna F Dekkers, Ricardo A Gogorza Gondra, Evelien Kruisselbrink, Annelotte M Vonk, Hettie M Janssens, Karin M de Winter-de Groot, Cornelis K van der Ent, Jeffrey M Beekman
Small-molecule therapies that restore defects in cystic fibrosis transmembrane conductance regulator (CFTR) gating (potentiators) or trafficking (correctors) are being developed for cystic fibrosis (CF) in a mutation-specific fashion. Options for pharmacological correction of CFTR-p.Phe508del (F508del) are being extensively studied but correction of other trafficking mutants that may also benefit from corrector treatment remains largely unknown.We studied correction of the folding mutants CFTR-p.Phe508del, -p...
August 2016: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
https://www.readbyqxmd.com/read/26863533/potentiation-of-%C3%AE-f508-and-g551d-cftr-mediated-cl-current-by-novel-hydroxypyrazolines
#18
Jinhong Park, Poonam Khloya, Yohan Seo, Satish Kumar, Ho K Lee, Dong-Kyu Jeon, Sungwoo Jo, Pawan K Sharma, Wan Namkung
The most common mutation of CFTR, affecting approximately 90% of CF patients, is a deletion of phenylalanine at position 508 (F508del, ΔF508). Misfolding of ΔF508-CFTR impairs both its trafficking to the plasma membrane and its chloride channel activity. To identify small molecules that can restore channel activity of ΔF508-CFTR, we synthesized and evaluated eighteen novel hydroxypyrazoline analogues as CFTR potentiators. To elucidate potentiation activities of hydroxypyrazolines for ΔF508-CFTR, CFTR activity was measured using a halide-sensitive YFP assay, Ussing chamber assay and patch-clamp technique...
2016: PloS One
https://www.readbyqxmd.com/read/26823603/correctors-of-mutant-cftr-enhance-subcortical-camp-pka-signaling-through-modulating-ezrin-phosphorylation-and-cytoskeleton-organization
#19
Anna C Abbattiscianni, Maria Favia, Maria T Mancini, Rosa A Cardone, Lorenzo Guerra, Stefania Monterisi, Stefano Castellani, Onofrio Laselva, Francesca Di Sole, Massimo Conese, Manuela Zaccolo, Valeria Casavola
The most common mutation of the cystic fibrosis transmembrane regulator (CFTR) gene, F508del, produces a misfolded protein resulting in its defective trafficking to the cell surface and an impaired chloride secretion. Pharmacological treatments partially rescue F508del CFTR activity either directly by interacting with the mutant protein and/or indirectly by altering the cellular protein homeostasis. Here, we show that the phosphorylation of ezrin together with its binding to phosphatidylinositol-4,5-bisphosphate (PIP2) tethers the F508del CFTR to the actin cytoskeleton, stabilizing it on the apical membrane and rescuing the sub-membrane compartmentalization of cAMP and activated PKA...
March 15, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/26800689/c-3623g%C3%A2-%C3%A2-a-mutation-encodes-a-cftr-protein-with-impaired-channel-function
#20
Xiaoying Zhang, Jaspal S Hothi, Yanhui H Zhang, Saumini Srinivasan, Dennis C Stokes, Weiqiang Zhang
BACKGROUND: The aims of this study were to characterize clinical features of a pediatric African-American cystic fibrosis (CF) patient heterozygous for F508del and a novel c.3623G > A mutation, and to identify the molecular defect(s) associated with c.3623G > A mutation. METHODS: The medical record of this patient was analyzed retrospectively. Western blotting and iodide efflux assay were used to study mutant CFTR protein expression level, maturation status, channel function, and the effects of CFTR modulation on these characteristics...
January 22, 2016: Respiratory Research
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