Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770

Goor, Fredrick Van; Burton, Bill; Hadida, Sabine; Grootenhuis, Peter D. J.; Olson, Eric R.; Wine, Jeffrey J.; Frizzell, R. A.; Ashlock, Melissa A.; Negulescu, Paul A.

doi:10.1016/s1569-1993(09)60072-2

Cited by 222 publications

(398 citation statements)

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“…These combined data are consistent with evidence that the ΔF508 mutation disrupts interactions between NBD1 and MSD2 (446). Another compound, Vertex-770, rescues the gating defect in a less common CFTR mutant (G551D) that leads to disease (507). More likely than not, this potentiator also binds directly to CFTR to increase the channel's open probability.…”

Section: A Current Experimental Treatments and Prospects For Future supporting

confidence: 80%

The Delicate Balance Between Secreted Protein Folding and Endoplasmic Reticulum-Associated Degradation in Human Physiology

Guerriero

Brodsky

2012

Physiological Reviews

361

355

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Protein folding is a complex, error-prone process that often results in an irreparable protein by-product. These by-products can be recognized by cellular quality control machineries and targeted for proteasome-dependent degradation. The folding of proteins in the secretory pathway adds another layer to the protein folding “problem,” as the endoplasmic reticulum maintains a unique chemical environment within the cell. In fact, a growing number of diseases are attributed to defects in secretory protein folding, and many of these by-products are targeted for a process known as endoplasmic reticulum-associated degradation (ERAD). Since its discovery, research on the mechanisms underlying the ERAD pathway has provided new insights into how ERAD contributes to human health during both normal and diseases states. Links between ERAD and disease are evidenced from the loss of protein function as a result of degradation, chronic cellular stress when ERAD fails to keep up with misfolded protein production, and the ability of some pathogens to coopt the ERAD pathway. The growing number of ERAD substrates has also illuminated the differences in the machineries used to recognize and degrade a vast array of potential clients for this pathway. Despite all that is known about ERAD, many questions remain, and new paradigms will likely emerge. Clearly, the key to successful disease treatment lies within defining the molecular details of the ERAD pathway and in understanding how this conserved pathway selects and degrades an innumerable cast of substrates.

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Section: A Current Experimental Treatments and Prospects For Future supporting

confidence: 80%

The Delicate Balance Between Secreted Protein Folding and Endoplasmic Reticulum-Associated Degradation in Human Physiology

Guerriero

Brodsky

2012

Physiological Reviews

361

355

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“…VX-770 was the first drug to target the CFTR channel directly, rather than disease symptoms. It is now approved to treat CF caused by a number of gating mutations (Van Goor et al, 2009Yu et al, 2012), and the clinical results have been very positive (Ramsey et al, 2011;Davies et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Potentiation of the cystic fibrosis transmembrane conductance regulator by VX‐770 involves stabilization of the pre‐hydrolytic, O₁ state

Langron

Prins

Vergani

2018

British J Pharmacology

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Similar potentiation of hydrolytic and non-hydrolytic mutants suggests that VX-770 increases CFTR open probability mainly by stabilizing pre-hydrolytic O states with respect to closed states. Potentiation of K464A-CFTR channels suggests action of VX-770 did not strongly alter conformational dynamics at site 1. Understanding potentiator mechanism could help develop improved treatment for CF patients. The fluorescence assay presented here is a robust tool for such investigations.

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“…Second, CFTR potentiators that enhance greatly mutant channel gating (Cai et al, 2011). When tested alone, neither CFTR correctors, such as lumacaftor (VX-809; Van Goor et al, 2011) nor CFTR potentiators, such as ivacaftor (VX-770;Van Goor et al, 2009) had clinical benefit for CF patients with the F508del mutation (Clancy et al, 2012;Flume et al, 2012). By contrast, chronic co-administration of lumacaftor and ivacaftor to CF patients homozygous for the F508del mutation increased modestly lung function, but improved markedly disease stability (Wainwright et al, 2015), leading to the approval of lumacaftor-ivacaftor combination therapy.…”

Section: Introductionmentioning

confidence: 99%

Partial rescue of F508del‐cystic fibrosis transmembrane conductance regulator channel gating with modest improvement of protein processing, but not stability, by a dual‐acting small molecule

Liu

Bihler

Farinha

et al. 2018

British J Pharmacology

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Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770

Cited by 222 publications

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The Delicate Balance Between Secreted Protein Folding and Endoplasmic Reticulum-Associated Degradation in Human Physiology

The Delicate Balance Between Secreted Protein Folding and Endoplasmic Reticulum-Associated Degradation in Human Physiology

Potentiation of the cystic fibrosis transmembrane conductance regulator by VX‐770 involves stabilization of the pre‐hydrolytic, O₁ state

Partial rescue of F508del‐cystic fibrosis transmembrane conductance regulator channel gating with modest improvement of protein processing, but not stability, by a dual‐acting small molecule

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Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770

Cited by 222 publications

References 0 publications

The Delicate Balance Between Secreted Protein Folding and Endoplasmic Reticulum-Associated Degradation in Human Physiology

The Delicate Balance Between Secreted Protein Folding and Endoplasmic Reticulum-Associated Degradation in Human Physiology

Potentiation of the cystic fibrosis transmembrane conductance regulator by VX‐770 involves stabilization of the pre‐hydrolytic, O1 state

Partial rescue of F508del‐cystic fibrosis transmembrane conductance regulator channel gating with modest improvement of protein processing, but not stability, by a dual‐acting small molecule

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Potentiation of the cystic fibrosis transmembrane conductance regulator by VX‐770 involves stabilization of the pre‐hydrolytic, O₁ state