Cystic fibrosis drug ivacaftor stimulates CFTR channels at picomolar concentrations

The devastating inherited disease cystic fibrosis (CF) is caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) anion channel. The recent approval of the CFTR potentiator drug ivacaftor (Vx-770) for the treatment of CF patients has marked the advent of causative CF therapy. Currently, thousands of patients are being treated with the drug, and its molecular mechanism of action is under intensive investigation. Here we determine the solubility profile and true stimulatory potency of Vx-770 towards wild-type (WT) and mutant human CFTR channels in cell-free patches of membrane. We find that its aqueous solubility is ~200-fold lower (~60 nanomolar), whereas the potency of its stimulatory effect is>100-fold higher, than reported, and is unexpectedly fully reversible. Strong, but greatly delayed, channel activation by picomolar Vx-770 identifies multiple sequential slow steps in the activation pathway. These findings provide solid guidelines for the design ofin vitro studies using Vx-770.
Source: eLife - Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Related Links:

Conclusions Cystic fibrosis or CFTR-RD can present as ARP/CP. Complete diagnostic testing for CFTR-RD in patients with ARP/CP will broaden treatment options and help to identify comorbid illness.
Source: Pancreas - Category: Gastroenterology Tags: Original Articles Source Type: research
Condition:   Cystic Fibrosis Intervention:   Device: Fitbit Tracker Sponsors:   Medical College of Wisconsin;   Cystic Fibrosis Foundation Not yet recruiting
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
Condition:   Cystic Fibrosis Intervention:   Behavioral: Motivational Interviewing Sponsors:   Belfast Health and Social Care Trust;   Queen's University, Belfast Completed
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
Condition:   Cystic Fibrosis Intervention:   Device: Fitbit Tracker Sponsors:   Medical College of Wisconsin;   Cystic Fibrosis Foundation Not yet recruiting
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
ConclusionsSPX-101 was well-tolerated across a range of doses and had little/no systemic exposure in healthy adults and adults with CF, thus supporting further study in patients with CF.Clinicaltrial.gov registrationNCT03056989.
Source: Pulmonary Pharmacology and Therapeutics - Category: Respiratory Medicine Source Type: research
Condition:   Cystic Fibrosis Intervention:   Behavioral: Motivational Interviewing Sponsors:   Belfast Health and Social Care Trust;   Queen's University, Belfast Completed
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
Condition:   Cystic Fibrosis Intervention:   Device: Fitbit Tracker Sponsors:   Medical College of Wisconsin;   Cystic Fibrosis Foundation Not yet recruiting
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
Gene Therapy, Published online: 12 July 2019; doi:10.1038/s41434-019-0092-5Beyond cystic fibrosis transmembrane conductance regulator therapy: a perspective on gene therapy and small molecule treatment for cystic fibrosis
Source: Gene Therapy - Category: Genetics & Stem Cells Authors: Source Type: research
Condition:   Cystic Fibrosis Intervention:   Sponsors:   Belfast Health and Social Care Trust;   Queen's University, Belfast Recruiting
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
Conditions:   Cystic Fibrosis;   Death;   Lung Transplantation Intervention:   Diagnostic Test: Lung function testing Sponsors:   University Hospital Inselspital, Berne;   Lindenhofspital Completed
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
More News: Biology | Biomedical Science | Cystic Fibrosis | Molecular Biology | Nanotechnology | Study