Novel tricyclic pyrrolo-quinolines as pharmacological correctors of the mutant CFTR chloride channel.

F508del, the most frequent mutation in cystic fibrosis (CF), impairs the stability and folding of the CFTR chloride channel, thus resulting in intracellular retention and CFTR degradation. The F508del defect can be targeted with pharmacological correctors, such as VX-809 and VX-445, that stabilize CFTR and improve its trafficking to plasma membrane. Using a functional test to evaluate a panel of chemical compounds, we have identified tricyclic pyrrolo-quinolines as novel F508del correctors with high efficacy on primary airway epithelial cells from CF patients.

Functional restoration of a CFTR splicing mutation through RNA delivery of CRISPR adenine base editor.

Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The 2789+5G>A CFTR mutation is a quite frequent defect causing an aberrant splicing and a non-functional CFTR protein. Here we used a CRISPR adenine base editing (ABE) approach to correct the mutation in the absence of DNA double-strand breaks (DSB).

Pharmacological potentiators of the calcium signaling cascade identified by high-throughput screening.

Pharmacological modulators of the Ca signaling cascade are important research tools and may translate into novel therapeutic strategies for a series of human diseases. We carried out a screening of a maximally diverse chemical library using the Ca-sensitive Cl channel TMEM16A as a functional readout. We found compounds that were able to potentiate UTP-dependent TMEM16A activation.

Analysis of inhibitors of the anoctamin-1 chloride channel (transmembrane member 16A, TMEM16A) reveals indirect mechanisms involving alterations in calcium signalling.

Background And Purpose: Pharmacological inhibitors of TMEM16A (ANO1), a Ca -activated Cl channel, are important tools of research and possible therapeutic agents acting on smooth muscle, airway epithelia and cancer cells. We tested a panel of TMEM16A inhibitors, including CaCC -A01, niclosamide, MONNA, Ani9 and niflumic acid, to evaluate their possible effect on intracellular Ca .

Experimental Approach: We recorded cytosolic Ca increase elicited with UTP, ionomycin or IP uncaging.

Airway surface hyperviscosity and defective mucociliary transport by IL-17/TNF-α are corrected by β-adrenergic stimulus.

The fluid covering the surface of airway epithelia represents a first barrier against pathogens. The chemical and physical properties of the airway surface fluid are controlled by the activity of ion channels and transporters. In cystic fibrosis (CF), loss of CFTR chloride channel function causes airway surface dehydration, bacterial infection, and inflammation.