scholarly journals Pore-forming small molecules offer a promising way to tackle cystic fibrosis

Nature ◽  
2019 ◽  
Vol 567 (7748) ◽  
pp. 315-317 ◽  
Author(s):  
David N. Sheppard ◽  
Anthony P. Davis
Keyword(s):  
Cystic Fibrosis ◽  
Small Molecules

scholarly journals Insulin signaling via the PI3-kinase/Akt pathway regulates airway glucose uptake and barrier function in a CFTR-dependent manner

2017 ◽  
Vol 312 (5) ◽  
pp. L688-L702 ◽  
Author(s):  
Samuel A. Molina ◽  
Hannah K. Moriarty ◽  
Daniel T. Infield ◽  
Barry R. Imhoff ◽  
Rachel J. Vance ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Small Molecules ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Airway Epithelia ◽  
Human Airway ◽  
Airway Cells

Cystic fibrosis-related diabetes is the most common comorbidity associated with cystic fibrosis (CF) and correlates with increased rates of lung function decline. Because glucose is a nutrient present in the airways of patients with bacterial airway infections and because insulin controls glucose metabolism, the effect of insulin on CF airway epithelia was investigated to determine the role of insulin receptors and glucose transport in regulating glucose availability in the airway. The response to insulin by human airway epithelial cells was characterized by quantitative PCR, immunoblot, immunofluorescence, and glucose uptake assays. Phosphatidylinositol 3-kinase/protein kinase B (Akt) signaling and cystic fibrosis transmembrane conductance regulator (CFTR) activity were analyzed by pharmacological and immunoblot assays. We found that normal human primary airway epithelial cells expressed glucose transporter 4 and that application of insulin stimulated cytochalasin B-inhibitable glucose uptake, consistent with a requirement for glucose transporter translocation. Application of insulin to normal primary human airway epithelial cells promoted airway barrier function as demonstrated by increased transepithelial electrical resistance and decreased paracellular flux of small molecules. This provides the first demonstration that airway cells express insulin-regulated glucose transporters that act in concert with tight junctions to form an airway glucose barrier. However, insulin failed to increase glucose uptake or decrease paracellular flux of small molecules in human airway epithelia expressing F508del-CFTR. Insulin stimulation of Akt1 and Akt2 signaling in CF airway cells was diminished compared with that observed in airway cells expressing wild-type CFTR. These results indicate that the airway glucose barrier is regulated by insulin and is dysfunctional in CF.

Rescue of ΔF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules

2006 ◽  
Vol 290 (6) ◽  
pp. L1117-L1130 ◽  
Author(s):  
Fredrick Van Goor ◽  
Kimberly S. Straley ◽  
Dong Cao ◽  
Jesús González ◽  
Sabine Hadida ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Small Molecules ◽  
Fluid Transport ◽  
Single Channel ◽  
Primary Cultures ◽  
Genetic Defect ◽  
Common Mutation ◽  
Compound Libraries ◽  
Epithelial Cultures ◽  
Δf508 Cftr

Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in cftr, a gene encoding a PKA-regulated Cl− channel. The most common mutation results in a deletion of phenylalanine at position 508 (ΔF508-CFTR) that impairs protein folding, trafficking, and channel gating in epithelial cells. In the airway, these defects alter salt and fluid transport, leading to chronic infection, inflammation, and loss of lung function. There are no drugs that specifically target mutant CFTR, and optimal treatment of CF may require repair of both the folding and gating defects. Here, we describe two classes of novel, potent small molecules identified from screening compound libraries that restore the function of ΔF508-CFTR in both recombinant cells and cultures of human bronchial epithelia isolated from CF patients. The first class partially corrects the trafficking defect by facilitating exit from the endoplasmic reticulum and restores ΔF508-CFTR-mediated Cl− transport to more than 10% of that observed in non-CF human bronchial epithelial cultures, a level expected to result in a clinical benefit in CF patients. The second class of compounds potentiates cAMP-mediated gating of ΔF508-CFTR and achieves single-channel activity similar to wild-type CFTR. The CFTR-activating effects of the two mechanisms are additive and support the rationale of a drug discovery strategy based on rescue of the basic genetic defect responsible for CF.

scholarly journals Integrative chemogenomic analysis identifies small molecules that partially rescue ΔF508‐CFTR for cystic fibrosis

2021 ◽  
Author(s):  
Rachel A. Hodos ◽  
Matthew D. Strub ◽  
Shyam Ramachandran ◽  
Ella A. Meleshkevitch ◽  
Dmitri Y. Boudko ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Small Molecules ◽  
Δf508 Cftr

scholarly journals Small molecules with antibiofilm, antivirulence and antibiotic synergy activities againstPseudomonas aeruginosa

2016 ◽  
Author(s):  
Erik van Tilburg Bernardes ◽  
Laetitia Charron-Mazenod ◽  
David Reading ◽  
Shauna L. Reckseidler-Zenteno ◽  
Shawn Lewenza
Keyword(s):  
Cystic Fibrosis ◽  
Extracellular Matrix ◽  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Small Molecules ◽  
Biofilm Formation ◽  
Chronic Infections ◽  
Term Survival ◽  
Lung Infections

AbstractBiofilm formation is a universal bacterial strategy for long-term survival in nature and during infections. Biofilms are dense microbial communities enmeshed within a polymeric extracellular matrix that protects bacteria from antibiotic exposure and the immune system and thus contribute to chronic infections.Pseudomonas aeruginosais an archetypal biofilm-forming organism that utilizes a biofilm growth strategy to cause chronic lung infections in Cystic Fibrosis (CF) patients. The extracellular matrix ofP. aeruginosabiofilms is comprised mainly of exopolysaccharides (EPS) and DNA. Both mucoid and non-mucoid isolates ofP. aeruginosaproduces the Pel and Psl EPS, each of which have important roles in antibiotic resistance, biofilm formation and immune evasion. Given the central importance of the Pel and Psl EPS in biofilm structure, they are attractive targets for novel anti-infective compounds. In this study we used a high throughput gene expression screen to identify compounds that repress expression ofpelandpslgenes as measured by transcriptionalluxfusions. Testing of thepel/pslrepressors demonstrated an antibiofilm activity against microplate and flow chamber biofilms formed by wild type and hyperbiofilm forming strains. To determine the potential role of EPS in virulence, mutants inpel/pslwere shown to have reduced virulence in the feeding behavior and slow killing virulence assays inCaenorhabditis elegans. The antibiofilm molecules also reducedP. aeruginosaPAO1 virulence in the nematode slow killing model. Importantly, the combination of antibiotics and antibiofilm compounds were synergistic in killingP. aeruginosabiofilms. These small molecules represent a novel anti-infective strategy for the possible treatment of chronicP. aeruginosainfections.Author summaryBacteria use the strategy of growing as a biofilm to promote long-term survival and therefore to cause chronic infections. One of the best examples isPseudomonas aeruginosaand the chronic lung infections in individuals with Cystic Fibrosis (CF). Biofilms are generally a dense community of bacteria enmeshed in an extracellular matrix that protects bacteria from numerous environmental stresses, including antibiotics and the immune system. In this study we developed an approach to identifyP. aeruginosabiofilm inhibitors by repressing the production of the matrix exopolysaccharide (EPS) polymers. Bacteria treated with compounds and then fed to the nematode also had showed reduced virulence by promoting nematode survival. To tackle the problem of biofilm tolerance of antibiotics, the compounds identified here also had the beneficial property of increasing the biofilm sensitivity to different classes of antibiotics. The compounds disarm bacteria but they do not kill or limit growth like antibiotics. We provide further support that disarmingP. aeruginosamay be a critical anti-infective strategy that limits the development of antibiotic resistance, and provides a new way for treating chronic infections.

scholarly journals Use of a High-Throughput Phenotypic Screening Strategy to Identify Amplifiers, a Novel Pharmacological Class of Small Molecules That Exhibit Functional Synergy with Potentiators and Correctors

2017 ◽  
Vol 23 (2) ◽  
pp. 111-121 ◽  
Author(s):  
Kenneth A. Giuliano ◽  
Shinichiro Wachi ◽  
Lawrence Drew ◽  
Danijela Dukovski ◽  
Olivia Green ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Small Molecules ◽  
High Throughput ◽  
Stress Responses ◽  
Genetic Disorder ◽  
Screening Strategy ◽  
New Class ◽  
Cftr Mutations ◽  
Cellular Stress Responses ◽  
Cftr Modulators

Cystic fibrosis (CF) is a lethal genetic disorder caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Despite recent groundbreaking approval of genotype-specific small-molecule drugs, a significant portion of CF patients still lack effective therapeutic options that address the underlying cause of the disease. Through a phenotypic high-throughput screen of approximately 54,000 small molecules, we identified a novel class of CFTR modulators called amplifiers. The identified compound, the characteristics of which are represented here by PTI-CH, selectively increases the expression of immature CFTR protein across different CFTR mutations, including F508del-CFTR, by targeting the inefficiencies of early CFTR biosynthesis. PTI-CH also augments the activity of other CFTR modulators and was found to possess novel characteristics that distinguish it from CFTR potentiator and corrector moieties. The PTI-CH–mediated increase in F508del-CFTR did not elicit cytosolic or endoplasmic reticulum–associated cellular stress responses. Based on these data, amplifiers represent a promising new class of CFTR modulators for the treatment of CF that can be used synergistically with other CFTR modulators.

II. Regulation of CFTR by small molecules including HCO 3 −

1998 ◽  
Vol 275 (6) ◽  
pp. G1221-G1226 ◽  
Author(s):  
Beate Illek ◽  
Horst Fischer ◽  
Terry E. Machen
Keyword(s):  
Cystic Fibrosis ◽  
Small Molecules ◽  
Protein Product ◽  
Mechanisms Of Action ◽  
Intestinal Cells ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Binding Domains ◽  
Cf Transmembrane Conductance Regulator

Cystic fibrosis (CF) affects a number of epithelial tissues, including those in the gastrointestinal tract. The goal of this review is to summarize data related to regulation of the protein product of the CF gene, CF transmembrane conductance regulator (CFTR), by a variety of small molecules. There has been a surge of interest in discovering small molecules that could be exogenously added to cells and tissues to regulate CFTR and could potentially be used alone or in combination with genetic approaches for therapy in CF. We will discuss the apparent mechanisms of action of genistein, milrinone, 8-cyclopentyl-1,3-dipropylxanthine, IBMX, and NS-004; several of which appear to interact directly with one or both nucleotide binding domains of CFTR. We also discuss how [Formula: see text]interacts with CFTR as both a permeating anion and a potential regulator of Cl−permeation through the CFTR ion channel. It is likely that there are complicated interactions between Cl−and[Formula: see text] in the secretion of both ions through the CFTR and the anion exchanger in intestinal cells, and these may yield a role of CFTR in regulation of intestinal[Formula: see text] secretion as well as of intra- and extracellular pH.

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