pyrimidinones and Cystic-Fibrosis

Deletion of phenylalanine at position 508 (F508del) in the CFTR protein, is the most common mutation causing cystic fibrosis (CF). F508del causes misfolding and rapid degradation of CFTR protein a defect that can be targeted with pharmacological agents termed "correctors". Correctors belong to various chemical classes but are generally small molecules based on nitrogen sulfur or oxygen heterocycles. The mechanism of action of correctors is generally unknown but there is experimental evidence that some of them can directly act on mutant CFTR improving folding and stability. Here we overview the characteristics of the various F508del correctors described so far to obtain indications on key chemical structures and modifications that are required for mutant protein rescue.

Topics: Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Protein Folding; Pyrimidinones; Thiazoles

The most common cause of cystic fibrosis (CF) is deletion of phenylalanine 508 (DeltaF508) in the CF transmembrane conductance regulator (CFTR) chloride channel. The DeltaF508 mutation produces defects in folding, stability, and channel gating. To identify small-molecule correctors of defective cellular processing, we assayed iodide flux in DeltaF508-CFTR-transfected epithelial cells using a fluorescent halide indicator. Screening of 150,000 chemically diverse compounds and more than 1,500 analogs of active compounds yielded several classes of DeltaF508-CFTR correctors (aminoarylthiazoles, quinazolinylaminopyrimidinones, and bisaminomethylbithiazoles) with micromolar potency that produced greater apical membrane chloride current than did low-temperature rescue. Correction was seen within 3-6 hours and persisted for more than 12 hours after washout. Functional correction was correlated with plasma membrane expression of complex-glycosylated DeltaF508-CFTR protein. Biochemical studies suggested a mechanism of action involving improved DeltaF508-CFTR folding at the ER and stability at the cell surface. The bisaminomethylbithiazoles corrected DeltaF508-CFTR in DeltaF508/DeltaF508 human bronchial epithelia but did not correct a different temperature-sensitive CFTR mutant (P574H-CFTR) or a dopamine receptor mutant. Small-molecule correctors may be useful in the treatment of CF caused by the DeltaF508 mutation.

Topics: Animals; Cells, Cultured; Colforsin; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Design; Enzyme Inhibitors; Epithelial Cells; Genistein; Humans; Iodides; Luminescent Proteins; Molecular Structure; Mutation; Pyrimidinones; Respiratory Mucosa; Thiazoles