Better correctors are needed to repair cystic fibrosis transmembrane conductance regulator (CFTR) processing mutants that cause cystic fibrosis. Determining where the correctors bind to CFTR would aid in the development of new correctors. A recent study reported that the second nucleotide-binding domain (NBD2) was involved in binding of bithiazole correctors. Here, we show that bithiazole correctors could also rescue CFTR mutants that lacked NBD2. These results suggest that bithiazoles rescue CFTR mutants by two different mechanisms.
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http://dx.doi.org/10.1021/bi4008758 | DOI Listing |
ACS Med Chem Lett
August 2023
Department of Molecular and Translational Medicine, University of Brescia, viale Europa 11, 25121 Brescia, Italy.
4'-Methyl-4,5'-bithiazoles were previously identified as cystic fibrosis transmembrane regulator (CFTR) correctors, thus being able to correct folding defective mutants of the channel regulating chloride transport through the membrane. Additionally, bithiazole derivative was reported to recover α-sarcoglycan and . We report here the synthesis of two new derivatives of , in which the two sides of the bithiazole scaffold were modified.
View Article and Find Full Text PDFChemMedChem
September 2022
Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze, 27/A, 43124, Parma, Italy.
Molecules
February 2021
Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy.
Cystic fibrosis (CF) is a genetic disease caused by mutations that impair the function of the CFTR chloride channel. The most frequent mutation, F508del, causes misfolding and premature degradation of CFTR protein. This defect can be overcome with pharmacological agents named "correctors".
View Article and Find Full Text PDFInt J Mol Sci
November 2019
Istituto di Biofisica, Consiglio Nazionale delle Ricerche, 16149 Genova, Italy.
Cystic fibrosis (CF) is a genetic disease associated with the defective function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein that causes obstructive disease and chronic bacterial infections in airway epithelia. The most prevalent CF-causing mutation, the deletion of phenylalanine at position 508 (F508del), leads to CFTR misfolding, trafficking defects and premature degradation. A number of correctors that are able to partially rescue F508del-CFTR processing defects have been identified.
View Article and Find Full Text PDFHum Mol Genet
March 2018
Department of Pediatric Pneumology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, German Centre for Lung Research (DZL), 80337 Munich, Germany.
Adenosine triphosphate (ATP)-binding cassette subfamily A member 3 (ABCA3), a phospholipid transporter in lung lamellar bodies (LBs), is essential for the assembly of pulmonary surfactant and LB biogenesis. Mutations in the ABCA3 gene are an important genetic cause for respiratory distress syndrome in neonates and interstitial lung disease in children and adults, for which there is currently no cure. The aim of this study was to prove that disease causing misfolding ABCA3 mutations can be corrected in vitro and to investigate available options for correction.
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