Odolczyk_2013_EMBO.Mol.Med_5_1484

The deletion of Phe508 (DeltaF508) in the first nucleotide binding domain (NBD1) of CFTR is the most common mutation associated with cystic fibrosis. The DeltaF508-CFTR mutant is recognized as improperly folded and targeted for proteasomal degradation. Based on molecular dynamics simulation results, we hypothesized that interaction between DeltaF508-NBD1 and housekeeping proteins prevents DeltaF508-CFTR delivery to the plasma membrane. Based on this assumption we applied structure-based virtual screening to identify new low-molecular-weight compounds that should bind to DeltaF508-NBD1 and act as protein-protein interaction inhibitors. Using different functional assays for CFTR activity, we demonstrated that in silico-selected compounds induced functional expression of DeltaF508-CFTR in transfected HeLa cells, human bronchial CF cells in primary culture, and in the nasal epithelium of homozygous DeltaF508-CFTR mice. The proposed compounds disrupt keratin8-DeltaF508-CFTR interaction in DeltaF508-CFTR HeLa cells. Structural analysis of DeltaF508-NBD1 in the presence of these compounds suggests their binding to NBD1. We conclude that our strategy leads to the discovery of new compounds that are among the most potent correctors of DeltaF508-CFTR trafficking defect known to date.