Despite the encouraging drug discovery results, to date no corrector mechanism of action and no corrector binding site have been defined. For this reason, in this project, a big effort was addressed to the identification of correctors’ binding sites. To achieve results, researchers prepared constructs codifying for WT and mutant F508del N-half of CFTR and expressed them alone or together with the C-half in mammalian cells. Cells preparations were incubated with different correctors (VX809, VX661, corr-4a and VX325) to evaluate the effect of each drug on the expression and stability of the two CFTR halves. The results show that expression and stability of WT N-half of the CFTR protein resulted enhanced by correctors VX809, VX661 and VX325, while only VX809 and VX661 demonstrated able to exert this effect on F508del N-half. Coexpression experiments indicated that the C-half of the CFTR is the main target of corr-4a. Retrieved results confirm that it is possible to quantitatively evaluate the effects of a corrector on each CFTR domain. Complementary approaches such as competition and cross-linking experiments will definitively allow to identify the binding sites of available correctors and provide useful information for the design of better corrector candidates.

Congress abstracts

– Moran O “Correction of the CFTR folding defect: a pessimistic view of the state of the art. Biophysical approaches to protein folding and disease” European Biophysics Societies Association 2017 Satellite Meeting, Edinburgh, United Kingdom, 20-21 July, 2017
– Moran O “Structural insights into the action of CFTR modulators” ECFS Conference, Sevilla, Spain, 7-10 June, 2017