Cyclic Peptidyl Inhibitors Against Cal/Cftr Interaction For Treatment Of Cystic Fibrosis

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, encoding for a chloride ion channel. Membrane expression of CFTR is negatively regulated by CFTR-associated ligand (CAL). We previously showed that inhibition of the CFTR/CAL interaction with a cell-permeable peptide improves the function of rescued F508del-CFTR. In this study, optimization of the peptidyl inhibitor yielded PGD97, which exhibits a K-D value of 6 nM for the CAL PDZ domain, >= 130-fold selectivity over closely related PDZ domains, and a serum t(1/2) of >24 h. In patient-derived F508del homozygous cells, PGD97 (100 nM) increased short-circuit currents by similar to 3-fold and further potentiated the therapeutic effects of small-molecule correctors (e.g., VX-661) by similar to 2-fold (with an EC50 of similar to 10 nM). Our results suggest that PGD97 may be used as a novel treatment for CF, either as a single agent or in combination with small-molecule correctors/potentiators.