Open AccessCyclic Peptidyl Inhibitors against CAL/CFTR Interaction for Treatment of Cystic Fibrosis
Author(s) -
Patrick G Dougherty,
Jack Wellmerling,
Amritendu Koley,
Jessica Lukowski,
Amanda B. Hummon,
Estelle CormetBoyaka,
Dehua Pei
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01528
Subject(s) - potentiator , cystic fibrosis , cystic fibrosis transmembrane conductance regulator , chemistry , pdz domain , chloride channel , ligand (biochemistry) , small molecule , biophysics , biochemistry , pharmacology , gene , medicine , receptor , biology
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 ∼3-fold and further potentiated the therapeutic effects of small-molecule correctors (e.g., VX-661) by ∼2-fold (with an EC 50 of ∼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.