Cyclic Peptidyl Inhibitors against CAL/CFTR Interaction for Treatment of Cystic Fibrosis
| Autor: | Amanda B. Hummon, Dehua Pei, Amritendu Koley, Jessica K Lukowski, Estelle Cormet-Boyaka, Jack Wellmerling, Patrick G Dougherty |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Sodium-Hydrogen Exchangers
Cystic Fibrosis Cell Survival Cystic Fibrosis Transmembrane Conductance Regulator PDZ Domains Ligands Bioinformatics Peptides Cyclic Cystic fibrosis Article Permeability Text mining Drug Stability Cell Line Tumor Drug Discovery medicine Humans Amino Acid Sequence Binding Sites Chemistry business.industry Phosphoproteins medicine.disease Molecular Docking Simulation Kinetics Mutation Molecular Medicine business |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c01528 |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|