Cyclic Peptidyl Inhibitors against CAL/CFTR Interaction for Treatment of Cystic Fibrosis.
J Med Chem
; 63(24): 15773-15784, 2020 12 24.
Article
em En
| MEDLINE
| ID: mdl-33314931
ABSTRACT
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 KD value of 6 nM for the CAL PDZ domain, ≥ 130-fold selectivity over closely related PDZ domains, and a serum t1/2 of >24 h. In patient-derived F508del homozygous cells, PGD97 (100 nM) increased short-circuit currents by â¼3-fold and further potentiated the therapeutic effects of small-molecule correctors (e.g., VX-661) by â¼2-fold (with an EC50 of â¼10 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos Cíclicos
/
Regulador de Condutância Transmembrana em Fibrose Cística
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2020
Tipo de documento:
Article