A uniquely efficacious type of CFTR corrector with complementary mode of action.
Sci Adv
; 10(9): eadk1814, 2024 Mar.
Article
in En
| MEDLINE
| ID: mdl-38427726
ABSTRACT
Three distinct pharmacological corrector types (I, II, III) with different binding sites and additive behavior only partially rescue the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) folding and trafficking defect observed in cystic fibrosis. We describe uniquely effective, macrocyclic CFTR correctors that were additive to the known corrector types, exerting a complementary "type IV" corrector mechanism. Macrocycles achieved wild-type-like folding efficiency of F508del-CFTR at the endoplasmic reticulum and normalized CFTR currents in reconstituted patient-derived bronchial epithelium. Using photo-activatable macrocycles, docking studies and site-directed mutagenesis a highly probable binding site and pose for type IV correctors was identified in a cavity between lasso helix-1 (Lh1) and transmembrane helix-1 of membrane spanning domain (MSD)-1, distinct from the known corrector binding sites. Since only F508del-CFTR fragments spanning from Lh1 until MSD2 responded to type IV correctors, these likely promote cotranslational assembly of Lh1, MSD1, and MSD2. Previously corrector-resistant CFTR folding mutants were also robustly rescued, suggesting substantial therapeutic potential for type IV correctors.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cystic Fibrosis Transmembrane Conductance Regulator
/
Cystic Fibrosis
Limits:
Humans
Language:
En
Journal:
Sci Adv
Year:
2024
Document type:
Article
Affiliation country:
Switzerland
Country of publication:
United States