Background: Deletion of phenylalanine 508 is the most frequent mutation causing
cystic fibrosis. It causes multiple defects: 1) misfolding of the protein causing retention
at the ER (processing defect); 2) reduced channel activity (gating defect); 3) reduced plasma
membrane residency time due to increased internalization rate and defective recycling.
Methods: Druggability of F508del-CFTR was demonstrated by several studies. Correctors
are molecules able to improve maturation and trafficking to the membrane of F508del-
CFTR. Correctors could act as pharmacological chaperones or as proteostasis regulators.
Pharmacological chaperones act directly on mutant CFTR, while proteostasis regulators
modify the proteostasis environment leading to beneficial effects on CFTR maturation.
Results: The use of a single compound is not sufficient to promote a therapeutically relevant
F508del-CFTR rescue. Drug therapy for CF will require combinations of correctors exploiting
different mechanisms of action, i.e. pharmacological chaperones combined together or with a proteostasis
Conclusion: Development of more effective CF drugs could therefore rely on a better understanding of the molecular
events underlying CFTR processing/degradation. This review will focus on most promising pathways and
related targets for the development of novel CF pharmacotherapies.