RNF5, DAB2 and Friends: Novel Drug Targets for Cystic Fibrosis

Title:RNF5, DAB2 and Friends: Novel Drug Targets for Cystic Fibrosis

Volume: 23 Issue: 1

Author(s): Elvira Sondo, Emanuela Pesce, Valeria Tomati, Monica Marini and Nicoletta Pedemonte

Affiliation:

Keywords: CFTR, drug therapy, proteostasis, corrector, chaperone, chloride secretion, trafficking.

Abstract: 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 regulator.

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.

Cite this article as:

Sondo Elvira, Pesce Emanuela, Tomati Valeria, Marini Monica and Pedemonte Nicoletta, RNF5, DAB2 and Friends: Novel Drug Targets for Cystic Fibrosis, Current Pharmaceutical Design 2017; 23 (1) . https://dx.doi.org/10.2174/1381612822666161006161033

DOI https://dx.doi.org/10.2174/1381612822666161006161033	Print ISSN 1381-6128
Publisher Name Bentham Science Publisher	Online ISSN 1873-4286