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

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

Journal Name: Current Pharmaceutical Design

Volume 23 , Issue 1 , 2017

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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.

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

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Article Details

Year: 2017
Page: [176 - 186]
Pages: 11
DOI: 10.2174/1381612822666161006161033
Price: $58

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