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

Elvira Sondo, Emanuela Pesce, Valeria Tomati, Monica Marini, Nicoletta Pedemonte

Research output: Contribution to journalReview article

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.

Original languageEnglish
Pages (from-to)176-186
Number of pages11
JournalCurrent Pharmaceutical Design
Volume23
Issue number1
DOIs
Publication statusPublished - 2017

Fingerprint

Cystic Fibrosis
Molecular Mechanisms of Pharmacological Action
Pharmacology
Drug Therapy
Recycling
Internship and Residency
Phenylalanine
Pharmaceutical Preparations
Cell Membrane
Mutation
Membranes
Proteins

Keywords

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cystic Fibrosis
  • DNA-Binding Proteins
  • Humans
  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases
  • Journal Article
  • Review

Cite this

RNF5, DAB2 and Friends : Novel Drug Targets for Cystic Fibrosis. / Sondo, Elvira; Pesce, Emanuela; Tomati, Valeria; Marini, Monica; Pedemonte, Nicoletta.

In: Current Pharmaceutical Design, Vol. 23, No. 1, 2017, p. 176-186.

Research output: Contribution to journalReview article

Sondo, Elvira ; Pesce, Emanuela ; Tomati, Valeria ; Marini, Monica ; Pedemonte, Nicoletta. / RNF5, DAB2 and Friends : Novel Drug Targets for Cystic Fibrosis. In: Current Pharmaceutical Design. 2017 ; Vol. 23, No. 1. pp. 176-186.
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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.",
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T2 - Novel Drug Targets for Cystic Fibrosis

AU - Sondo, Elvira

AU - Pesce, Emanuela

AU - Tomati, Valeria

AU - Marini, Monica

AU - Pedemonte, Nicoletta

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N2 - 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.

AB - 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.

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