title: RNF5, DAB2 and Friends: Novel Drug Targets for Cystic Fibrosis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.forename: Elvira
authors.initials: E
authors.lastname: Sondo
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pesce
authors.forename: Valeria
authors.initials: V
authors.lastname: Tomati
authors.forename: Monica
authors.initials: M
authors.lastname: Marini
authors.affiliation: U.O.C. Genetica Medica, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Pedemonte
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C111501:RNF5 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: CFTR; chaperone; chloride secretion; corrector; drug therapy; proteostasis; trafficking