May 15, 2018

Pharmacological Inhibition of the Ubiquitin Ligase RNF5 Rescues F508del-CFTR in Cystic Fibrosis Airway Epithelia

Cell Chemical Biology
Elvira SondoNicoletta Pedemonte

Abstract

In cystic fibrosis (CF), deletion of phenylalanine 508 (F508del) in the CFTR channel is associated with misfolding and premature degradation of the mutant protein. Among the known proteins associated with F508del-CFTR processing, the ubiquitin ligase RNF5/RMA1 is particularly interesting. We previously demonstrated that genetic suppression of RNF5 in vivo leads to an attenuation of intestinal pathological phenotypes in CF mice, validating the relevance of RNF5 as a drug target for CF. Here, we used a computational approach, based on ligand docking and virtual screening, to discover inh-02, a drug-like small molecule that inhibits RNF5. In in vitro experiments, treatment with inh-02 modulated ATG4B and paxillin, both known RNF5 targets. In immortalized and primary bronchial epithelial cells derived from CF patients homozygous for the F508del mutation, long-term incubation with inh-02 caused significant F508del-CFTR rescue. This work validates RNF5 as a drug target for CF, providing evidence to support its druggability.

  • References
  • Citations2

References

  • We're still populating references for this paper, please check back later.
  • References
  • Citations2

Citations

Mentioned in this Paper

In Vivo
Cratoxylum formosum
Bronchial System
RNF5
RNF5 gene
Apoptosis, Intrinsic Pathway
Cftr
Structure-Activity Relationship
CFTR protein, human
Ubiquitin

Related Feeds

Allergy and Asthma

Allergy and asthma are inflammatory disorders that are triggered by the activation of an allergen-specific regulatory t cell. These t cells become activated when allergens are recognized by allergen-presenting cells. Here is the latest research on allergy and asthma.

CFTR Mutant Structural Therapy

Over 1700 different mutations in the CFTR genes have been shown to cause cystic fibrosis. Here is the latest research on structural therapy for CFTR mutants.

Asthma

This feed focuses in Asthma in which your airways narrow and swell. This can make breathing difficult and trigger coughing, wheezing and shortness of breath.