Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Genes (Basel). 2020 May 13;11(5):546. doi: 10.3390/genes11050546.


Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The diversity of mutations and the multiple ways by which the protein is affected present challenges for therapeutic development. The observation that the Phe508del-CFTR mutant protein is temperature sensitive provided proof of principle that mutant CFTR could escape proteosomal degradation and retain partial function. Several specific protein interactors and quality control checkpoints encountered by CFTR during its proteostasis have been investigated for therapeutic purposes, but remain incompletely understood. Furthermore, pharmacological manipulation of many CFTR interactors has not been thoroughly investigated for the rescue of Phe508del-CFTR. However, high-throughput screening technologies helped identify several small molecule modulators that rescue CFTR from proteosomal degradation and restore partial function to the protein. Here, we discuss the current state of CFTR transcriptomic and biogenesis research and small molecule therapy development. We also review recent progress in CFTR proteostasis modulators and discuss how such treatments could complement current FDA-approved small molecules.

Keywords: CFTR; cystic fibrosis; drug development; proteostasis; small molecules; transcriptomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Binding Sites
  • Clinical Trials as Topic
  • Cystic Fibrosis / drug therapy*
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / chemistry
  • Cystic Fibrosis Transmembrane Conductance Regulator / drug effects
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Drug Discovery*
  • Endoplasmic Reticulum Stress
  • High-Throughput Screening Assays
  • Humans
  • Ion Channel Gating / genetics
  • Models, Molecular
  • Molecular Chaperones / metabolism
  • Mutation*
  • Protein Conformation
  • Protein Domains
  • Protein Folding
  • Protein Stability
  • Protein Transport
  • Proteostasis* / drug effects
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics
  • RNA, Untranslated / genetics
  • Sequence Deletion
  • Structure-Activity Relationship
  • Transcriptome*
  • Ubiquitin-Protein Ligases / metabolism


  • CFTR protein, human
  • Molecular Chaperones
  • RNA, Messenger
  • RNA, Untranslated
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Ubiquitin-Protein Ligases