Novel Approaches for Potential Therapy of Cystic Fibrosis

Curr Drug Targets. 2015;16(9):923-36. doi: 10.2174/1389450116666150102113314.

Abstract

Cystic fibrosis (CF) is a lethal autosomal recessive disease that causes severe damage to the respiratory and digestive systems. It results from a dysfunctional CF Transmembrane Conductance Regulator (CFTR) protein, which is a cAMP- regulated epithelial chloride channel. CFTR is also a subtype of the ABC-transporter superfamily, and is expressed primarily in the apical membrane of epithelial cells in the airways, pancreas, and intestines. A single amino acid deletion of phenylalanine (Phe) is the most common mutation in CF patients known as F508del-CFTR. Normally, wild-type CFTR is largely degraded before reaching the cell membrane and F508del-CFTR virtually never reaches the cell surface. Ultimately, our goal is to correct dysfunctional CFTR proteins in CF patients. Via high-throughput screening techniques, several novel compounds for potential drugs effective in reversing the molecular CF defect and prohibiting further progression of CF have recently been discovered. S-nitrosothiols (SNOs) are small, naturally occurring endogenous cell signaling compounds, which have potential relevance to human lung diseases, including CF. Remarkably, researchers have found that the level of SNOs are reduced in the CF airway. It was previously reported that different types of SNOs, such as GSNO and S-nitrosoglutathione diethyl ester will increase CFTR maturation and function at the plasma membrane in human airway epithelial cells. The mechanisms by which SNOs improve CFTR maturation remain elusive. Currently, clinical trials are still investigating the effectiveness and safety of novel corrector and potentiator drugs for F508del- CFTR. This review article offers a summary of our knowledge on the most up-to-date CF therapies.

Publication types

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

MeSH terms

  • Clinical Trials as Topic
  • Cystic Fibrosis / drug therapy*
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / pathology
  • Cystic Fibrosis Transmembrane Conductance Regulator / chemistry
  • Cystic Fibrosis Transmembrane Conductance Regulator / drug effects
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Humans
  • Molecular Targeted Therapy / methods*
  • Protein Folding / drug effects
  • Protein Transport / drug effects
  • S-Nitrosothiols / pharmacology
  • S-Nitrosothiols / therapeutic use*
  • Sequence Deletion

Substances

  • CFTR protein, human
  • S-Nitrosothiols
  • Cystic Fibrosis Transmembrane Conductance Regulator