Identification of a NBD1-binding pharmacological chaperone that corrects the trafficking defect of F508del-CFTR

Heidi M. Sampson, Renaud Robert, Jie Liao, Elizabeth Matthes, Graeme W. Carlile, John W. Hanrahan, David Y. Thomas

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

Most cases of cystic fibrosis (CF) are attributable to the F508del allele of CFTR, which causes the protein to be retained in the endoplasmic reticulum (ER) and subsequently degraded. One strategy for CF therapy is to identify corrector compounds that help traffic F508del-CFTR to the cell surface. Pharmacological chaperones, or correctors that bind specifically to F508del-CFTR and restore function, would be the most promising drug development candidates, but few pharmacological chaperones exist for F508del-CFTR. Using differential scanning fluorimetry (DSF), we have surveyed corrector compounds and identified one, RDR1, which binds directly to the first nucleotide binding domain (NBD1) of F508del-CFTR. We show that RDR1 treatment partially rescues F508del-CFTR function in both cells and in an F508del-CF mouse model. Thus, RDR1 is a pharmacological chaperone of F508del-CFTR and represents a novel scaffold for drug development.

Original languageEnglish (US)
Pages (from-to)231-242
Number of pages12
JournalChemistry and Biology
Volume18
Issue number2
DOIs
StatePublished - Feb 25 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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