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

doi:10.1016/j.chembiol.2010.11.016

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

Pathology

Research output: Contribution to journal › Article › peer-review

90 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 language	English (US)
Pages (from-to)	231-242
Number of pages	12
Journal	Chemistry and Biology
Volume	18
Issue number	2
DOIs	https://doi.org/10.1016/j.chembiol.2010.11.016
State	Published - Feb 25 2011

Funding

We thank Dr. Phil Thomas at the University of Texas Southwestern Medical Center at Dallas and members of his lab for providing initial purified murine NBD1 deltaF508 and detailed purification protocols, Dr. Jason Young and Anna Fan at McGill for helpful discussions regarding the protein purification, Dr. Masoud Vedadi and colleagues at the Structural Genomics Consortium for training and expertise in DSF. We are grateful to Dr. Hugo de Jonge, Dr. Bob Scholte, and Martina Wilke at Erasmus University for providing the CF F508del mouse model (contact: [email protected]) and for helpful comments on the manuscript, Dr. Robert J. Bridges at Rosalind Franklin University of Medicine and Science in Chicago and the CFFT for providing CFTR modulator compounds, and Dr. Robert Annan for providing helpful comments on the manuscript. This work was funded by grants from the Canadian Cystic Fibrosis Foundation, Cystic Fibrosis Foundation Therapeutics, Inc., and the Canadian Institutes of Health Research. H.M.S. was supported by a post-doctoral fellowship from the Canadian Cystic Fibrosis Foundation.

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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10.1016/j.chembiol.2010.11.016

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title = "Identification of a NBD1-binding pharmacological chaperone that corrects the trafficking defect of F508del-CFTR",

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.",

author = "Sampson, {Heidi M.} and Renaud Robert and Jie Liao and Elizabeth Matthes and Carlile, {Graeme W.} and Hanrahan, {John W.} and Thomas, {David Y.}",

note = "Funding Information: We thank Dr. Phil Thomas at the University of Texas Southwestern Medical Center at Dallas and members of his lab for providing initial purified murine NBD1 deltaF508 and detailed purification protocols, Dr. Jason Young and Anna Fan at McGill for helpful discussions regarding the protein purification, Dr. Masoud Vedadi and colleagues at the Structural Genomics Consortium for training and expertise in DSF. We are grateful to Dr. Hugo de Jonge, Dr. Bob Scholte, and Martina Wilke at Erasmus University for providing the CF F508del mouse model (contact: [email protected]) and for helpful comments on the manuscript, Dr. Robert J. Bridges at Rosalind Franklin University of Medicine and Science in Chicago and the CFFT for providing CFTR modulator compounds, and Dr. Robert Annan for providing helpful comments on the manuscript. This work was funded by grants from the Canadian Cystic Fibrosis Foundation, Cystic Fibrosis Foundation Therapeutics, Inc., and the Canadian Institutes of Health Research. H.M.S. was supported by a post-doctoral fellowship from the Canadian Cystic Fibrosis Foundation. ",

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AU - Carlile, Graeme W.

AU - Hanrahan, John W.

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N2 - 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.

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

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