A novel triple combination of pharmacological chaperones improves F508del-CFTR correction View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-07-30

AUTHORS

Graeme W. Carlile, Qi Yang, Elizabeth Matthes, Jie Liao, Stevo Radinovic, Carol Miyamoto, Renaud Robert, John W. Hanrahan, David Y. Thomas

ABSTRACT

Pharmacological chaperones (e.g. VX-809, lumacaftor) that bind directly to F508del-CFTR and correct its mislocalization are promising therapeutics for Cystic Fibrosis (CF). However to date, individual correctors provide only ~4% improvement in lung function measured as FEV1, suggesting that multiple drugs will be needed to achieve substantial clinical benefit. Here we examine if multiple sites for pharmacological chaperones exist and can be targeted to enhance the rescue of F508del-CFTR with the premise that additive or synergistic rescue by multiple pharmacological chaperones compared to single correctors indicates that they have different sites of action. First, we found that a combination of the pharmacological chaperones VX-809 and RDR1 provide additive correction of F508del-CFTR. Then using cellular thermal stability assays (CETSA) we demonstrated the possibility of a third pharmacologically important site using the novel pharmacological chaperone tool compound 4-methyl-N-[3-(morpholin-4-yl) quinoxalin-2-yl] benzenesulfonamide (MCG1516A). All three pharmacological chaperones appear to interact with the first nucleotide-binding domain (NBD1). The triple combination of MCG1516A, RDR1, and VX-809 restored CFTR function to >20% that of non-CF cells in well differentiated HBE cells and to much higher levels in other cell types. Thus the results suggest the presence of at least three distinct sites for pharmacological chaperones on F508del-CFTR NBD1, encouraging the development of triple corrector combinations. More... »

PAGES

11404

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-018-29276-y

DOI

http://dx.doi.org/10.1038/s41598-018-29276-y

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1105814150

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30061653


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