Carlile, Graeme W., Yang, Qi, Matthes, Elizabeth et al. (7 more authors) (2022) The NSAID glafenine rescues class 2 CFTR mutants via cyclooxygenase 2 inhibition of the arachidonic acid pathway. Scientific reports. 4595. ISSN 2045-2322
Abstract
Most cases of cystic fibrosis (CF) are caused by class 2 mutations in the cystic fibrosis transmembrane regulator (CFTR). These proteins preserve some channel function but are retained in the endoplasmic reticulum (ER). Partial rescue of the most common CFTR class 2 mutant, F508del-CFTR, has been achieved through the development of pharmacological chaperones (Tezacaftor and Elexacaftor) that bind CFTR directly. However, it is not clear whether these drugs will rescue all class 2 CFTR mutants to a medically relevant level. We have previously shown that the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen can correct F508del-CFTR trafficking. Here, we utilized RNAi and pharmacological inhibitors to determine the mechanism of action of the NSAID glafenine. Using cellular thermal stability assays (CETSAs), we show that it is a proteostasis modulator. Using medicinal chemistry, we identified a derivative with a fourfold increase in CFTR corrector potency. Furthermore, we show that these novel arachidonic acid pathway inhibitors can rescue difficult-to-correct class 2 mutants, such as G85E-CFTR > 13%, that of non-CF cells in well-differentiated HBE cells. Thus, the results suggest that targeting the arachidonic acid pathway may be a profitable way of developing correctors of certain previously hard-to-correct class 2 CFTR mutations.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Funding Information: The work was supported by grants from the Canadian Institutes of Health Research to D.Y. T (MOP-119341), JH (MOP-287879), and J.W.H. and D.Y.T. (PJT-156183), Cystic Fibrosis Canada (#561848) and by funding from Cystic Fib Canada for the Primary Airway Cell Biobank at the McGill CF Translational Research Center (CFTRc). Publisher Copyright: © 2022, The Author(s). |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) |
Depositing User: | Pure (York) |
Date Deposited: | 15 Feb 2023 11:10 |
Last Modified: | 18 Dec 2024 00:23 |
Published Version: | https://doi.org/10.1038/s41598-022-08661-8 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1038/s41598-022-08661-8 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:196427 |
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Description: The NSAID glafenine rescues class 2 CFTR mutants via cyclooxygenase 2 inhibition of the arachidonic acid pathway
Licence: CC-BY 2.5