The NSAID glafenine rescues class 2 CFTR mutants via cyclooxygenase 2 inhibition of the arachidonic acid pathway.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
17 03 2022
17 03 2022
Historique:
received:
09
11
2021
accepted:
09
03
2022
entrez:
18
3
2022
pubmed:
19
3
2022
medline:
6
5
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35302062
doi: 10.1038/s41598-022-08661-8
pii: 10.1038/s41598-022-08661-8
pmc: PMC8930988
doi:
Substances chimiques
Anti-Inflammatory Agents, Non-Steroidal
0
CFTR protein, human
0
Cystic Fibrosis Transmembrane Conductance Regulator
126880-72-6
Arachidonic Acid
27YG812J1I
Glafenine
46HL4I09AH
Cyclooxygenase 2
EC 1.14.99.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4595Subventions
Organisme : CIHR
ID : MOP-119341
Pays : Canada
Organisme : CIHR
ID : MOP-287879
Pays : Canada
Organisme : CIHR
ID : PJT-156183
Pays : Canada
Informations de copyright
© 2022. The Author(s).
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