Evaluation of aminopyrrolidine amide to improve chloride transport in CFTR-defective cells. (15th September 2022)

• Record Type: Journal Article
• Authors: Huguet, Florentin; Guellec, Julie; Kerbiriou, Mathieu; Gandy, Maxime; Thomas, Johan; Férec, Claude; Benz, Nathalie; Trouvé, Pascal
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 72(2022)
• Publication Date: 2022-09-15
• Subjects: ATF6 Activating Transcription Factor 6 -- S1P Site-1 Protease -- UPR Unfolded Protein Response -- CF Cystic Fibrosis -- CFTR Cystic Fibrosis Transmembrane conductance Regulator; Aminopyrrolidine amide (PF-429242) -- ATF6 -- S1P -- UPR -- CFTR; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128866
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The aminopyrrolidine amide PF-429242 is a specific inhibitor of the Site-1 Protease which is responsible for the cleavage, and thus the activation of the Activating Transcription Factor 6 that down regulates many genes, during the Unfolded Protein Response. We hypothesized that PF-429242 could be used to prevent the ATF6-dependent down regulation of some genes. We chose the CFTR gene encoding the CFTR chloride channel as a model because it is down-regulated by ATF6 in Cystic Fibrosis. We evaluated the action of PF-429242 in human bronchial cells expressing the most frequent mutation of CFTR (p.Phe508del) found in patients. We observed that PF-429242 increases the synthesis of the mRNA and the protein encoded by the CFTR gene harbouring the mutation. We also observed that PF-429242 alleviates the defects of the p.Phe508del-CFTR channel in human Cystic Fibrosis cells. Our results suggest that aminopyrrolidine amide is a potential therapeutic target for Cystic Fibrosis that could also have beneficial effects in other diseases involving CFTR, such as the Chronic Obstructive Pulmonary Disease.