Improved correction of F508del-CFTR biogenesis with a folding facilitator and an inhibitor of protein ubiquitination. (15th September 2021)

• Record Type: Journal Article
• Authors: Goeckeler-Fried, Jennifer L.; Aldrin Denny, Rajiah; Joshi, Disha; Hill, Clare; Larsen, Mads B.; Chiang, Annette N.; Frizzell, Raymond A.; Wipf, Peter; Sorscher, Eric J.; Brodsky, Jeffrey L.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 48(2021)
• Publication Date: 2021-09-15
• Subjects: Cystic fibrosis -- CFTR -- ERAD -- Ubiquitin -- Protein folding -- Protein degradation -- E1 ubiquitin activating enzyme -- Trikafta -- Proteasome -- Structure-activity relationship; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.128243
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A growing number of diseases are linked to the misfolding of integral membrane proteins, and many of these proteins are targeted for ubiquitin-proteasome-dependent degradation. One such substrate is a mutant form of the Cystic Fibrosis Transmembrane Conductance Regulator (F508del-CFTR). Protein folding "correctors" that repair the F508del-CFTR folding defect have entered the clinic, but they are unlikely to protect the entire protein from degradation. To increase the pool of F508del-CFTR protein that is available for correction by existing treatments, we determined a structure-activity relationship to improve the efficacy and reduce the toxicity of an inhibitor of the E1 ubiquitin activating enzyme that facilitates F508del-CFTR maturation. A resulting lead compound lacked measurable toxicity and improved the ability of an FDA-approved corrector to augment F508del-CFTR folding, transport the protein to the plasma membrane, and maintain its activity. These data support a proof-of-concept that modest inhibition of substrate ubiquitination improves the activity of small molecule correctors to treat CF and potentially other protein conformational disorders.