Improved correction of F508del-CFTR biogenesis with a folding facilitator and an inhibitor of protein ubiquitination

• Type of Material: Article
• Authors: Jennifer L Goeckeler-Fried, University of Pittsburgh; Rajiah A Denny, Pfizer Inc; Disha Joshi, Emory University; Clare Hill, University of Pittsburgh; Mads B Larsen, UPMC Childrens Hosp Pittsburgh; Annette N Chiang, University of Pittsburgh; Raymond A Frizzell, UPMC Childrens Hosp Pittsburgh; Peter Wipf, University of Pittsburgh; Eric Sorscher, Emory University; Jeffrey L Brodsky, University of Pittsburgh
• Language: English
• Date: 2021-07-14
• Publisher: PERGAMON-ELSEVIER SCIENCE LTD
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 Elsevier Ltd. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bmcl.2021.128243
• Title of Journal or Parent Work: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• Volume: 48
• Start Page: 128243
• End Page: 128243
• Grant/Funding Information: This work was supported by National Institutes of Health grants GM131732 and DK079307 and grant BRODSK18G0 from the Cystic Fibrosis Foundation to J.L.B., by National Institutes of Health grant HL139876 to E.J.S., and by National Institutes of Health grant DK068196 and grant FRIZZE13XX0 from the Cystic Fibrosis Foundation to R.A.F.
• Keywords: Ubiquitin; CYSTIC-FIBROSIS; Proteasome; ERAD; Protein folding; PROTEASOME; Structure-activity relationship; E1 ubiquitin activating enzyme; Protein degradation; Physical Sciences; TRANSMEMBRANE CONDUCTANCE REGULATOR; Chemistry, Medicinal; PHENOTYPE; E1; DEGRADATION; Chemistry, Organic; Cystic fibrosis; Chemistry; Life Sciences & Biomedicine; CFTR; Science & Technology; Pharmacology & Pharmacy; Trikafta

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.