Improved correction of F508del-CFTR biogenesis with a folding facilitator and an inhibitor of protein ubiquitination.
Basic Information
ID: ALA5230148
Journal: Bioorg Med Chem Lett
Title: Improved correction of F508del-CFTR biogenesis with a folding facilitator and an inhibitor of protein ubiquitination.
Authors: Goeckeler-Fried JL, Aldrin Denny R, Joshi D, Hill C, Larsen MB, Chiang AN, Frizzell RA, Wipf P, Sorscher EJ, Brodsky JL.
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.
CiteXplore: 34246753
DOI: 10.1016/j.bmcl.2021.128243
Patent ID: ┄