The synthetic aminoglycoside ELX-02 induces readthrough of G550X-CFTR producing superfunctional protein that can be further enhanced by CFTR modulators
Jianguo Chen, K. Thrasher, Lianwu Fu, Wei Wang, Soheil Aghamohammadzadeh, Hui Wen, Liping Tang, Kim M. Keeling, Emily Falk Libby, David M. Bedwell, Steven M. Rowe
2023American Journal of Physiology-Lung Cellular and Molecular Physiology19 citationsDOIOpen Access PDF
Abstract
We found that forskolin-induced swelling in G550X-CFTR patient-derived intestinal organoids (PDOs) was significantly higher than in G542X-CFTR PDOs after treatment with ELX-02. Tryptophan (W) was the sole amino acid inserted in the G550X position after readthrough. Resulting G550W-CFTR protein exhibited supernormal CFTR activity, PKA sensitivity, and open probability. These results show that aminoglycoside-induced readthrough of G550X produces greater CFTR function because of the gain-of-function properties of the CFTR readthrough product.
Topics & Concepts
Amino acidCystic fibrosisCystic fibrosis transmembrane conductance regulatorTryptophanChemistryArginineMutationAlleleMolecular biologyNonsense mutationWild typeAminoglycosideBiochemistryBiologyGeneticsGeneMutantAntibioticsMissense mutationCystic Fibrosis Research AdvancesBacterial Genetics and BiotechnologyNeonatal Respiratory Health Research