A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion

• Type of Material: Article
• Authors: Jyoti Sharma, University of Alabama; Ming Du, University of Alabama; Eric Wong, Cystic Fibrosis Foundation; Venkateshwar Mutyam, University of Alabama; Yao Li, University of Alabama; Jianguo Chen, University of Alabama; Jamie Wangen, Johns Hopkins University; Kari Thrasher, University of Alabama; Lianwu Fu, University of Alabama; Ning Peng, University of Alabama; Liping Tang, University of Alabama; Kaimao Liu, University of Alabama; Bini Mathew, Southern Research; Robert J. Bostwick, Southern Research; Corinne E. Augelli-Szafran, Southern Research; Hermann Bihler, Cystic Fibrosis Foundation; Feng Liang, Cystic Fibrosis Foundation; Jerome Mahiou, Cystic Fibrosis Foundation; Josef Saltz, Cystic Fibrosis Foundation; Andras Rab, Emory University; Jeong Hong, Emory University; Eric Sorscher, Emory University; Eric M. Mendenhall, University of Alabama Huntsville; Candice J. Coppola, University of Alabama Huntsville; Kim M. Keeling, University of Alabama; Rachel Green, Johns Hopkins University; Martin Mense, Cystic Fibrosis Foundation; Mark J. Suto, Southern Research; Steven M. Rowe, University of Alabama; David M. Bedwell, University of Alabama
• Language: English
• Date: 2021-07-16
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-021-24575-x
• Title of Journal or Parent Work: Nature Communications
• Volume: 12
• Keywords: Molecular medicine; RNA; RNA decay; Cystic fibrosis
• Research Categories: Biology, Genetics; Biology, Molecular

Abstract

Premature termination codons (PTCs) prevent translation of a full-length protein and trigger nonsense-mediated mRNA decay (NMD). Nonsense suppression (also termed readthrough) therapy restores protein function by selectively suppressing translation termination at PTCs. Poor efficacy of current readthrough agents prompted us to search for better compounds. An NMD-sensitive NanoLuc readthrough reporter was used to screen 771,345 compounds. Among the 180 compounds identified with readthrough activity, SRI-37240 and its more potent derivative SRI-41315, induce a prolonged pause at stop codons and suppress PTCs associated with cystic fibrosis in immortalized and primary human bronchial epithelial cells, restoring CFTR expression and function. SRI-41315 suppresses PTCs by reducing the abundance of the termination factor eRF1. SRI-41315 also potentiates aminoglycoside-mediated readthrough, leading to synergistic increases in CFTR activity. Combining readthrough agents that target distinct components of the translation machinery is a promising treatment strategy for diseases caused by PTCs.