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

Jyoti Sharma, Ming Du, Eric Wong, Venkateshwar Mutyam, Yao Li, Jianguo Chen, Jamie Wangen, Kari Thrasher, Lianwu Fu, Ning Peng, Liping Tang, Kaimao Liu, Bini Mathew, Robert J. Bostwick, Corinne E. Augelli-Szafran, Hermann Bihler, Feng Liang, Jerome Mahiou, Josef Saltz, Andras Rab, Jeong Hong, Eric J. Sorscher, Eric M. Mendenhall, Candice J. Coppola, Kim M. Keeling, Rachel Green, Martin Mense, Mark J. Suto, Steven M. Rowe and David M. Bedwell ()
Additional contact information
Jyoti Sharma: University of Alabama at Birmingham (UAB)
Ming Du: University of Alabama at Birmingham (UAB)
Eric Wong: CFFT Lab, Cystic Fibrosis Foundation
Venkateshwar Mutyam: University of Alabama at Birmingham (UAB)
Yao Li: University of Alabama at Birmingham (UAB)
Jianguo Chen: University of Alabama at Birmingham (UAB)
Jamie Wangen: Johns Hopkins University School of Medicine
Kari Thrasher: University of Alabama at Birmingham (UAB)
Lianwu Fu: University of Alabama at Birmingham (UAB)
Ning Peng: University of Alabama at Birmingham (UAB)
Liping Tang: University of Alabama at Birmingham (UAB)
Kaimao Liu: University of Alabama at Birmingham (UAB)
Bini Mathew: Southern Research
Robert J. Bostwick: Southern Research
Corinne E. Augelli-Szafran: Southern Research
Hermann Bihler: CFFT Lab, Cystic Fibrosis Foundation
Feng Liang: CFFT Lab, Cystic Fibrosis Foundation
Jerome Mahiou: CFFT Lab, Cystic Fibrosis Foundation
Josef Saltz: CFFT Lab, Cystic Fibrosis Foundation
Andras Rab: Emory University
Jeong Hong: Emory University
Eric J. Sorscher: Emory University
Eric M. Mendenhall: The University of Alabama in Huntsville
Candice J. Coppola: The University of Alabama in Huntsville
Kim M. Keeling: University of Alabama at Birmingham (UAB)
Rachel Green: Johns Hopkins University School of Medicine
Martin Mense: CFFT Lab, Cystic Fibrosis Foundation
Mark J. Suto: Southern Research
Steven M. Rowe: University of Alabama at Birmingham (UAB)
David M. Bedwell: University of Alabama at Birmingham (UAB)

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24575-x

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