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.© 2021. The Author(s).
About The Expert
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
David M Bedwell
References
PubMed
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