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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. 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M.M., E.W., F.L., and H.B. are the employees of the Cystic Fibrosis Foundation. D.M.B. is a paid consultant for PTC Therapeutics, Inc. and Zikani Therapeutics, Inc. S.M.R. reports grants from PTC Therapeutics, grants, personal fees and non-financial support from Vertex Pharmaceuticals Incorporated, grants, personal fees and non-financial support from Novartis, grants from Eloxx, and grants from Galapagos\/Abbvie during the conduct of the study. Grants from Bayer, grants from Forest Research Institute, grants from AstraZeneca, grants from N30\/Nivalis, grants from Galapagos\/AbbVie, grants from Proteostasis, grants and personal fees from Celtaxsys, personal fees from Bayer, personal fees from Renovion, grants and personal fees from Synden\/Synspira, personal fees from Genentech, personal fees and non-financial support from Boeringher Ingelheim, grants from Jannssen, Vivus, Actelion, Johnson and Johnson, and other related entities are outside the submitted work. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"4358"}}