2. Academic Validation
  3. A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion

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

  • Nat Commun. 2021 Jul 16;12(1):4358. doi: 10.1038/s41467-021-24575-x.
Jyoti Sharma  # 1 2 3,  Ming Du  # 1 4,  Eric Wong 5,  Venkateshwar Mutyam 1 2,  Yao Li 1 2,  Jianguo Chen 1 2,  Jamie Wangen 6,  Kari Thrasher 1 4,  Lianwu Fu 1 7,  Ning Peng 1 2,  Liping Tang 1 2,  Kaimao Liu 1 4,  Bini Mathew 8,  Robert J Bostwick 8,  Corinne E Augelli-Szafran 8,  Hermann Bihler 5,  Feng Liang 5,  Jerome Mahiou 5,  Josef Saltz 5,  Andras Rab 9,  Jeong Hong 9,  Eric J Sorscher 9,  Eric M Mendenhall 10,  Candice J Coppola 10,  Kim M Keeling 1 4,  Rachel Green 6,  Martin Mense 5,  Mark J Suto 8,  Steven M Rowe 1 2 11,  David M Bedwell 12 13
Affiliations

Affiliations

  • 1 Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
  • 2 Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
  • 3 Department of Microbiology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
  • 4 Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
  • 5 CFFT Lab, Cystic Fibrosis Foundation, Lexington, MA, USA.
  • 6 Department of Molecular Biology and Genetics and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 7 Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
  • 8 Southern Research, Birmingham, AL, USA.
  • 9 Department of Pediatrics, Emory University, Atlanta, Georgia.
  • 10 Department of Biological Sciences, The University of Alabama in Huntsville, Huntsville, AL, USA.
  • 11 Department of Pediatrics, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
  • 12 Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham (UAB), Birmingham, AL, USA. dbedwell@uab.edu.
  • 13 Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham (UAB), Birmingham, AL, USA. dbedwell@uab.edu.
  • # Contributed equally.
PMID: 34272367 DOI: 10.1038/s41467-021-24575-x
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.

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