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

Author

Listed:
  • Jyoti Sharma

    (University of Alabama at Birmingham (UAB)
    University of Alabama at Birmingham (UAB)
    University of Alabama at Birmingham (UAB))

  • Ming Du

    (University of Alabama at Birmingham (UAB)
    University of Alabama at Birmingham (UAB))

  • Eric Wong

    (CFFT Lab, Cystic Fibrosis Foundation)

  • Venkateshwar Mutyam

    (University of Alabama at Birmingham (UAB)
    University of Alabama at Birmingham (UAB))

  • Yao Li

    (University of Alabama at Birmingham (UAB)
    University of Alabama at Birmingham (UAB))

  • Jianguo Chen

    (University of Alabama at Birmingham (UAB)
    University of Alabama at Birmingham (UAB))

  • Jamie Wangen

    (Johns Hopkins University School of Medicine)

  • Kari Thrasher

    (University of Alabama at Birmingham (UAB)
    University of Alabama at Birmingham (UAB))

  • Lianwu Fu

    (University of Alabama at Birmingham (UAB)
    University of Alabama at Birmingham (UAB))

  • Ning Peng

    (University of Alabama at Birmingham (UAB)
    University of Alabama at Birmingham (UAB))

  • Liping Tang

    (University of Alabama at Birmingham (UAB)
    University of Alabama at Birmingham (UAB))

  • Kaimao Liu

    (University of Alabama at Birmingham (UAB)
    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)
    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)
    University of Alabama at Birmingham (UAB)
    University of Alabama at Birmingham (UAB))

  • David M. Bedwell

    (University of Alabama at Birmingham (UAB)
    University of Alabama at Birmingham (UAB))

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.

Suggested Citation

  • 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 & , 2021. "A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24575-x
    DOI: 10.1038/s41467-021-24575-x
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    Cited by:

    1. Edward J. Sanderlin & Melissa M. Keenan & Martin Mense & Alexey S. Revenko & Brett P. Monia & Shuling Guo & Lulu Huang, 2022. "CFTR mRNAs with nonsense codons are degraded by the SMG6-mediated endonucleolytic decay pathway," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Nikhil Bharti & Leonardo Santos & Marcos Davyt & Stine Behrmann & Marie Eichholtz & Alejandro Jimenez-Sanchez & Jeong S. Hong & Andras Rab & Eric J. Sorscher & Suki Albers & Zoya Ignatova, 2024. "Translation velocity determines the efficacy of engineered suppressor tRNAs on pathogenic nonsense mutations," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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