Related Experiment Video

Updated: Oct 28, 2025

Functional Reconstitution and Channel Activity Measurements of Purified Wildtype and Mutant CFTR Protein
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Functional Reconstitution and Channel Activity Measurements of Purified Wildtype and Mutant CFTR Protein

Published on: March 9, 2015

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

Jyoti Sharma1,2,3, Ming Du1,4, Eric Wong5

  • 1Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.

Nature Communications
|July 17, 2021
PubMed

Insights

Researchers discovered novel compounds that promote readthrough of premature termination codons (PTCs), restoring protein function. A potent compound, SRI-41315, shows promise for treating genetic diseases like cystic fibrosis by enhancing CFTR expression.

Area of Science:

  • Molecular Biology
  • Genetics
  • Drug Discovery

Background:

  • Premature termination codons (PTCs) disrupt protein synthesis and trigger nonsense-mediated mRNA decay (NMD).
  • Nonsense suppression therapy aims to restore protein function by readthrough of PTCs, but current agents have limited efficacy.

Purpose of the Study:

  • To identify novel compounds with improved nonsense suppression (readthrough) activity.
  • To evaluate the efficacy of identified compounds in restoring protein function in cystic fibrosis models.

Main Methods:

  • High-throughput screening of 771,345 compounds using an NMD-sensitive NanoLuc readthrough reporter.
  • Characterization of lead compounds, including SRI-41315, in human bronchial epithelial cells.
  • Assessment of CFTR expression and function restoration.

Main Results:

  • Identified 180 compounds with readthrough activity, including SRI-37240 and its derivative SRI-41315.
  • SRI-41315 demonstrated prolonged pause at stop codons, suppressed PTCs in cystic fibrosis cells, and restored CFTR expression and function.
  • SRI-41315 reduces eRF1 abundance and synergizes with aminoglycosides for enhanced CFTR activity.

Conclusions:

  • SRI-41315 is a potent nonsense suppression agent with therapeutic potential for PTC-related diseases.
  • Combining readthrough agents targeting different translation machinery components offers a promising therapeutic strategy.

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