A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34272367.
- Also identified by DOI 10.1038/s41467-021-24575-x and PMC identifier 8285393.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Codon, Nonsense
- Cystic Fibrosis Transmembrane Conductance Regulator
- Epithelial Cells
- Nonsense Mediated mRNA Decay
- Peptide Chain Termination, Translational
- Peptide Termination Factors