Study Describes New Compound for Nonsense Mutations

Marisa Wexler MS avatar

by Marisa Wexler MS |

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A novel compound that may hold promise for treating the roughly 11% of cases of cystic fibrosis (CF) that are caused by nonsense mutations has been described in a new study.

The study, “A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion,” was published in the journal Nature Communications.

CF is caused by mutations in a gene called CFTR. Mutations in this gene lead to dysfunction of the protein that the gene provides instructions to make, which also is called CFTR. There are different types of CFTR mutations, with different effects on the CFTR protein.

One type of mutation is a nonsense mutation. A protein-coding gene like CFTR is “read” into an intermediate molecule called messenger RNA (mRNA), which is then translated to a protein in structures known as

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ribosomes. A specific sequence in mRNA, called a stop codon, indicates where the translation ends — sort of like how a period denotes the end of a sentence.

A nonsense mutation results in a premature stop codon introduced in the DNA sequence. This causes the cell to produce a truncated form of the CFTR protein, which is quickly degraded within the cell.

In the new study, a team led by scientists at the University of Alabama at Birmingham set out to identify novel readthrough compounds that might be useful for treating CF and other diseases caused by nonsense mutations. As the name suggests, the goal of a readthrough compound is to let ribosomes “read through” the erroneous stop codon to produce a full-length protein.

The team used a cell model that basically consisted of cells engineered with a gene encoding a detectable protein that had a nonsense mutation in it. The researchers used this model to screen 771,345 small molecules, and found that 180 of them had readthrough activity.

Among these molecules, the most active was called SRI-37240. Further testing using cellular models of CF with nonsense mutations demonstrated that treatment with this small molecule could allow the cells to produce functional, full-length CFTR protein.

The researchers next synthesized dozens of derivatives of SRI-37240, and they found one — called SRI-41315 — that had even more potent readthrough activity. The increased readthrough efficacy of SRI-41315 was confirmed in lung cells from people with CF, particularly when used with G418, a type of antibiotic known to aid readthrough of premature codon mutations.

Further investigation revealed these readthrough small molecules work by reducing levels of eRF1, a protein used to recognize stop codons. The team suggested that targeting eRF1 may be a useful strategy in CF or other conditions caused by nonsense mutations.

“To our knowledge, this is the first example of a pharmacological agent that can induce readthrough by affecting eRF1 levels, demonstrating an important therapeutic target for nonsense mutation suppression,” the researchers wrote.

“While further medicinal chemistry is needed to identify readthrough compounds that maximally impact CFTR function without undesirable off-target effects, the results presented here suggest this path is clearly achievable,” they concluded.

Notably, although both SRI-37240 and SRI-41315 were identified through screens in this study, both were described previously as readthrough agents in a patent held by Novartis.


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