A small molecule can induce nonsense mutations in CFTR in cystic fibrosis

An experimental drug published in the journal Nature Communications showed that there is an "obviously feasible way" to treat currently incurable cystic fibrosis caused by nonsense mutations

Dr.

To understand how meaningless mutations cause disease, and how experimental drugs inhibit mutations, it is necessary to carefully study the biological mechanisms of protein production in cells

A protein is a chain made up of hundreds of amino acids, which is then folded into a proper shape and moved to the proper position to perform its function

In cystic fibrosis, mutations affect the CFTR protein, which acts on the surface of lung cells to regulate the flow of water to mucus

Therefore, Bedwell, Rowe and colleagues wanted to find small molecule compounds that would allow the ribosome to skip the meaningless premature stop mutations and allow the ribosome to continue to fully synthesize proteins

The researchers used mouse cells with modified genes extracted from deep-sea shrimp to test hundreds of thousands of compounds

This reporter gene allowed a research team from the Southern Research Institute to test 771,345 compounds through high-throughput screening

In rat cell culture, the researchers found that SRI-37240 can restore the function of the human CFTR gene with premature stop codon mutations

They found that SRI-37240 induced a long pause at the stop codon of the messenger RNA and inhibited the termination of protein synthesis at the premature stop codon, without stimulating the read-through of the normal stop codon of the protein coding sequence at the end of the messenger RNA

Medicinal chemists synthesized 40 derivatives of SRI-37240, of which SRI-41315 was more effective and showed better physical and chemical characteristics

The ribosomal complex includes ribosomal proteins and other proteins that act as termination factors, translation factors, and nonsense-mediated mRNA attenuation factors

To predict the clinical efficacy of cystic fibrosis, the researchers tested primary human bronchial epithelial cells with endogenous CFTR premature stop codons

Bedwell and Rowe said that this is progress, but obstacles still exist

Bedwell and Rowe say that it is increasingly possible that a variety of different drugs with different mechanisms of action are needed to produce a clinically effective response

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