New Approach to Cystic Fibrosis Targets Anomaly Protein and Naturally Occurring Substance

New Approach to Cystic Fibrosis Targets Anomaly Protein and Naturally Occurring Substance

A study from researchers at Eindhoven University of Technology in the Netherlands and McGill University in Montreal, Canada, has demonstrated important progress toward the development of a new drug to battle cystic fibrosis (CF).

Cystic fibrosis is a genetic disorder that can be caused by more than 1,900 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. These mutations can be divided into two classes according to the mechanism by which they disrupt CFTR gene expression. Most patients suffer from the class II mutation, which is present in about 70 percent of patients in Europe, North America, and Australia.

In cells containing class II mutations, the protein is retained inside the cell and not transported to the cell membrane, which results in a dysfunctional anion transport across the plasma membrane in epithelial cells. This dysfunction leads to complications in a variety of organs, including chronic airway infection and obstruction, pancreatic insufficiency, and intestinal obstruction. Advances in diagnosis and therapies have significantly improved the life expectancy quality of life of CF patients, but there is no cure.

Researchers have now succeeded in enhancing the CFTR protein trafficking to the cell membrane. Their achievements were summarized in a paper “Characterization and small-molecule stabilization of the multisite tandem binding between 14-3-3 and the R domain of CFTR,” and were published in the journal Proceedings of the National Academy of Sciences.

Earlier research showed that 14-3-3 proteins play an important role in the transport of the CFTR protein to the cell membrane. The study’s authors showed that fusicoccin-A, a natural molecule produced by a fungus, can stabilize the interaction between 14-3-3 and CFTR proteins, which stimulates the movement of mutant CFTR to the plasma membrane.

The article provides a detailed characterization of the 14-3-3-CFTR interaction, showing that several phosphorylated binding sites in the CFTR protein are necessary for significant interaction with 14-3-3. Aditionally , the definition of the drug therapies of the 14-3-3–CFTR, protein-protein interface is also discussed, which might offer a new approach for CF therapeutics.

Although the characterization of the 14-3-3–CFTR interaction is important, more research is needed to determine if a drug based on such interaction can be developed to stop CF. Researchers also need to confirm if the mutant CFTR protein, which remains in the cell membrane, can function properly. Also, an alternative to fusicoccin-A is required, with the same therapeutic effect and optimal drug properties, since fusicoccin-A has properties that are not predisposed to being a suitable drug candidate.

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