Dual-action therapy for cystic fibrosis shows promise: Study
Experimental compound 3b addresses disease itself, viral threats
Researchers in Italy have developed a new experimental compound called 3b, which has shown early promise as a dual-action therapy for cystic fibrosis (CF). It addresses the dysfunction of the CFTR protein that causes the disease, as well as protects against viral threats that can worsen lung problems.
In lab tests, compound 3b restored CFTR activity, blocked the growth of several respiratory viruses in different cell models, and even enhanced the effect of certain CFTR modulators.
Such a multitarget therapy could simplify treatment for people with CF, reducing the therapy burden and risk of drug interactions caused by the combined medications patients usually rely on to manage their symptoms.
“These findings collectively highlight compound 3b as a promising multitarget candidate for cystic fibrosis, providing a solid foundation for the development of a simplified CF therapy to mitigate [pulmonary exacerbations],” the researchers wrote. They added that while it’s still early, 3b could be used as an add-on to existing therapies, as a replacement for one of their components, or as part of a new combination treatment.
The study, “Developing Type II F508del-CFTR correctors with a protective effect against respiratory viruses,” was published in the European Journal of Medicinal Chemistry.
Lung infections common in CF
CF is caused by mutations in the CFTR gene. This gene normally makes a protein of the same name that controls the movement of salt and water in and out of cells. When this protein is abnormal or missing, thick and sticky mucus builds up in different organs. In the lungs, it blocks airways and increases the risk of infections, fueling chronic inflammation and tissue damage.
Lung infections are common in CF and drive pulmonary exacerbations, which are flare-ups that worsen symptoms and speed up lung decline, often leading to hospitalizations and a higher risk of death. Bacteria have long been known as the primary cause, but viruses — especially rhinoviruses, which cause the common cold — are increasingly recognized.
Current CF therapies include antibiotics to fight bacterial infections, mucolytics to thin mucus, and CFTR modulators, a newer class of medications designed to improve the function of the faulty CFTR protein in people with certain mutations, including F508del, the most common CF-causing variant.
While effective at relieving symptoms and improving quality of life, their combined use increases the risk of drug interactions, requiring careful management. There are no antiviral drugs available to treat rhinovirus infection.
“Building on these premises, the development of multitarget drugs that both correct defective CFTR function and inhibit pulmonary virus replication could provide an effective and simplified strategy for managing this complex disease,” the researchers wrote.
Compound called 3b most effective at stopping viruses
To explore this idea, a team of researchers in Italy designed and tested new molecules that block PI4KB, a protein in human cells that many viruses depend on to multiply. They aimed to create compounds with dual activity: blocking viral replication and correcting the faulty F508del CFTR protein.
Because the approach targets a host protein rather than the virus itself, it could also reduce the risk of viruses developing resistance — a common problem with standard antivirals.
After an initial screen, the most promising candidates were tested against a panel of respiratory viruses — including rhinoviruses, enteroviruses, Zika virus, and SARS-CoV-2, all of which rely on PI4KB. In these tests, a group of compounds, labeled 3a–g, showed a clear link between PI4KB inhibition and reduced viral growth.
One compound, 3b, was the most effective, stopping several tested respiratory viruses from multiplying at very low doses. Its antiviral activity was further confirmed in human-derived cell models, including liver cells and lung airway cells.
Taken together, these findings support compound 3b as a promising preclinical candidate for treating cystic fibrosis, offering dual-action potential to address both the underlying CFTR dysfunction and viral triggers of pulmonary exacerbations.
The team then looked at whether the compounds could also improve CFTR function. Several showed activity, but 3b again emerged as the most promising. The molecule restored F508del-CFTR in relevant cell models and stayed effective when combined with approved CFTR modulators.
In airway cells derived from patients carrying F508del mutations, 3b significantly boosted the effect of elexacaftor (VX-445), a CFTR corrector that’s part of the triple-combination therapy Trikafta.
In addition, the 3b/elexacaftor combination performed as well as pairing elexacaftor with lumacaftor (VX-809), another CFTR corrector used in Orkambi.
Beyond its biological activity, 3b showed promising drug-like properties in lab tests. It was chemically stable, dissolved well in water, and passed easily through membrane models used to mimic how medicines enter cells — features that could make it suitable for development as an inhaled or nebulised treatment.
“Taken together, these findings support compound 3b as a promising preclinical candidate for the treatment of cystic fibrosis, offering dual-action potential to address both the underlying CFTR dysfunction and viral triggers of pulmonary exacerbations,” the researchers wrote. They added that future studies will explore whether 3b can correct CFTR function in other hard-to-treat mutations, refine its delivery to the lungs, and evaluate its effects in animal models of CF.
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