Developing Type II F508del-CFTR correctors with a protective effect against respiratory viruses

Cystic fibrosis (CF) is a multifaceted disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The resulting thick mucus accumulation increases the risk of microbial infections, leading to chronic lung inflammation, progressive tissue damage, and pulmonary exacerbations (PEs). Respiratory viruses may facilitate bacterial colonization, significantly contributing to PEs. Therefore, patients with CF could benefit from a timely antiviral treatment targeting respiratory viruses (e.g., rhinoviruses). Herein, we present novel multitarget agents that combine F508del-CFTR correction with broad-spectrum antiviral activity through inhibition of the host protein PI4KB, offering a promising therapeutic strategy to prevent pulmonary exacerbations in cystic fibrosis with no risk of developing antiviral drug resistance. Among the most active candidates, the bithiazole 3b showed broad-spectrum antiviral activity in the sub- or low-micromolar range against selected viruses from the Picornaviridae, Flaviviridae, and Coronaviridae families, and a notable F508del-CFTR correction-both alone and in combination with VX809-in FRT cells. Further confirmation of CFTR correction was obtained in the CFBE41o^- cell line and in primary cultures of human airway epithelial cells homozygous for F508del, the gold standard for evaluating CFTR rescue strategies, particularly in combination with VX445. In addition to its biological activity, compound 3b exhibited a favorable preclinical pharmacokinetic profile in vitro. 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 PE.