Current therapy based on correctors and enhancers of CFTR is effective in restoring the protein’s activity, but treating lung infections remains a major challenge. 

Antimicrobial peptides, derived from the natural compound esculentin, have been identified by previous projects (FFC#14/2011, FFC#11/2014, FFC#15/2017 and FFC#8/2019) to be very effective against the bacterium Pseudomonas aeruginosa, the main lung pathogen in CF. These peptides, called Esc, can act as enhancers of CFTR with the F508del mutation. Antimicrobial peptides are small proteins that are very important in activating a particular type of immune response, which is the first barrier against pathogens that come into contact with the body. 

In this new project, the researchers optimised the efficacy of the Esc peptides for their dual antimicrobial and CFTR-enhancing function using a multidisciplinary approach.

Using electrophysiology studies, the researchers investigated the effect of the selected peptides and/or their derivatives both on epithelia from bronchial cells derived from patients and carrying the F508del mutation on only one or both copies of the CFTR gene, and on epithelia obtained from cell lines containing CFTR with the G551D or G1349D mutation. Through computational studies, they then investigated the interaction of the peptides with the CFTR protein. 

Esc peptides enhance CFTR activity with mutations that alter the channel opening mechanism, possibly stabilising the open state. In addition, a molecule similar to Esc peptides was found to be active also against Gram-positive bacteria (such as Staphylococcus aureus) relevant in CF, and capable of enhancing mutated CFTR without damaging human cells. These peptides also maintain antibacterial efficacy in the lungs of animal models in which sticky mucus is produced.

The research will now be extended to different CFTR mutations, to pave the way for the development of a new therapeutic strategy for the treatment of CF lung disease, based on the use of molecules with antibacterial and CFTR-enhancing functions after administration in the airways.