# Esc peptides and derivatives potentiate the activity of CFTR with gating defects and display antipseudomonal activity in cystic fibrosis-like lung disease

## TL;DR

Researchers found that Esc peptides can improve CFTR function in cystic fibrosis and fight Pseudomonas infections, offering a dual-purpose treatment.

## Contribution

Esc peptides and their derivatives are shown to potentiate CFTR gating mutants and exhibit antipseudomonal activity, a novel dual therapeutic approach.

## Key findings

- Esc peptides and analogs recover function of CFTR mutations affecting channel gating (G551D and G1349D).
- Peptides stabilize the open conformation of CFTR by interacting with nucleotide binding domains.
- Promising peptides show antipseudomonal activity more effective than colistin in CF-like conditions.

## Abstract

Cystic fibrosis (CF) is a rare disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), a chloride channel with an important role in the airways. Despite the clinical efficacy of present modulators in restoring the activity of defective CFTR, there are patients who show persistent pulmonary infections, mainly due to Pseudomonas aeruginosa. Recently, we reported an unprecedented property of antimicrobial peptides i.e. Esc peptides, which consists in their ability to act as potentiators of CFTR carrying the most common mutation (the loss of phenylalanine 508) affecting protein folding, trafficking and gating. In this work, by electrophysiology experiments and computational studies, the capability of these peptides and de-novo designed analogs was demonstrated to recover the function of other mutated forms of CFTR which severely affect the channel gating (G551D and G1349D). This is presumably due to direct interaction of the peptides with the nucleotide binding domains (NBDs) of CFTR, followed by a novel local phenomenon consisting in distancing residues located at the cytosolic side of the NBDs interface, thus stabilizing the open conformation of the pore at its cytosolic end. The most promising peptides for the dual antimicrobial and CFTR potentiator activities were also shown to display antipseudomonal activity in conditions mimicking the CF pulmonary ion transport and mucus obstruction, with a higher efficacy than the clinically used colistin. These studies should assist in development of novel drugs for lung pathology in CF, with dual CFTR potentiator and large spectrum antibiotic activities.

The online version contains supplementary material available at 10.1007/s00018-025-05633-9.