Esc peptides as novel potentiators of defective cystic fibrosis transmembrane conductance regulator: an unprecedented property of antimicrobial peptides

Loretta Ferrera,Floriana Cappiello,Luis J. V. Galietta,Mattia Mori,Maria Rosa Loffredo,Bruno Casciaro,Elena Puglisi,Bruno Botta,Maria Luisa Mangoni

doi:10.1007/s00018-021-04030-2

Abstract

Mutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein lead to persistent lung bacterial infections, mainly due to Pseudomonas aeruginosa, causing loss of respiratory function and finally death of people affected by CF. Unfortunately, even in the era of CFTR modulation therapies, management of pulmonary infections in CF remains highly challenging especially for patients with advanced stages of lung disease. Recently, we identified antimicrobial peptides (AMPs), namely Esc peptides, with potent antipseudomonal activity. In this study, by means of electrophysiological techniques and computational studies we discovered their ability to increase the CFTR-controlled ion currents, by direct interaction with the F508del-CFTR mutant. Remarkably, this property was not explored previously with any AMPs or peptides in general. More interestingly, in contrast with clinically used CFTR modulators, Esc peptides would give particular benefit to CF patients by combining their capability to eradicate lung infections and to act as promoters of airway wound repair with their ability to ameliorate the activity of the channel with conductance defects. Overall, our findings not only highlighted Esc peptides as the first characterized AMPs with a novel property, that is the potentiator activity of CFTR, but also paved the avenue to investigate the functions of AMPs and/or other peptide molecules, for a new up-and-coming pharmacological approach to address CF lung disease.

Highlights

Cystic Fibrosis (CF) is the most common autosomal recessive disease among individuals of caucasian origin, with an incidence of approximately 1 out of 2,500 new births in Europe and 1 out of 3,500 newborns in the United States of America (USA) [1,2,3]
We initially monitored the transepithelial electrical resistance (TEER) in polarized epithelia formed by Fischer rat thyroid (FRT) cells with stable expression of mutated or wild-type CFTR (F508del-FRT and wt-FRT, respectively), 24 h after peptide treatment at different concentrations
As for airway epithelial cells, FRT cells, form a cellular monolayer stabilized via intercellular junctions that regulate diffusion of water and solutes allowing the establishment of selectively permeable barriers [34]

Summary

Introduction

Cystic Fibrosis (CF) is the most common autosomal recessive disease among individuals of caucasian origin, with an incidence of approximately 1 out of 2,500 new births in Europe and 1 out of 3,500 newborns in the United States of America (USA) [1,2,3]. The most prevalent CF-associated mutation is the loss of phenylalanine at position 508 (F508del-CFTR) which causes an incorrectly folded protein that is rapidly degraded by the ubiquitin–proteasome pathway [11]. Because of this trafficking fault, a small fraction of F508del-CFTR reaches the plasma membrane [12]; the mutated protein exhibits a defect in channel gating [13]. The formation of a sticky and dehydrated mucus occurs on the airway surfaces with serious decay of mucociliary defense system This favors the entrapment and accumulation of inhaled microbes, such as Pseudomonas aeruginosa which quickly gives rise to biofilm communities [14]. A chronic pulmonary infection takes hold with progressive damage to the pulmonary tissue

Methods

Results

Conclusion