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

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.

Esculentin-1a Derived Peptide Diastereomers to Target Pseudomonas aeruginosa Lung Infection in Cystic Fibrosis: From Nature to Bench towards Therapeutic Application

“…Electrophysiological experiments, including measurements of transepithelial conductance across epithelia expressing F508del-CFTR as well as measurements of membrane currents in single cells expressing F508del-CFTR (patch-clamp technique) after correction with lumacaftor (which acts as a protein-folding chaperone to assist the delivery of the mutated protein to the plasma membrane) were performed. Our results demonstrated the ability of these two Esc peptides to restore the activity of F508del-CFTR, likely upon direct interaction with the channel [16]. This effect was more pronounced for the peptide analog carrying a D-phosphoserine at position 17 [16].…”

“…Our results demonstrated the ability of these two Esc peptides to restore the activity of F508del-CFTR, likely upon direct interaction with the channel [16]. This effect was more pronounced for the peptide analog carrying a D-phosphoserine at position 17 [16]. Computational studies indicated its interaction with the cytosolic side of the complex made by the two NBDs bound to ATP [16].…”

“…This effect was more pronounced for the peptide analog carrying a D-phosphoserine at position 17 [16]. Computational studies indicated its interaction with the cytosolic side of the complex made by the two NBDs bound to ATP [16]. The peptide bridges the two NBD domains, thanks to a network of hydrophobic and electrostatic interactions reinforced by hydrogen bonds with Glu 632 and Arg 1386 .…”

Myxinidin-Derived Peptide against Biofilms Caused by Cystic Fibrosis Emerging Pathogens

“…For example, the peptide Esculentin-1a isolated from the skin of Rana esculenta eradicates biofilms of P. aeruginosa through membrane-perturbing activity [ 42 , 43 ]. β-defensin analogues were developed with enhanced antimicrobial activity against P. aeruginosa , even with elevated salt concentrations, which is a relevant feature in CF patients [ 44 , 45 ].…”

Improved Database Filtering Technology Enables More Efficient Ab Initio Design of Potent Peptides against Ebola Viruses

“…Antimicrobial peptides (AMPs) are an important factor of the innate immune defense for both invertebrates and vertebrates, including humans [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. Recently, human defensins have been shown to inhibit SARS-CoV-2 infection [ 15 ].…”