An Update on CFTR Drug Discovery: Opportunities and Challenges

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 9507

Special Issue Editors


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Guest Editor
Department of Pharmacy, Universita degli Studi di Genova, Genoa, Italy
Interests: medicinal chemistry; drug design

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Guest Editor
Institute of Biomedical Technologies-CNR, Segrate, Italy
Interests: structural bioinformatics

Special Issue Information

Dear Colleagues,

We invite you to contribute to this Special Issue of Biomolecules entitled An Update on CFTR Drug Discovery: Opportunities and Challenges.

Cystic fibrosis transmembrane conductance regulator (CFTR) rescuing drugs have already transformed cystic fibrosis from a fatal disease to a treatable chronic condition. However, a new generation of drugs able to bind CFTR or other CF protein targets are needed. These drugs are expected to act with high specificity and potency, thus exerting stronger therapeutic benefits and fewer side effects in comparison with drugs that are already marketed.

This Special Issue will focus on experimental and computational studies in the research area of CF therapy. It will include identification and characterization studies of new chemical scaffolds and protein targets, evaluation of their molecular mechanism of action by means of several available tools, such as bioinformatics, biosensors, omics, and cellular tests.

Prof. Dr. Paola Fossa
Dr. Pasqualina D'Ursi
Guest Editors

Manuscript Submission Information

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Keywords

  • mutated CFTR
  • F508del-CFTR
  • modulators (correctors, potentiators)
  • CF therapy, including nanomedicine
  • new target proteins involved in CF disease
  • biomarkers for mutated CFTR
  • molecular mechanisms involved in CF
  • omics

Published Papers (4 papers)

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Editorial

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2 pages, 172 KiB  
Editorial
An Update on CFTR Drug Discovery: Opportunities and Challenges
by Pasqualina D’Ursi and Paola Fossa
Biomolecules 2022, 12(6), 792; https://doi.org/10.3390/biom12060792 - 06 Jun 2022
Viewed by 1054
Abstract
The Biomolecules Special issue on “An Update on CFTR Drug Discovery: Opportunities and Challenges” includes three original research articles and a webinar session focusing on some recent findings concerning CFTR drug discovery [...] Full article
(This article belongs to the Special Issue An Update on CFTR Drug Discovery: Opportunities and Challenges)

Research

Jump to: Editorial

23 pages, 3520 KiB  
Article
NBD2 Is Required for the Rescue of Mutant F508del CFTR by a Thiazole-Based Molecule: A Class II Corrector for the Multi-Drug Therapy of Cystic Fibrosis
by Chiara Brandas, Alessandra Ludovico, Alice Parodi, Oscar Moran, Enrico Millo, Elena Cichero and Debora Baroni
Biomolecules 2021, 11(10), 1417; https://doi.org/10.3390/biom11101417 - 28 Sep 2021
Cited by 9 | Viewed by 2275
Abstract
Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein, an anion channel that regulates epithelial surface fluid secretion. The deletion of phenylalanine at position 508 (F508del) is the most common CFTR mutation. F508del CFTR is characterized [...] Read more.
Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein, an anion channel that regulates epithelial surface fluid secretion. The deletion of phenylalanine at position 508 (F508del) is the most common CFTR mutation. F508del CFTR is characterized by folding and trafficking defects, resulting in decreased functional expression of the protein on the plasma membrane. Several classes of small molecules, named correctors, have been developed to rescue defective F508del CFTR. Although individual correctors failed to improve the clinical status of CF patients carrying the F508del mutation, better results were obtained using correctors combinations. These results were obtained according to the premise that the administration of correctors having different sites of action should enhance F508del CFTR rescue. We investigated the putative site of action of an aminoarylthiazole 4-(3-chlorophenyl)-N-(3-(methylthio)phenyl)thiazol-2-amine, named FCG, with proven CFTR corrector activity, and its synergistic effect with the corrector VX809. We found that neither the total expression nor the maturation of WT CFTR transiently expressed in human embryonic kidney 293 cells was influenced by FCG, administrated alone or in combination with VX809. On the contrary, FCG was able to enhance F508del CFTR total expression, and its combination with VX809 provided a further effect, being able to increase not only the total expression but also the maturation of the mutant protein. Analyses on different CFTR domains and groups of domains, heterologously expressed in HEK293 cells, show that NBD2 is necessary for FCG corrector activity. Molecular modelling analyses suggest that FCG interacts with a putative region located into the NBD2, ascribing this molecule to class II correctors. Our study indicates that the continuous development and testing of combinations of correctors targeting different structural and functional defects of mutant CFTR is the best strategy to ensure a valuable therapeutic perspective to a larger cohort of CF patients. Full article
(This article belongs to the Special Issue An Update on CFTR Drug Discovery: Opportunities and Challenges)
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14 pages, 2452 KiB  
Article
Lumacaftor and Matrine: Possible Therapeutic Combination to Counteract the Inflammatory Process in Cystic Fibrosis
by Michela Pecoraro, Silvia Franceschelli and Maria Pascale
Biomolecules 2021, 11(3), 422; https://doi.org/10.3390/biom11030422 - 13 Mar 2021
Cited by 5 | Viewed by 2390
Abstract
Cystic fibrosis is a monogenic, autosomal, recessive disease characterized by an alteration of chloride transport caused by mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene. The loss of Phe residue in position 508 (ΔF508-CFTR) causes an incorrect folding of the protein [...] Read more.
Cystic fibrosis is a monogenic, autosomal, recessive disease characterized by an alteration of chloride transport caused by mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene. The loss of Phe residue in position 508 (ΔF508-CFTR) causes an incorrect folding of the protein causing its degradation and electrolyte imbalance. CF patients are extremely predisposed to the development of a chronic inflammatory process of the bronchopulmonary system. When the cells of a tissue are damaged, the immune cells are activated and trigger the production of free radicals, provoking an inflammatory process. In addition to routine therapies, today drugs called correctors are available for mutations such as ΔF508-CFTR as well as for others less frequent ones. These active molecules are supposed to facilitate the maturation of the mutant CFTR protein, allowing it to reach the apical membrane of the epithelial cell. Matrine induces ΔF508-CFTR release from the endoplasmic reticulum to cell cytosol and its localization on the cell membrane. We now have evidence that Matrine and Lumacaftor not only restore the transport of mutant CFTR protein, but probably also counteract the inflammatory process by improving the course of the disease. Full article
(This article belongs to the Special Issue An Update on CFTR Drug Discovery: Opportunities and Challenges)
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20 pages, 5557 KiB  
Article
Actin-Resistant DNase1L2 as a Potential Therapeutics for CF Lung Disease
by Danila Delfino, Giulia Mori, Claudio Rivetti, Antonella Grigoletto, Gloria Bizzotto, Cristian Cavozzi, Marco Malatesta, Davide Cavazzini, Gianfranco Pasut and Riccardo Percudani
Biomolecules 2021, 11(3), 410; https://doi.org/10.3390/biom11030410 - 10 Mar 2021
Cited by 8 | Viewed by 2965
Abstract
In cystic fibrosis (CF), the accumulation of viscous lung secretions rich in DNA and actin is a major cause of chronic inflammation and recurrent infections leading to airway obstruction. Mucolytic therapy based on recombinant human DNase1 reduces CF mucus viscosity and promotes airway [...] Read more.
In cystic fibrosis (CF), the accumulation of viscous lung secretions rich in DNA and actin is a major cause of chronic inflammation and recurrent infections leading to airway obstruction. Mucolytic therapy based on recombinant human DNase1 reduces CF mucus viscosity and promotes airway clearance. However, the marked susceptibility to actin inhibition of this enzyme prompts the research of alternative treatments that could overcome this limitation. Within the human DNase repertoire, DNase1L2 is ideally suited for this purpose because it exhibits metal-dependent endonuclease activity on plasmid DNA in a broad range of pH with acidic optimum and is minimally inhibited by actin. When tested on CF artificial mucus enriched with actin, submicromolar concentrations of DNase1L2 reduces mucus viscosity by 50% in a few seconds. Inspection of superimposed model structures of DNase1 and DNase1L2 highlights differences at the actin-binding interface that justify the increased resistance of DNase1L2 toward actin inhibition. Furthermore, a PEGylated form of the enzyme with preserved enzymatic activity was obtained, showing interesting results in terms of activity. This work represents an effort toward the exploitation of natural DNase variants as promising alternatives to DNase1 for the treatment of CF lung disease. Full article
(This article belongs to the Special Issue An Update on CFTR Drug Discovery: Opportunities and Challenges)
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