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Pharmaceuticals
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Emerging Therapies for the Treatment of Cystic Fibrosis
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Emerging Therapies for the Treatment of Cystic Fibrosis

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (1 September 2022) | Viewed by 15356

Special Issue Editors

Dr. Giorgio Cozza

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Guest Editor
Department of Molecular Medicine, University of Padova, 35131 Padova, Italy
Interests: biochemistry and computational chemistry; cystic fibrosis; ferroptosis; lipid peroxidation; neurodegeneration; cancer reasearch; protein phoshorylation; signal transduction; drug design and development; drug repurposing
Special Issues, Collections and Topics in MDPI journals
Dr. Andrea Venerando

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Guest Editor
Department of Comparative Biomedicine and Food Science, University of Padova, 35020 Legnaro (PD), Italy
Interests: protein kinases; protein phosphorylation; kinase; signal transduction; apoptosis; cell signaling; signaling; cancer cell signaling; cellular biochemistry; cancer research, cystic fibrosis, nanotechnologies
Special Issues, Collections and Topics in MDPI journals
Prof. Valeria Raia

E-Mail Website
Guest Editor
Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, Federico II University Naples, 80134 Naples, Italy
Interests: cystic fibrosis
Prof. Dr. Mauro Piacentini

E-Mail Website
Guest Editor
Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy
Interests: molecular mechanisms of autophagy/cell death and their involvement in human diseases pathogenesis

Special Issue Information

Dear Colleagues,

Cystic fibrosis (CF) is a common life-shortening rare disease caused by mutations in the gene coding for CF transmembrane conductance regulator (CFTR), a chloride and bicarbonate channel located at the apical membranes of epithelial cells. CF mainly affects lungs, leading to infections, inflammation, and respiratory failure, being the principal cause of mortality. Besides, the complex and heterogeneous clinical manifestations that involve several organs (pancreas, liver, kidneys, and intestine, among others) highlight the crucial role of this single protein in CF pathophysiology. Although the vast majority of CF patients bear the class II F508del mutation, which is retained in the endoplasmic reticulum and degraded before reaching the plasma membrane, over 2000 mutations have been identified in the CFTR protein, grouped into six categories. At present, although several drugs have been approved, and clinical care ensures steady gains in the quality of life of CF patients, the development of new therapies targeting not only the most common mutations but also the orphan ones remains challenging.

With this Special Issue entitled “Emerging Therapies for the Treatment of Cystic Fibrosis”, we would like to invite authors to contribute with review or original research articles dedicated to the most recent advances on the discovery of new perspective therapeutics for CF. Contributions will include but are not limited to emerging therapies targeting different CFTR class mutations, novel treatments that could help to control the symptoms or prevent complications, studies concerning the elucidation of the mechanisms of action of promising CF treating molecules, and those which discuss different approaches and pharmaceutical strategies in this pathology. 

Dr. Giorgio Cozza
Dr. Andrea Venerando
Dr. Valeria Raia
Prof. Dr. Mauro Piacentini
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cystic fibrosis
  • CFTR mutations
  • pathophysiology
  • inflammation
  • infection
  • high-throughput screening
  • drug development
  • therapies
  • treatments
  • clinical trials

Published Papers (4 papers)

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Research

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12 pages, 1718 KiB  
Article
Elexacaftor-Tezacaftor-Ivacaftor as a Final Frontier in the Treatment of Cystic Fibrosis: Definition of the Clinical and Microbiological Implications in a Case-Control Study
by Giuseppe Migliorisi, Mirella Collura, Francesca Ficili, Tiziana Pensabene, Dafne Bongiorno, Antonina Collura, Francesca Di Bernardo and Stefania Stefani
Pharmaceuticals 2022, 15(5), 606; https://doi.org/10.3390/ph15050606 - 14 May 2022
Cited by 6 | Viewed by 2273
Abstract
The use of modulator drugs that target the Cystic Fibrosis transmembrane conductance regulator (CFTR) is the final frontier in the treatment of Cystic Fibrosis (CF), a genetic multiorgan disease. F508del is the most common mutation causing defective formation and function of CFTR. Elexacaftor-tezacaftor-ivacaftor [...] Read more.
The use of modulator drugs that target the Cystic Fibrosis transmembrane conductance regulator (CFTR) is the final frontier in the treatment of Cystic Fibrosis (CF), a genetic multiorgan disease. F508del is the most common mutation causing defective formation and function of CFTR. Elexacaftor-tezacaftor-ivacaftor is the first triple combination of CFTR modulators. Herein, we report on a one-year case-control study that involved 26 patients with at least one F508del mutation. Patients were assigned to two similar groups, and patients with the worse clinical condition received treatment with the triple combination therapy. The study aimed to define the clinical and especially microbiological implications of treatment administration. The treatment provided significant clinical benefits in terms of respiratory, pancreatic, and sweat function. After one year of therapy, airway infection rates decreased and pulmonary exacerbations were dramatically reduced. Finally, treated patients reported a surprising improvement in their quality of life. The use of triple combination therapy has become essential in most CF people carrying the F508del mutation. Although the clinical and instrumental benefits of treatment are thoroughly known, further investigations are needed to properly define its microbiological respiratory implications and establish the real advantage of life-long treatment with elexacaftor-tezacaftor-ivacaftor. Full article
(This article belongs to the Special Issue Emerging Therapies for the Treatment of Cystic Fibrosis)
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35 pages, 9158 KiB  
Article
Journey on VX-809-Based Hybrid Derivatives towards Drug-like F508del-CFTR Correctors: From Molecular Modeling to Chemical Synthesis and Biological Assays
by Alice Parodi, Giada Righetti, Emanuela Pesce, Annalisa Salis, Valeria Tomati, Cristina Pastorino, Bruno Tasso, Mirko Benvenuti, Gianluca Damonte, Nicoletta Pedemonte, Elena Cichero and Enrico Millo
Pharmaceuticals 2022, 15(3), 274; https://doi.org/10.3390/ph15030274 - 23 Feb 2022
Cited by 4 | Viewed by 2046
Abstract
Cystic fibrosis (CF) is a genetic disease affecting the lungs and pancreas and causing progressive damage. CF is caused by mutations abolishing the function of CFTR, a protein whose role is chloride’s mobilization in the epithelial cells of various organs. Recently a therapy [...] Read more.
Cystic fibrosis (CF) is a genetic disease affecting the lungs and pancreas and causing progressive damage. CF is caused by mutations abolishing the function of CFTR, a protein whose role is chloride’s mobilization in the epithelial cells of various organs. Recently a therapy focused on small molecules has been chosen as a main approach to contrast CF, designing and synthesizing compounds acting as misfolding (correctors) or defective channel gating (potentiators). Multi-drug therapies have been tested with different combinations of the two series of compounds. Previously, we designed and characterized two series of correctors, namely, hybrids, which were conceived including the aminoarylthiazole (AAT) core, merged with the benzodioxole carboxamide moiety featured by VX-809. In this paper, we herein proceeded with molecular modeling studies guiding the design of a new third series of hybrids, featuring structural variations at the thiazole moiety and modifications on position 4. These derivatives were tested in different assays including a YFP functional assay on models F508del-CFTR CFBE41o-cells, alone and in combination with VX-445, and by using electrophysiological techniques on human primary bronchial epithelia to demonstrate their F508del-CFTR corrector ability. This study is aimed (i) at identifying three molecules (9b, 9g, and 9j), useful as novel CFTR correctors with a good efficacy in rescuing the defect of F508del-CFTR; and (ii) at providing useful information to complete the structure–activity study within all the three series of hybrids as possible CFTR correctors, supporting the development of pharmacophore modelling studies, taking into account all the three series of hybrids. Finally, in silico evaluation of the hybrids pharmacokinetic (PK) properties contributed to highlight hybrid developability as drug-like correctors. Full article
(This article belongs to the Special Issue Emerging Therapies for the Treatment of Cystic Fibrosis)
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25 pages, 9555 KiB  
Article
Probing Allosteric Hsp70 Inhibitors by Molecular Modelling Studies to Expedite the Development of Novel Combined F508del CFTR Modulators
by Roberto Sabbadini, Emanuela Pesce, Alice Parodi, Eleonora Mustorgi, Santina Bruzzone, Nicoletta Pedemonte, Monica Casale, Enrico Millo and Elena Cichero
Pharmaceuticals 2021, 14(12), 1296; https://doi.org/10.3390/ph14121296 - 12 Dec 2021
Cited by 5 | Viewed by 3290
Abstract
Cystic fibrosis (CF) is caused by different mutations related to the cystic fibrosis transmembrane regulator protein (CFTR), with F508del being the most common. Pioneering the development of CFTR modulators, thanks to the development of effective correctors or potentiators, more recent studies deeply encouraged [...] Read more.
Cystic fibrosis (CF) is caused by different mutations related to the cystic fibrosis transmembrane regulator protein (CFTR), with F508del being the most common. Pioneering the development of CFTR modulators, thanks to the development of effective correctors or potentiators, more recent studies deeply encouraged the administration of triple combination therapeutics. However, combinations of molecules interacting with other proteins involved in functionality of the CFTR channel recently arose as a promising approach to address a large rescue of F508del-CFTR. In this context, the design of compounds properly targeting the molecular chaperone Hsp70, such as the allosteric inhibitor MKT-077, proved to be effective for the development of indirect CFTR modulators, endowed with ability to amplify the accumulation of the rescued protein. Herein we performed structure-based studies of a number of allosteric HSP70 inhibitors, considering the recent X-ray crystallographic structure of the human enzyme. This allowed us to point out the main interaction supporting the binding mode of MKT-077, as well as of the related analogues. In particular, cation-π and π–π stacking with the conserve residue Tyr175 deeply stabilized inhibitor binding at the HSP70 cavity. Molecular docking studies had been followed by QSAR analysis and then by virtual screening of aminoaryl thiazoles (I–IIIa) as putative HSP70 inhibitors. Their effectiveness as CFTR modulators has been verified by biological assays, in combination with VX-809, whose positive results confirmed the reliability of the whole applied computational method. Along with this, the “in-silico” prediction of absorption, distribution, metabolism, and excretion (ADME) properties highlighted, once more, that AATs may represent a chemical class to be further investigated for the rational design of novel combination of compounds for CF treatment. Full article
(This article belongs to the Special Issue Emerging Therapies for the Treatment of Cystic Fibrosis)
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Review

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16 pages, 1144 KiB  
Review
N-acetylcysteine (NAC) and Its Role in Clinical Practice Management of Cystic Fibrosis (CF): A Review
by Marta Guerini, Giorgia Condrò, Valeria Friuli, Lauretta Maggi and Paola Perugini
Pharmaceuticals 2022, 15(2), 217; https://doi.org/10.3390/ph15020217 - 11 Feb 2022
Cited by 17 | Viewed by 6839
Abstract
N-acetylcysteine is the acetylated form of the amino acid L-cysteine and a precursor to glutathione (GSH). It has been known for a long time as a powerful antioxidant and as an antidote for paracetamol overdose. However, other activities related to this molecule have [...] Read more.
N-acetylcysteine is the acetylated form of the amino acid L-cysteine and a precursor to glutathione (GSH). It has been known for a long time as a powerful antioxidant and as an antidote for paracetamol overdose. However, other activities related to this molecule have been discovered over the years, making it a promising drug for diseases such as cystic fibrosis (CF). Its antioxidant activity plays a key role in CF airway inflammation and redox imbalance. Furthermore, this molecule appears to play an important role in the prevention and eradication of biofilms resulting from CF airway infections, in particular that of Pseudomonas aeruginosa. The aim of this review is to provide an overview of CF and the role that NAC could play in preventing and eliminating biofilms, as a modulator of inflammation and as an antioxidant, restoring the redox balance within the airways in CF patients. To do this, NAC can act alone, but it can also be used as an adjuvant molecule to known drugs (antibiotics/anti-inflammatories) to increase their activity. Full article
(This article belongs to the Special Issue Emerging Therapies for the Treatment of Cystic Fibrosis)
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