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Pharmaceuticals
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Cystic Fibrosis and Rare Mutations: New Promising Approaches via Proteostase...
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Cystic Fibrosis and Rare Mutations: New Promising Approaches via Proteostase Modulators

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

Deadline for manuscript submissions: closed (16 February 2024) | Viewed by 2073

Special Issue Editor

Dr. Elena Cichero

E-Mail Website
Guest Editor
Department of Pharmacy, University of Genoa, Viale Benedetto XV, 16132 Genoa, Italy
Interests: medicinal chemistry; GPCR; enzyme; neuroprotective agents; cystic fibrosis; cancer; molecular modeling; virtual screening; homology modeling; repositioning
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes a cAMP-regulated chloride (Cl-) and bicarbonate (HCO3-) channel expressed at the apical membrane of epithelial cells. The most common mutation—F508del—is present in 80% of individuals with CF worldwide.

New curative treatments aimed at rescuing CFTR dysfunctionality have emerged, although the proven efficacy of some of these treatments has been explored only for particular mutations. A total of 15% of patients cannot be treated with CFTR-directed therapeutics. Hence, there is an interest in finding an alternative strategy to treat patients with CF independently of CFTR mutations.  Pharmacological chaperones (PCs) are correctors that directly bind to the F508del-CFTR mutant and promote its folding and trafficking. Conversely, proteostasis modulators (PMs) act indirectly by altering protein synthesis, trafficking and degradation. The development of new compounds that target the biological components of the CFTR physiological pathway may be useful to optimize combination therapies for those patients that do not respond to the current treatments. In particular, the identification of new candidate drugs acting as PMs for the correction of the basic defect in cystic fibrosis is expected to be of high relevance.

This Special Issue invites both reviews and original articles that shed light on the rational design and development of new PMs to be exploited in CF patients, including virtual screening applications and high-throughput screening (HTS) campaigns. Biological assays that lead to the discovery of novel hit compounds that can be further probed for different CFTR mutants are also included in the scope of the Special Issue. This Special Issue aims to summarize the state of the-art, and the latest findings published in the cystic fibrosis field, as well as to elucidate future directions.

Dr. Elena Cichero
Guest Editor

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.

Published Papers (2 papers)

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Research

16 pages, 1728 KiB  
Article
New Pyrazolyl Thioureas Active against the Staphylococcus Genus
by Anna Maria Schito, Debora Caviglia, Susanna Penco, Andrea Spallarossa, Elena Cichero, Bruno Tasso and Chiara Brullo
Pharmaceuticals 2024, 17(3), 376; https://doi.org/10.3390/ph17030376 - 15 Mar 2024
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Abstract
To meet the urgent need for new antibacterial molecules, a small library of pyrazolyl thioureas (PTUs) was designed, synthesized and tested against difficult-to-treat human pathogens. The prepared derivatives are characterized by a carboxyethyl functionality on C4 and different hydroxyalkyl chains on N1. Compounds [...] Read more.
To meet the urgent need for new antibacterial molecules, a small library of pyrazolyl thioureas (PTUs) was designed, synthesized and tested against difficult-to-treat human pathogens. The prepared derivatives are characterized by a carboxyethyl functionality on C4 and different hydroxyalkyl chains on N1. Compounds 1a–o were first evaluated against a large panel of Gram-positive and Gram-negative pathogens. In particular, the majority of PTUs proved to be active against different species of the Staphylococcus genus, with MIC values ranging from 32 to 128 µg/mL on methicillin-resistant Staphylococcus strains, often responsible for severe pulmonary disease in cystic fibrosis patients. Time-killing experiments were also performed for the most active compounds, evidencing a bacteriostatic mechanism of action. For most active derivatives, cytotoxicity was evaluated in Vero cells, and at the tested concentrations and at the experimental exposure time of 24 h, none of the compounds analysed showed significant toxicity. In addition, favourable drug-like, pharmacokinetic and toxicity properties were predicted for all new synthesized derivatives. Overall, the collected data confirmed the PTU scaffold as a promising chemotype for the development of novel antibacterial agents active against Gram-positive multi-resistant strains frequently isolated from cystic fibrosis patients. Full article
(This article belongs to the Special Issue Cystic Fibrosis and Rare Mutations: New Promising Approaches via Proteostase Modulators)
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23 pages, 5883 KiB  
Article
In Silico and In Vitro Evaluation of the Mechanism of Action of Three VX809-Based Hybrid Derivatives as Correctors of the F508del CFTR Protein
by Debora Baroni, Naomi Scarano, Alessandra Ludovico, Chiara Brandas, Alice Parodi, Dario Lunaccio, Paola Fossa, Oscar Moran, Elena Cichero and Enrico Millo
Pharmaceuticals 2023, 16(12), 1702; https://doi.org/10.3390/ph16121702 - 08 Dec 2023
Viewed by 1106
Abstract
Cystic fibrosis (CF), the most common autosomal recessive fatal genetic disease in the Caucasian population, is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel that regulates salt and water transport across a variety of [...] Read more.
Cystic fibrosis (CF), the most common autosomal recessive fatal genetic disease in the Caucasian population, is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel that regulates salt and water transport across a variety of secretory epithelia. Deletion of phenylalanine at position 508, F508del, the most common CF-causing mutation, destabilises the CFTR protein, causing folding and trafficking defects that lead to a dramatic reduction in its functional expression. Small molecules called correctors have been developed to rescue processing-defective F508del CFTR. We have combined in silico and in vitro approaches to investigate the mechanism of action and potential as CFTR correctors of three hybrid derivatives (2a, 7a, and 7m) obtained by merging the amino-arylthiazole core with the benzodioxole carboxamide moiety characterising the corrector lumacaftor. Molecular modelling analyses suggested that the three hybrids interact with a putative region located at the MSD1/NBD1 interface. Biochemical analyses confirmed these results, showing that the three molecules affect the expression and stability of the F508del NBD1. Finally, the YFP assay was used to evaluate the influence of the three hybrid derivatives on F508del CFTR function, assessing that their effect is additive to that of the correctors VX661 and VX445. Our study shows that the development and testing of optimised compounds targeting different structural and functional defects of mutant CFTR is the best strategy to provide more effective correctors that could be used alone or in combination as a valuable therapeutic option to treat an even larger cohort of people affected by CF. Full article
(This article belongs to the Special Issue Cystic Fibrosis and Rare Mutations: New Promising Approaches via Proteostase Modulators)
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