Cystic Fibrosis: Overview of the Current Development Trends and Innovative Therapeutic Strategies

Almughem, Fahad A.; Aldossary, Ahmad M.; Tawfik, Essam A.; Alomary, Mohammad N.; Alharbi, Waleed S.; Alshahrani, Mohammad Y.; Alshehri, Abdullah A.

doi:10.3390/pharmaceutics12070616

Cited by 22 publications

(19 citation statements)

References 226 publications

(299 reference statements)

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“…Trapped chloride ions in cells cannot attract the fluids necessary to hydrate the cell surface and in the absence of the fluids, mucus becomes dehydrated and takes on a viscous consistency. 41 CFTR modulator therapy proposed by Jarosz-Griffiths and co-workers could confer additional benefit to patients and may also contribute to improved clinical outcomes. 42 …”

Section: Association Of Immune Response With Mucus Secretionmentioning

confidence: 99%

Cytokine Storm and Mucus Hypersecretion in COVID-19: Review of Mechanisms

Khan¹,

Khan²,

Munier³

et al. 2021

JIR

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Mucus is an integral part of the respiratory physiology. It protects the respiratory tract by acting as a physical barrier against inhaled particles and microbes. Excessive inflammation in conditions such as COVID-19 can result in over-production of mucus which obstructs the airway. Build-up of mucus can also contribute to recurrent airway infection, causing further obstruction. This article summarizes the current understanding and knowledge of respiratory mucus production and proposes the role of cytokine storm in inducing sudden mucus hypersecretion in COVID-19. Based on these cascades, the active constituents that inhibit or activate several potential targets are outlined for further research. These may be explored for the discovery and design of drugs to combat cytokine storm and its ensuing complications.

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Section: Association Of Immune Response With Mucus Secretionmentioning

confidence: 99%

Cytokine Storm and Mucus Hypersecretion in COVID-19: Review of Mechanisms

Khan¹,

Khan²,

Munier³

et al. 2021

JIR

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“…Novel treatment strategies target the CFTR at various levels, which include increasing CFTR mRNA levels (nonsense-mediated mRNA decay (NMD) inhibitors); suppressing translation termination at premature stop codon (PTC) in CFTR mRNA (readthrough therapies); correction of CFTR folding and trafficking to apical membrane (correctors); increasing the channel function (potentiators); stimulation of CFTR expression (amplifiers); and increasing the stability/decreasing degradation rate of CFTR protein at the plasma membrane (stabilizers) [177,178]. Some of the best known SMDs are CFTR corrector VX-809 (lumacaftor) for class II mutations and CFTR potentiator VX-770 (ivacaftor) for the G551D mutation [179]. Ivacaftor (brand name Kalydeco), the first CFTR modulator approved by the FDA (2012), brought proof that CFTR protein correction can improve the health of CF patients.…”

Section: Therapiesmentioning

confidence: 99%

The Distribution and Role of the CFTR Protein in the Intracellular Compartments

Łukasiak

Zając

2021

Membranes

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Cystic fibrosis is a hereditary disease that mainly affects secretory organs in humans. It is caused by mutations in the gene encoding CFTR with the most common phenylalanine deletion at position 508. CFTR is an anion channel mainly conducting Cl− across the apical membranes of many different epithelial cells, the impairment of which causes dysregulation of epithelial fluid secretion and thickening of the mucus. This, in turn, leads to the dysfunction of organs such as the lungs, pancreas, kidney and liver. The CFTR protein is mainly localized in the plasma membrane; however, there is a growing body of evidence that it is also present in the intracellular organelles such as the endosomes, lysosomes, phagosomes and mitochondria. Dysfunction of the CFTR protein affects not only the ion transport across the epithelial tissues, but also has an impact on the proper functioning of the intracellular compartments. The review aims to provide a summary of the present state of knowledge regarding CFTR localization and function in intracellular compartments, the physiological role of this localization and the consequences of protein dysfunction at cellular, epithelial and organ levels. An in-depth understanding of intracellular processes involved in CFTR impairment may reveal novel opportunities in pharmacological agents of cystic fibrosis.

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“…S6). In [dLeu 14 , dphosphoSer 17 ]Esc, the phosphorylated Ser 17 performs a highly persistent intramolecular salt-bridge (average persistence in MD replicas is around 88%) with Lys 20 , which formally decreases the overall basicity of the peptide and sequestrates the basic residue from its potential interaction with the NBDs. Accordingly, MD simulations suggested that [dLeu 14 , dphosphoSer 17 ]Esc preferentially binds into a more hydrophobic binding site of the NBDs compared to Esc(1-21).…”

Section: Esc Peptides Potentially Interact With F508del-cftrmentioning

confidence: 99%

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

Ferrera

Cappiello

Loffredo

et al. 2021

Cell. Mol. Life Sci.

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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.

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Cystic Fibrosis: Overview of the Current Development Trends and Innovative Therapeutic Strategies

Cited by 22 publications

References 226 publications

Cytokine Storm and Mucus Hypersecretion in COVID-19: Review of Mechanisms

Cytokine Storm and Mucus Hypersecretion in COVID-19: Review of Mechanisms

The Distribution and Role of the CFTR Protein in the Intracellular Compartments

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

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