Molecular mechanisms of cystic fibrosis – how mutations lead to misfunction and guide therapy

Farinha, Carlos M.; Callebaut, Isabelle

doi:10.1042/bsr20212006

Cited by 16 publications

(9 citation statements)

References 157 publications

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“…Chloride channels can be activated by voltage (CLC channels), volume (volume-regulated anion channels (VRACs)), ligands (GABA and glycine), or Ca 2+ (calcium-activated chloride channels (CaCCs)). A particular type is the CFTR (cystic fibrosis transmembrane conductance regulator), epithelial chloride channel regulating secretion and water balance in multiple organs, and whose loss of function mutations underlie cystic fibrosis pathologies [ 119 , 120 ]. Localized either at the plasma membrane or in intracellular organelles, their function is required for adequate ion homeostasis.…”

Section: Ion Channel Repertoiresmentioning

confidence: 99%

Down the membrane hole: Ion channels in protozoan parasites

Jiménez

Sebastian

2022

PLoS Pathog

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Parasitic diseases caused by protozoans are highly prevalent around the world, disproportionally affecting developing countries, where coinfection with other microorganisms is common. Control and treatment of parasitic infections are constrained by the lack of specific and effective drugs, plus the rapid emergence of resistance. Ion channels are main drug targets for numerous diseases, but their potential against protozoan parasites is still untapped. Ion channels are membrane proteins expressed in all types of cells, allowing for the flow of ions between compartments, and regulating cellular functions such as membrane potential, excitability, volume, signaling, and death. Channels and transporters reside at the interface between parasites and their hosts, controlling nutrient uptake, viability, replication, and infectivity. To understand how ion channels control protozoan parasites fate and to evaluate their suitability for therapeutics, we must deepen our knowledge of their structure, function, and modulation. However, methodological approaches commonly used in mammalian cells have proven difficult to apply in protozoans. This review focuses on ion channels described in protozoan parasites of clinical relevance, mainly apicomplexans and trypanosomatids, highlighting proteins for which molecular and functional evidence has been correlated with their physiological functions.

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Section: Ion Channel Repertoiresmentioning

confidence: 99%

Down the membrane hole: Ion channels in protozoan parasites

Jiménez

Sebastian

2022

PLoS Pathog

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“…Finally, class VII mutations, recently introduced, lead to the absence of full-length mature RNA interfering with mRNA splicing so that CFTR protein is totally absent. [8][9][10][11] Traditionally, CF treatment was oriented on symptom control and prevention of complications. [5,6] Recently, novel drugs able to modulate CFTR activity have been identified and effectively introduced in the treatment of CF patients.…”

Section: Introductionmentioning

confidence: 99%

“…Class V mutations diminish the quantities of CFTR protein and class VI alterations produce unstable channels with a short half‐life. Finally, class VII mutations, recently introduced, lead to the absence of full‐length mature RNA interfering with mRNA splicing so that CFTR protein is totally absent [8–11] …”

Section: Introductionmentioning

confidence: 99%

Cyclic diacyl thioureas enhance activity of corrector Lumacaftor on F508del‐CFTR

Spallarossa,

Pedemonte,

Pesce

et al. 2024

ChemMedChem

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Cystic fibrosis is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. In the search of novel series of CFTR modulators, a library of mono and diacyl thioureas were prepared by sequential synthesis. When tested alone, the obtained compounds 5 and 6 poorly affected F508del‐CFTR conductance but, in combination with Lumacaftor, selected derivatives showed the ability to increase the activity of the approved modulator. Analogue 6i displayed the most marked enhancing effect and acylthioureas 6d and 6f were also able to improve efficacy of Lumacaftor. All compounds proved to be non‐cytotoxic against different cancer cell lines. Good pharmacokinetic properties were predicted for derivatives 5 and 6, thus supporting the value of these compounds for the development of novel modulators potentially useful for cystic fibrosis.

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“…The increased viscosity is clinically transposed to airways obstruction, followed by pathogens colonization, triggering infection and inflammation, all resulting shortly in an impaired respiratory process, even severe respiratory failure. This mechanism depicted at the level of the airway epithelial cell develops similarly in other epithelial cells of exocrine glands, e.g., the pancreas [ 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Current and Future Therapeutic Approaches of Exocrine Pancreatic Insufficiency in Children with Cystic Fibrosis in the Era of Personalized Medicine

et al. 2023

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This review presents current updates of pancreatic enzyme replacement therapy in children with cystic fibrosis based on literature published in the last decade and some special considerations regarding pancreatic enzyme replacement therapy in the era of new therapies, such as cystic fibrosis transmembrane conductance regulator modulator therapies. Few articles evaluate the efficacy of pancreatic enzyme replacement therapy in the pediatric population, and most studies also included children and adults with cystic fibrosis. Approximately 85% of cystic fibrosis patients have exocrine pancreatic insufficiency and need pancreatic enzyme replacement therapy. Fecal elastase is the most commonly used diagnostic test for exocrine pancreatic insufficiency, although this value can fluctuate over time. While it is used as a diagnostic test, it cannot be used for monitoring the effectiveness of pancreatic enzyme replacement therapy and for adjusting doses. Pancreatic enzyme replacement therapy, the actual treatment for exocrine pancreatic insufficiency, is essential in children with cystic fibrosis to prevent malabsorption and malnutrition and needs to be urgently initiated. This therapy presents many considerations for physicians, patients, and their families, including types and timing of administration, dose monitoring, and therapy failures. Based on clinical trials, pancreatic enzyme replacement therapy is considered effective and well-tolerated in children with cystic fibrosis. An important key point in cystic fibrosis treatment is the recent hypothesis that cystic fibrosis transmembrane conductance regulator modulators could improve pancreatic function, further studies being essential. Pancreatic enzyme replacement therapy is addressed a complication of the disease (exocrine pancreatic insufficiency), while modulators target the defective cystic fibrosis transmembrane conductance regulator protein. Exocrine pancreatic insufficiency in cystic fibrosis remains an active area of research in this era of cystic fibrosis transmembrane conductance regulator modulator therapies. This new therapy could represent an example of personalized medicine in cystic fibrosis patients, with each class of modulators being addressed to patients with specific genetic mutations.

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Molecular mechanisms of cystic fibrosis – how mutations lead to misfunction and guide therapy

Cited by 16 publications

References 157 publications

Down the membrane hole: Ion channels in protozoan parasites

Down the membrane hole: Ion channels in protozoan parasites

Cyclic diacyl thioureas enhance activity of corrector Lumacaftor on F508del‐CFTR

Current and Future Therapeutic Approaches of Exocrine Pancreatic Insufficiency in Children with Cystic Fibrosis in the Era of Personalized Medicine

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