scholarly journals Chloride transport modulators as drug candidates

2021 ◽  
Author(s):  
Alan S. Verkman ◽  
Luis J. V. Galietta
Keyword(s):  
Cystic Fibrosis ◽  
Drug Discovery ◽  
Small Molecule ◽  
Kidney Stones ◽  
Chloride Channel ◽  
Chloride Channels ◽  
Chloride Transport ◽  
Secretory Diarrhea ◽  
Small Molecule Modulators ◽  
Made In

Chloride transport across cell membranes is broadly involved in epithelial fluid transport, cell volume and pH regulation, muscle contraction, membrane excitability, and organellar acidification. The human genome encodes at least 53 chloride transporting proteins with expression in cell plasma or intracellular membranes, which include chloride channels, exchangers and cotransporters, some having broad anion specificity. Loss of function mutations in chloride transporters cause a wide variety of human diseases, including cystic fibrosis, secretory diarrhea, kidney stones, salt wasting nephropathy, myotonia, osteopetrosis, hearing loss and goiter. While impactful advances have been made in the past decade in drug treatment of cystic fibrosis using small molecule modulators of the defective cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, other chloride channels and solute carrier proteins (SLCs) represent relatively underexplored target classes for drug discovery. New opportunities have emerged for development of chloride transport modulators as potential therapeutics for secretory diarrheas, constipation, dry eye disorders, kidney stones, polycystic kidney disease, hypertension and osteoporosis. Approaches to chloride transport-targeted drug discovery are reviewed herein, with focus on chloride channel and exchanger classes in which recent preclinical advances have been made in the identification of small molecule modulators and in proof of concept testing in experimental animal models.

ClC-5: ontogeny of an alternative chloride channel in respiratory epithelia

2002 ◽  
Vol 282 (3) ◽  
pp. L501-L507 ◽  
Author(s):  
Rebecca D. Edmonds ◽  
Ian V. Silva ◽  
William B. Guggino ◽  
Robert B. Butler ◽  
Pamela L. Zeitlin ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Chloride Channel ◽  
Chloride Channels ◽  
Chloride Transport ◽  
Premature Death ◽  
Fetal Lung ◽  
Chloride Secretion ◽  
Normal Lung ◽  
Ribonuclease Protection Assay

Chloride transport is critical to many functions of the lung. Molecular defects in the best-known chloride channel, cystic fibrosis transmembrane conductance regulator (CFTR), lead to impaired function of airway defensins, hydration of airway surface fluid, and mucociliary clearance leading to chronic lung disease, and premature death, but do not cause defects in lung development. We examined the expression of one member of the ClC family of volume- and voltage-regulated channels using the ribonuclease protection assay and Western blot analysis in rats. ClC-5 mRNA and protein are most strongly expressed in the fetal lung, and expression is maintained although downregulated postnatally. In addition, using immunocytochemistry, we find that ClC-5 is predominantly expressed along the luminal surface of the airway epithelium, suggesting that ClC-5 may participate in lung chloride secretion. Identifying candidate genes for critical ion transport functions is essential for understanding normal lung morphogenesis and the pathophysiology of several lung diseases. In addition, the manipulation of non-CFTR chloride channels may provide a viable approach for treating cystic fibrosis lung disease.

In vivo role of CLC chloride channels in the kidney

2000 ◽  
Vol 279 (5) ◽  
pp. F802-F808 ◽  
Author(s):  
Shinichi Uchida
Keyword(s):  
Chloride Channel ◽  
Chloride Channels ◽  
Cellular Localization ◽  
Chloride Transport ◽  
Kidney Diseases ◽  
Cell Volume Regulation ◽  
Special Focus ◽  
Loss Of Function ◽  
Intracellular Vesicles

Chloride channels in the kidney are involved in important physiological functions such as cell volume regulation, acidification of intracellular vesicles, and transepithelial chloride transport. Among eight mammalian CLC chloride channels expressed in the kidney, three (CLC-K1, CLC-K2, and CLC-5) were identified to be related to kidney diseases in humans or mice. CLC-K1 mediates a transepithelial chloride transport in the thin ascending limb of Henle's loop and is essential for urinary concentrating mechanisms. CLC-K2 is a basolateral chloride channel in distal nephron segments and is necessary for chloride reabsorption. CLC-5 is a chloride channel in intracellular vesicles of proximal tubules and is involved in endocytosis. This review will cover the recent advances in research on the CLC chloride channels of the kidney with a special focus on the issues most necessary to understand their physiological roles in vivo, i.e., their intrarenal and cellular localization and their phenotypes of humans and mice that have their loss-of-function mutations.

Chloride channels and cystic fibrosis of the pancreas

1995 ◽  
Vol 15 (6) ◽  
pp. 531-541 ◽  
Author(s):  
M. A. Gray ◽  
J. P. Winpenny ◽  
B. Verdon ◽  
H. McAlroy ◽  
B. E. Argent
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Channel ◽  
Chloride Channels ◽  
Secretory Activity ◽  
Caucasian Population ◽  
Pharmacological Intervention ◽  
Apical Plasma Membrane ◽  
Pancreatic Dysfunction ◽  
Strong Candidate ◽  
Cl Conductance

Cystic fibrosis (CF) affects approximately 1 in 2000 people making it one of the commonest fatal, inherited diseases in the Caucasian population. CF is caused by mutations in a cyclic AMP-regulated chloride channel known as CFTR, which is found on the apical plasma membrane of many exocrine epithelial cells. In the CF pancreas, dysfunction of the CFTR reduces the secretory activity of the tubular duct cells, which leads to blockage of the ductal system and eventual fibrosis of the whole gland. One possible approach to treating the disease would be to activate an alternative chloride channel capable of bypassing defective CFTR. A strong candidate for this is a chloride channel regulated by intracellular calcium, which has recently been shown to protect the pancreas in transgenic CF mice. Pharmacological intervention directed at activating this calcium-activated Cl− conductance might provide a possible therapy to treat the problems of pancreatic dysfunction in CF.

Chloride channels of intracellular organelles and their potential role in cystic fibrosis.

1992 ◽  
Vol 172 (1) ◽  
pp. 245-266 ◽  
Author(s):  
Q al-Awqati ◽  
J Barasch ◽  
D Landry
Keyword(s):  
Cystic Fibrosis ◽  
Fusion Protein ◽  
Cdna Library ◽  
Chloride Channel ◽  
Chloride Channels ◽  
Kidney Cortex ◽  
Affinity Column ◽  
Channel Activity ◽  
Planar Bilayers ◽  
Intracellular Organelles

Chloride channels were previously purified from bovine kidney cortex membranes using a drug affinity column. Reconstitution of the purified proteins into artificial liposomes and planar bilayers yielded chloride channels. A 64 x 10(3) M(r) protein, p64, identified as a component of this chloride channel, was used to generate antibodies which depleted solubilized kidney membranes of all chloride channel activity. This antibody has now been used to identify a clone, H2B, from a kidney cDNA library. Antibodies, affinity-purified against the fusion protein of H2B, from a kidney cDNA library. Antibodies, affinity-purified against the fusion protein of H2B, also depleted solubilized kidney cortex from all chloride channel activity. The predicted amino acid sequence of p64 shows that it contains two and possibly four putative transmembrane domains and potential phosphorylation sites by protein kinases A and C. There was no significant homology to other protein (or DNA) sequences in the data base including other anion channels or the cystic fibrosis transmembrane conductance regulator. The protein is expressed in all cells tested and probably represents the chloride channel of intracellular organelles. Cystic fibrosis (CF) is associated with a defect in a cyclic-AMP-activated chloride channel in secretory epithelia which leads to decreased fluid secretion. In addition, many mucus glycoproteins show decreased sialylation but increased sulfation. We have recently shown that the pH of intracellular organelles is more alkaline in CF cells, an abnormality that is due to defective chloride conductance in the vesicle membranes. We postulate that the defect in the intracellular chloride channel, and hence the alkalization, could explain the glycosylation abnormalities since the pH optimum of Golgi sialyltransferase is acid while that of focusyl- and sulfotransferases is alkaline. Defects in sialyation of glycolipids might also generate receptors for Pseudomonas, which is known to colonize the respiratory tract of CF patients.

Insights into the mechanisms underlying CFTR channel activity, the molecular basis for cystic fibrosis and strategies for therapy

2011 ◽  
Vol 50 ◽  
pp. 233-248 ◽  
Author(s):  
Patrick Kim Chiaw ◽  
Paul D.W. Eckford ◽  
Christine E. Bear
Keyword(s):  
Cystic Fibrosis ◽  
Small Molecule ◽  
Molecular Basis ◽  
Structural Changes ◽  
Common Mutation ◽  
Channel Activity ◽  
Wild Type ◽  
In The Wild ◽  
Cftr Protein ◽  
Small Molecule Modulators

Mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) cause CF (cystic fibrosis), a fatal genetic disease commonly leading to airway obstruction with recurrent airway inflammation and infection. Pulmonary obstruction in CF has been linked to the loss of CFTR function as a regulated Cl− channel on the lumen-facing membrane of the epithelium lining the airways. We have learned much about the molecular basis for nucleotide- and phosphorylation-dependent regulation of channel activity of the normal (wild-type) version of the CFTR protein through electrophysiological studies. The major CF-causing mutation, F508del-CFTR, causes the protein to misfold and be retained in the ER (endoplasmic reticulum). Importantly, recent studies in cell culture have shown that retention in the ER can be ‘corrected’ through the application of certain small-molecule modulators and, once at the surface, the altered channel function of the major mutant can be ‘potentiated’, pharmacologically. Importantly, two such small molecules, a ‘corrector’ (VX-809) and a ‘potentiator’ (VX-770) compound are undergoing clinical trial for the treatment of CF. In this chapter, we describe recent discoveries regarding the wild-type CFTR and F508del-CFTR protein, in the context of molecular models based on X-ray structures of prokaryotic ABC (ATP-binding cassette) proteins. Finally, we discuss the promise of small-molecule modulators to probe the relationship between structure and function in the wild-type protein, the molecular defects caused by the most common mutation and the structural changes required to correct these defects.

scholarly journals Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR

2022 ◽  
Author(s):  
Loes M Stevers ◽  
Madita Wolter ◽  
Graeme Carlile ◽  
Dwight Macdonald ◽  
Luc Richard ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Plasma Membrane ◽  
Mechanism Of Action ◽  
Chloride Channel ◽  
Chloride Transport ◽  
Membrane Localization ◽  
Pharmacological Chaperone ◽  
Plasma Membrane Localization

Impaired activity of the chloride channel CFTR is the cause of cystic fibrosis. 14-3-3 proteins have been shown to stabilize CFTR and increase its biogenesis and activity. Here, we report the identification and mechanism of action of a macrocycle stabilizing the 14-3-3/CFTR complex, a first-in-class molecular glue. This molecule rescues plasma membrane localization and chloride transport of F508del-CFTR and works additively with the CFTR pharmacological chaperone corrector lumacaftor (VX-809).

Sign in / Sign up

Export Citation Format

Share Document