Identification of Natural Coumarin Compounds That Rescue Defective Δf508‐cftr Chloride Channel Gating

Xu, Lingyu; Na, Wanli; Liu, Xin; Hou, Shuguang; Lin, Shan‐Yang; Yang, Hong; Ma, Tiantian

doi:10.1111/j.1440-1681.2008.04943.x

Cited by 16 publications

(19 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In fact, genistein has been demonstrated to be more effective in partial restoration of the F508 CFTR activity than other potentiators, including scopoletin, isopsoralen, osthole, imperatorin, praeruptorin A and UC CF -029 (7,8-benzoflavone) [23,24].…”

Section: Genistein As a Potential Drug In Cf (Cystic Fibrosis)mentioning

confidence: 98%

“…Although several other potentiators of F508 CFTR were found [23,24], genistein is still one of the most efficient activators of the mutant protein, and, because of its low toxicity [4], it can be placed among the best candidates for a CF therapeutic. In fact, genistein has been demonstrated to be more effective in partial restoration of the F508 CFTR activity than other potentiators, including scopoletin, isopsoralen, osthole, imperatorin, praeruptorin A and UC CF -029 (7,8-benzoflavone) [23,24].…”

Section: Genistein As a Potential Drug In Cf (Cystic Fibrosis)mentioning

confidence: 99%

See 1 more Smart Citation

Genistein: a natural isoflavone with a potential for treatment of genetic diseases

Węgrzyn

Jakóbkiewicz‐Banecka

Gabig-Cimińska

et al. 2010

Biochemical Society Transactions

View full text Add to dashboard Cite

Genistein [4',5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one] is a natural isoflavone occurring in many plants known to possess various biological activities, ranging from phyto-oestrogenic to antioxidative actions. Recent studies indicated that this isoflavone can also be considered as a drug for as yet untreatable genetic diseases. In the present review, we discuss a plausible use of genistein in treatment of two genetic disorders: CF (cystic fibrosis) and MPS (mucopolysaccharidosis). Although various biological actions of genistein are employed in these two cases, in vitro studies, tests on animal models and pilot clinical trials suggest that this plant-derived compound might be a real hope for patients suffering from severe inherited disorders with relatively complicated pathomechanisms, including those affecting the central nervous system.

show abstract

Section: Genistein As a Potential Drug In Cf (Cystic Fibrosis)mentioning

confidence: 98%

Section: Genistein As a Potential Drug In Cf (Cystic Fibrosis)mentioning

confidence: 99%

Genistein: a natural isoflavone with a potential for treatment of genetic diseases

Węgrzyn

Jakóbkiewicz‐Banecka

Gabig-Cimińska

et al. 2010

Biochemical Society Transactions

View full text Add to dashboard Cite

show abstract

“…HTS exploits a reliable, sensitive, cost-effective assay to screen libraries of chemically diverse small molecules (eg approved drugs [51] , drug-like chemicals [52] and natural products [53] ) to identify lead compounds for medicinal chemistry optimization. For example, Alan Verkman (UCSF, San Francisco, USA) used Fischer rat thyroid cells, epithelial cells devoid of CFTR expression and cAMP-stimulated Cl -currents [54] engineered to co-express recombinant human CFTR and a green fl uorescent protein (GFP) with ultra high halide sensitivity in a halide fl ux assay (eg Yang et al [52] ) .…”

Section: Rational New Therapies For Cf That Target Defects In F508delmentioning

confidence: 99%

Targeting F508del-CFTR to develop rational new therapies for cystic fibrosis

Cai

Liu

et al. 2011

Acta Pharmacol Sin

View full text Add to dashboard Cite

The mutation F508del is the commonest cause of the genetic disease cystic fi brosis (CF). CF disrupts the function of many organs in the body, most notably the lungs, by perturbing salt and water transport across epithelial surfaces. F508del causes harm in two principal ways. First, the mutation prevents delivery of the cystic fi brosis transmembrane conductance regulator (CFTR) to its correct cellular location, the apical (lumen-facing) membrane of epithelial cells. Second, F508del perturbs the Cl -channel function of CFTR by disrupting channel gating. Here, we discuss the development of rational new therapies for CF that target F508del-CFTR. We highlight how structural studies provide new insight into the role of F508 in the regulation of channel gating by cycles of ATP binding and hydrolysis. We emphasize the use of high-throughput screening to identify lead compounds for therapy development. These compounds include CFTR correctors that restore the expression of F508del-CFTR at the apical membrane of epithelial cells and CFTR potentiators that rescue the F508del-CFTR gating defect. Initial results from clinical trials of CFTR correctors and potentiators augur well for the development of small molecule therapies that target the root cause of CF: mutations in CFTR.

show abstract

“…To screen potential activators of CFTR-mediated Cl − flux, a YFP mutant with higher halide sensitivity (YFP-H148Q/I152L) has been co-expressed with defective ΔF508-CFTR in FRT epithelial cells (Yang et al, 2003; Xu et al, 2008). It has been shown that natural cumarine compounds rescue defective ΔF508-CFTR chloride channel gating (Xu et al, 2008).…”

Section: Genetically Encoded Cl− Indicatorsmentioning

confidence: 99%

“…It has been shown that natural cumarine compounds rescue defective ΔF508-CFTR chloride channel gating (Xu et al, 2008). …”

Section: Genetically Encoded Cl− Indicatorsmentioning

confidence: 99%

Genetically encoded optical sensors for monitoring of intracellular chloride and chloride-selective channels activity

Bregestovski

Waseem

Mukhtarov

2009

Front. Mol. Neurosci.

View full text Add to dashboard Cite

This review briefly discusses the main approaches for monitoring chloride (Cl−), the most abundant physiological anion. Noninvasive monitoring of intracellular Cl− ([Cl−]i) is a challenging task owing to two main difficulties: (i) the low transmembrane ratio for Cl−, approximately 10:1; and (ii) the small driving force for Cl−, as the Cl− reversal potential (ECl) is usually close to the resting potential of the cells. Thus, for reliable monitoring of intracellular Cl−, one has to use highly sensitive probes. From several methods for intracellular Cl− analysis, genetically encoded chloride indicators represent the most promising tools. Recent achievements in the development of genetically encoded chloride probes are based on the fact that yellow fluorescent protein (YFP) exhibits Cl−-sensitivity. YFP-based probes have been successfully used for quantitative analysis of Cl− transport in different cells and for high-throughput screening of modulators of Cl−-selective channels. Development of a ratiometric genetically encoded probe, Clomeleon, has provided a tool for noninvasive estimation of intracellular Cl− concentrations. While the sensitivity of this protein to Cl− is low (EC50 about 160 mM), it has been successfully used for monitoring intracellular Cl− in different cell types. Recently a CFP–YFP-based probe with a relatively high sensitivity to Cl− (EC50 about 30 mM) has been developed. This construct, termed Cl-Sensor, allows ratiometric monitoring using the fluorescence excitation ratio. Of particular interest are genetically encoded probes for monitoring of ion channel distribution and activity. A new molecular probe has been constructed by introducing into the cytoplasmic domain of the Cl−-selective glycine receptor (GlyR) channel the CFP–YFP-based Cl-Sensor. This construct, termed BioSensor-GlyR, has been successfully expressed in cell lines. The new genetically encoded chloride probes offer means of screening pharmacological agents, analysis of Cl− homeostasis and functions of Cl−-selective channels under different physiological and pathological conditions.

show abstract

Identification of Natural Coumarin Compounds That Rescue Defective Δf508‐cftr Chloride Channel Gating

Cited by 16 publications

References 25 publications

Genistein: a natural isoflavone with a potential for treatment of genetic diseases

Genistein: a natural isoflavone with a potential for treatment of genetic diseases

Targeting F508del-CFTR to develop rational new therapies for cystic fibrosis

Genetically encoded optical sensors for monitoring of intracellular chloride and chloride-selective channels activity

Contact Info

Product

Resources

About