Synthesis of diacylated γ-glutamyl-cysteamine prodrugs, and in vitro evaluation of their cytotoxicity and intracellular delivery of cysteamine

Frost, Lisa; Suryadevara, P; Cannell, Stephanie J.; Groundwater, Paul W.; Hambleton, Paul; Anderson, Rosaleen J.

doi:10.1016/j.ejmech.2015.12.027

Cited by 14 publications

(8 citation statements)

References 36 publications

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“…These disadvantages greatly affect drug compliance especially in adolescents and young adults 55 . To avoid such adverse effects many drugs are being investigated to find an alternative therapeutic agent, especially among the structurally related cysteamine analogues and prodrugs 56 57 . On the other hand, substances targeting pathogenic mechanisms not related to cystine accumulation, such as autophagy and impaired endocytosis, are currently considered as an adjuvant therapy to cystine depletion 48 52 .…”

Section: Discussionmentioning

confidence: 99%

Cystinosis (ctns) zebrafish mutant shows pronephric glomerular and tubular dysfunction

Elmonem

Khalil

Khodaparast

et al. 2017

Sci Rep

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The human ubiquitous protein cystinosin is responsible for transporting the disulphide amino acid cystine from the lysosomal compartment into the cytosol. In humans, Pathogenic mutations of CTNS lead to defective cystinosin function, intralysosomal cystine accumulation and the development of cystinosis. Kidneys are initially affected with generalized proximal tubular dysfunction (renal Fanconi syndrome), then the disease rapidly affects glomeruli and progresses towards end stage renal failure and multiple organ dysfunction. Animal models of cystinosis are limited, with only a Ctns knockout mouse reported, showing cystine accumulation and late signs of tubular dysfunction but lacking the glomerular phenotype. We established and characterized a mutant zebrafish model with a homozygous nonsense mutation (c.706 C > T; p.Q236X) in exon 8 of ctns. Cystinotic mutant larvae showed cystine accumulation, delayed development, and signs of pronephric glomerular and tubular dysfunction mimicking the early phenotype of human cystinotic patients. Furthermore, cystinotic larvae showed a significantly increased rate of apoptosis that could be ameliorated with cysteamine, the human cystine depleting therapy. Our data demonstrate that, ctns gene is essential for zebrafish pronephric podocyte and proximal tubular function and that the ctns-mutant can be used for studying the disease pathogenic mechanisms and for testing novel therapies for cystinosis.

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Section: Discussionmentioning

confidence: 99%

Cystinosis (ctns) zebrafish mutant shows pronephric glomerular and tubular dysfunction

Elmonem

Khalil

Khodaparast

et al. 2017

Sci Rep

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“…This conjugate could effectively rescue F508del-CFTR to the PM at a substantially lower concentration, thus warranting its further evaluation in a clinical setting. In another report, nine “prodrugs” of -glutamyl-cysteamine were tested in cultured kidney cells, to overcome its major disadvantages (Frost et al, 2016). These prodrugs could undertake successful delivery of cysteamine into kidney epithelial cells with improved bioavailability and low toxicity (Frost et al, 2016).…”

Section: Cysteamine: a Multi-pronged Drug For Cfmentioning

confidence: 99%

“…In another report, nine “prodrugs” of -glutamyl-cysteamine were tested in cultured kidney cells, to overcome its major disadvantages (Frost et al, 2016). These prodrugs could undertake successful delivery of cysteamine into kidney epithelial cells with improved bioavailability and low toxicity (Frost et al, 2016). This approach seems promising and needs further evaluation in pre-clinical CF models.…”

Section: Cysteamine: a Multi-pronged Drug For Cfmentioning

confidence: 99%

Adapting Proteostasis and Autophagy for Controlling the Pathogenesis of Cystic Fibrosis Lung Disease

Bodas

Vij

2019

Front. Pharmacol.

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Cystic fibrosis (CF), a fatal genetic disorder predominant in the Caucasian population, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (Cftr) gene. The most common mutation is the deletion of phenylalanine from the position-508 (F508del-CFTR), resulting in a misfolded-CFTR protein, which is unable to fold, traffic and retain its plasma membrane (PM) localization. The resulting CFTR dysfunction, dysregulates variety of key cellular mechanisms such as chloride ion transport, airway surface liquid (ASL) homeostasis, mucociliary-clearance, inflammatory-oxidative signaling, and proteostasis that includes ubiquitin-proteasome system (UPS) and autophagy. A collective dysregulation of these key homoeostatic mechanisms contributes to the development of chronic obstructive cystic fibrosis lung disease, instead of the classical belief focused exclusively on ion-transport defect. Hence, therapeutic intervention(s) aimed at rescuing chronic CF lung disease needs to correct underlying defect that mediates homeostatic dysfunctions and not just chloride ion transport. Since targeting all the myriad defects individually could be quite challenging, it will be prudent to identify a process which controls almost all disease-promoting processes in the CF airways including underlying CFTR dysfunction. There is emerging experimental and clinical evidence that supports the notion that impaired cellular proteostasis and autophagy plays a central role in regulating pathogenesis of chronic CF lung disease. Thus, correcting the underlying proteostasis and autophagy defect in controlling CF pulmonary disease, primarily via correcting the protein processing defect of F508del-CFTR protein has emerged as a novel intervention strategy. Hence, we discuss here both the rationale and significant therapeutic utility of emerging proteostasis and autophagy modulating drugs/compounds in controlling chronic CF lung disease, where targeted delivery is a critical factor-influencing efficacy.

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“…In the present study, the colorimetric MTT assay was employed to detect cell viability [37]. For this purpose, DEX-RA was dissolved in medium and cells were exposed to the polymeric conjugate at different concentrations for 24 h at 37 • C under 5% CO 2 .…”

Section: Cell Viability By Mtt Assaymentioning

confidence: 99%

Safety and Efficacy of Dextran-Rosmarinic Acid Conjugates as Innovative Polymeric Antioxidants in Skin Whitening: What Is the Evidence?

et al. 2017

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Background: Melanins are high molecular weight pigments responsible for the mammalian skin and hair colour and play a key role in skin protection from UV radiation; however, their overproduction and excessive accumulation lead to pigmentation problems including melasma, freckles, uneven colouring, and age spots. Therefore, the modulation of melanin synthesis represents a critical issue in medicine and cosmetology. In the present study, an innovative polymeric antioxidant to be used as skin whitening agent is developed by the conjugation of dextran with rosmarinic acid. Methods: Dextran-rosmarinic acid conjugates (DEX-RA) were synthesized in a one-pot method starting from Origanum vulgare aqueous leaf extract and dextran. The total polyphenol content and the antioxidant activity were assessed by Folin-Ciocalteau assay and 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) and bleaching tests, respectively. The efficacy of DEX-RA was evaluated by inhibition of tyrosinase activity, in vitro diffusion and stability studies and in vivo studies. The biocompatibility of the conjugates was investigated by 3-[4,5-Dimethylthiaoly]-2,5-diphenyltetrazoliumbromide (MTT) and EPISKIN™ model. Results: Efficacy and safety studies confirmed the antioxidant and tyrosinase inhibitory activities and the biocompatibility of the synthesized conjugates. Conclusion: The polymeric conjugates, comparing to the free antioxidant, show a long-lasting efficacy combined to an enhanced stability resulting in an improved performance of the cosmetic formulations prepared using this innovative whitening agent as a bioactive ingredient.

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Synthesis of diacylated γ-glutamyl-cysteamine prodrugs, and in vitro evaluation of their cytotoxicity and intracellular delivery of cysteamine

Cited by 14 publications

References 36 publications

Cystinosis (ctns) zebrafish mutant shows pronephric glomerular and tubular dysfunction

Cystinosis (ctns) zebrafish mutant shows pronephric glomerular and tubular dysfunction

Adapting Proteostasis and Autophagy for Controlling the Pathogenesis of Cystic Fibrosis Lung Disease

Safety and Efficacy of Dextran-Rosmarinic Acid Conjugates as Innovative Polymeric Antioxidants in Skin Whitening: What Is the Evidence?

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