Synthesis and structure–activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis

Pesce, Emanuela; Bellotti, Marta; Liessi, Nara; Guariento, Sara; Damonte, Gianluca; Cichero, Elena; Galatini, Andrea; Salis, Annalisa; Gianotti, Ambra; Pedemonte, Nicoletta; Zegarra‐Moran, Olga; Fossa, Paola; Galietta, Luis J. V.; Millo, Enrico

doi:10.1016/j.ejmech.2015.05.030

Cited by 32 publications

(45 citation statements)

References 30 publications

(39 reference statements)

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“…We performed functional analysis of Tα-1 activity as F508del-CFTR corrector by means of the microfluorimetric assay based on the HS-YFP that has been extensively used to investigate various rescue maneuvers (36)(37)(38)(39)(40) and by means of whole-cell patch-clamp analyses. In parallel, we also performed immunolocalization experiments and biochemical analyses of the electrophoretic mobility of the different CFTR forms expressed by the cells under resting conditions or following treatment with Tα-1.…”

Section: Discussionmentioning

confidence: 99%

“…F508del-CFTR CFBE41o-cells were subsequently engineered to stably express the halide-sensitive yellow fluorescent protein (HS-YFP). This cell line has been extensively used by our group to identify and characterize various CFTR modulators, including proteostasis regulators (36)(37)(38)(39)(40). CFBE41o-cells, coexpressing F508del-CFTR and HS-YFP, plated on 96-well plates, were treated for 24 hours with vehicle alone (DMSO), Tα-1 (25, 50, 100, or 200 ng/ml, all containing the same amount of DMSO), scrambled peptide (100 ng/ml, also containing DMSO), or cysteamine (250 μM).…”

Section: Tα-1 Does Not Increase F508del-cftr Expression/function In Pmentioning

confidence: 99%

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Thymosin α-1 does not correct F508del-CFTR in cystic fibrosis airway epithelia

et al. 2018

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Section: Discussionmentioning

confidence: 99%

Section: Tα-1 Does Not Increase F508del-cftr Expression/function In Pmentioning

confidence: 99%

Thymosin α-1 does not correct F508del-CFTR in cystic fibrosis airway epithelia

et al. 2018

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“…Aminoarylthiazoles (AATs) 64 are an interesting example of dual active compounds. 65 Moreover, 4,6,4'-trimethylangelicin was found to potentiate wild-type CFTR as well as to rescue the F508del-CFTR protein in human bronchial epithelial cells. 66 In addition, CFTR modulating effects have been achieved in preclinical models by phosphodiesterase-5 inhibitors that exhibit both potentiator and corrector activity through cGMP-dependent and independent mechanisms, respectively.…”

Section: Pharmacological Strategies For Cftr Repairmentioning

confidence: 98%

Strategies for the etiological therapy of cystic fibrosis

2017

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Etiological therapies aim at repairing the underlying cause of cystic fibrosis (CF), which is the functional defect of the cystic fibrosis transmembrane conductance regulator (CFTR) protein owing to mutations in the CFTR gene. Among these, the F508del CFTR mutation accounts for more than two thirds of CF cases worldwide. Two somehow antinomic schools of thought conceive CFTR repair in a different manner. According to one vision, drugs should directly target the mutated CFTR protein to increase its plasma membrane expression (correctors) or improve its ion transport function (potentiators). An alternative strategy consists in modulating the cellular environment and proteostasis networks in which the mutated CFTR protein is synthesized, traffics to its final destination, the plasma membrane, and is turned over. We will analyze distinctive advantages and drawbacks of these strategies in terms of their scientific and clinical dimensions, and we will propose a global strategy for CF research and development based on a reconciliatory approach. Moreover, we will discuss the utility of preclinical biomarkers that may guide the personalized, patient-specific implementation of CF therapies.

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“…This study eventually culminated in the identification of 443 , which maintained in vitro activity against MDR strains as well as displaying metabolic stability, and which was not susceptible to efflux pumps . A related compound ( 444 ) featured in a study which identified correctors of cystic fibrosis transmembrane conductance regulating chloride channel …”

Section: Tuberculosismentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.

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Synthesis and structure–activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis

Cited by 32 publications

References 30 publications

Thymosin α-1 does not correct F508del-CFTR in cystic fibrosis airway epithelia

Thymosin α-1 does not correct F508del-CFTR in cystic fibrosis airway epithelia

Strategies for the etiological therapy of cystic fibrosis

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

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