Rescuing the CFTR protein function: Introducing 1,3,4-oxadiazoles as translational readthrough inducing drugs

Pibiri, Ivana; Lentini, Laura; Melfi, Raffaella; Tutone, Marco; Baldassano, Sara; Galluzzo, Paola; Leonardo, Aldo Di; Pace, Andrea

doi:10.1016/j.ejmech.2018.09.057

Cited by 31 publications

(42 citation statements)

References 39 publications

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“…Ataluren has shown to produce full length, functional dystrophin ( 2 , 4 , 13 ) in the nonsense mutation mdx mouse and sapje zebrafish models of DMD. Ataluren activity has also been demonstrated in multiple cell‐based and animal disease models of other nonsense mutation genetic disorders, corroborating its ability to promote readthrough of premature stop codons and its potential for treating genetic disease caused by nonsense mutations 14–19 . Comprehensive nonclinical studies have been conducted in safety pharmacology and secondary pharmacodynamics, pharmacokinetics and metabolism, and toxicology programs.…”

Section: Introductionmentioning

confidence: 83%

In vitro metabolism, reaction phenotyping, enzyme kinetics, CYP inhibition and induction potential of ataluren

Kong

Hwang

et al. 2020

Pharmacology Res & Perspec

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Ataluren promotes ribosomal readthrough of premature termination codons in mRNA which result from nonsense mutations. In vitro studies were performed to characterize the metabolism and enzyme kinetics of ataluren and its interaction potential with CYP enzymes. Incubation of [14C]‐ataluren with human liver microsomes indicated that the major metabolic pathway for ataluren is via direct glucuronidation and that the drug is not metabolized via cytochrome P450 (CYP). Glucuronidation was also observed in the incubation in human intestinal and kidney microsomes, but not in human pulmonary microsomes. UGT1A9 was found to be the major uridine diphosphate glucuronosyltransferase (UGT) responsible for ataluren glucuronidation in the liver and kidney microsomes. Enzyme kinetic analysis of the formation of ataluren acyl glucuronide, performed in human liver, kidney, and intestinal microsomes and recombinant human UGT1A9, found that increasing bovine serum albumin (BSA) levels enhanced the glucuronidation Michaelis‐Menten constant (Km) and ataluren protein binding but had a minimal effect on maximum velocity (Vmax) of glucuronidation. Due to the decreased unbound Michaelis‐Menten constant (Km,u), the ataluren unbound intrinsic clearance (CLint,u) increased for all experimental systems and BSA concentrations. Human kidney microsomes were about 3.7‐fold more active than human liver microsomes, in terms of CLint,u/mg protein, indicating that the kidney is also a key organ for the metabolism and disposition of ataluren in humans. Ataluren showed no or little potential to inhibit or induce most of the CYP enzymes.

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Section: Introductionmentioning

confidence: 83%

In vitro metabolism, reaction phenotyping, enzyme kinetics, CYP inhibition and induction potential of ataluren

Kong

Hwang

et al. 2020

Pharmacology Res & Perspec

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“…A search in the Cambridge Structural Database (CSD version 5.39, update of May 2018; Groom et al, 2016) for substituted oxadiazoles revealed two structures, viz. 3-amino-4-methylfurazan (Pibiri et al, 2018) and 4-amino-1,2,5-oxadiazole-3carboxamide oxime (Zhang & Jian, 2009). Tl I complexes with comparable organic ligands have been reported for thallium (anthranoyl)anthranilate (Wiesbrock & Schmidbaur, 2004), thallium(I) 2-amino-benzoate (Wiesbrock & Schmidbaur, 2003), thallium(I) arylcyanoxime (Robertson et al, 2004) [Tl 4 (H 2 O) 2 (anthracene-9-carboxylate) 4 ] (Kumar et al, 2015) (Britton, 2001) and thallium(I) 4-hydroxybenzylidene-4-aminobenzoate (Akhbari et al, 2009).…”

Section: Database Surveymentioning

confidence: 99%

Crystal structure of poly[(μ₃-4-amino-1,2,5-oxadiazole-3-hydroxamato)thallium(I)]

et al. 2020

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The title compound represents the thallium(I) salt of a substituted 1,2,5-oxadiazole, [Tl(C3H3N4O3)] n , with amino- and hydroxamate groups in the 4- and 3- positions of the oxadiazole ring, respectively. In the crystal, the deprotonated hydroxamate group represents an intermediate between the keto/enol tautomers and forms a five-membered chelate ring with the thallium(I) cation. The coordination sphere of the cation is augmented to a distorted disphenoid by two monodentately binding O atoms from two adjacent anions, leading to the formation of zigzag chains extending parallel to the b axis. The cohesion within the chains is supported by π–π stacking [centroid–centroid distance = 3.746 (3) Å] and intermolecular N—H...N hydrogen bonds.

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“…Our previous studies on ataluren and its analogs aimed to look for alternative molecules and to understand the effective biological target and mechanism of action of TRIDs [ 9 , 10 , 51 , 52 , 53 , 54 ].…”

Section: Introductionmentioning

confidence: 99%

“…The flaws in the clinical trials for ataluren, as well as the discrete toxicity evidenced in the MTT test (see Figure S1 ) for our recently reported lead compound NV2445 [ 54 ], pushed us to find new alternative leads.…”

Section: Introductionmentioning

confidence: 99%

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Targeting Nonsense: Optimization of 1,2,4-Oxadiazole TRIDs to Rescue CFTR Expression and Functionality in Cystic Fibrosis Cell Model Systems

Pibiri

Melfi

Tutone

et al. 2020

IJMS

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Cystic fibrosis (CF) patients develop a severe form of the disease when the cystic fibrosis transmembrane conductance regulator (CFTR) gene is affected by nonsense mutations. Nonsense mutations are responsible for the presence of a premature termination codon (PTC) in the mRNA, creating a lack of functional protein. In this context, translational readthrough-inducing drugs (TRIDs) represent a promising approach to correct the basic defect caused by PTCs. By using computational optimization and biological screening, we identified three new small molecules showing high readthrough activity. The activity of these compounds has been verified by evaluating CFTR expression and functionality after treatment with the selected molecules in cells expressing nonsense–CFTR–mRNA. Additionally, the channel functionality was measured by the halide sensitive yellow fluorescent protein (YFP) quenching assay. All three of the new TRIDs displayed high readthrough activity and low toxicity and can be considered for further evaluation as a therapeutic approach toward the second major cause of CF.

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Rescuing the CFTR protein function: Introducing 1,3,4-oxadiazoles as translational readthrough inducing drugs

Cited by 31 publications

References 39 publications

In vitro metabolism, reaction phenotyping, enzyme kinetics, CYP inhibition and induction potential of ataluren

In vitro metabolism, reaction phenotyping, enzyme kinetics, CYP inhibition and induction potential of ataluren

Crystal structure of poly[(μ₃-4-amino-1,2,5-oxadiazole-3-hydroxamato)thallium(I)]

Targeting Nonsense: Optimization of 1,2,4-Oxadiazole TRIDs to Rescue CFTR Expression and Functionality in Cystic Fibrosis Cell Model Systems

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Rescuing the CFTR protein function: Introducing 1,3,4-oxadiazoles as translational readthrough inducing drugs

Cited by 31 publications

References 39 publications

In vitro metabolism, reaction phenotyping, enzyme kinetics, CYP inhibition and induction potential of ataluren

In vitro metabolism, reaction phenotyping, enzyme kinetics, CYP inhibition and induction potential of ataluren

Crystal structure of poly[(μ3-4-amino-1,2,5-oxadiazole-3-hydroxamato)thallium(I)]

Targeting Nonsense: Optimization of 1,2,4-Oxadiazole TRIDs to Rescue CFTR Expression and Functionality in Cystic Fibrosis Cell Model Systems

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Crystal structure of poly[(μ₃-4-amino-1,2,5-oxadiazole-3-hydroxamato)thallium(I)]