Search results for " readthrough"

Inhibition of FTSJ1, a tryptophan tRNA-specific 2’-O-methyltransferase as possible mechanism to readthrough premature termination codons (UGAs) of th…

2022

Cystic Fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the CFTR gene, coding for the CFTR chloride channel. About 10 % of the mutations affecting the CFTR gene are "stop" mutations, which generate a Premature Termination Codon (PTC), thus resulting in the synthesis of a truncated CFTR protein. A way to bypass PTC relies on ribosome readthrough, that is the capacity of the ribosome to skip a PTC, thus generating a full-length protein. “TRIDs” are molecules exerting ribosome readthrough and for some of them the mechanism of action is still under debate. By in silico analysis as well as in vitro studies, we investigate a possible mechanism of action (MOA) by whic…

STUDY OF SMALL MOLECULES IN THE FIGHT AGAINST NONSENSE AND SPLICING MUTATIONS THAT CAUSE CYSTIC FIBROSIS.

2023

Nonsense codons suppression. An acute toxicity study of three optimized TRIDs in murine model, safety and tolerability evaluation.

2022

Stop mutations cause 11% of the genetic diseases, due to the introduction of a premature termination codon (PTC) in the mRNA, followed by the production of a truncated protein. A promising therapeutic approach is the suppression therapy by Translational Readthrough Inducing Drugs (TRIDs), restoring the expression of the protein. Recently, three new TRIDs (NV848, NV914, NV930) have been proposed, and validated by several in vitro assays, for the rescue of the CFTR protein, involved in Cystic Fibrosis disease. In this work, an acute toxicological study for the three TRIDs was conducted in vivo on mice, according to the OECD No.420 guidelines. Animals were divided into groups and treated with …

Identification and validation of novel molecules obtained by integrated computational and experimental approaches for the readthrough of PTCs in CF c…

2014

Cystic Fibrosis patients with nonsense-mutation in h-CFTR gene generally make virtually no CFTR protein and thus often have a more severe form of CF. Ataluren (PTC124) was suggested to induce read-through of premature but not normal termination codons. Despite the promising results there is not a general consensus on the mechanism of its action (protein stabilization or codon read-through) and its efficacy, the identification of new PTC124 analogues and the study of the mechanism of action may led to a new strategy for the development of a pharmacologic approach to the cure of CF.

Investigating the inhibition of FTSJ1 a tryptophan tRNA-specific 2’-O-methyltransferase by NV TRIDs, as a mechanism of readthrough in nonsense mutate…

2023

Abstract: Cystic Fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the CFTR gene, coding for the CFTR chloride channel. About 10% of the CFTR gene mutations are "stop" mutations, which generate a Premature Termination Codon (PTC), thus synthesizing a truncated CFTR protein. A way to bypass PTC relies on ribosome readthrough, which is the ri-bosome’s capacity to skip a PTC, thus generating a full-length protein. “TRIDs” are molecules exerting ribosome readthrough; for some, the mechanism of action is still under debate. We in-vestigate a possible mechanism of action (MOA) by which our recently synthesized TRIDs, namely NV848, NV914, and NV930, could exert their r…

Valutazione dell'azione readthorough della molecola PTC124 su sistemi modello cellulari contenenti mutazioni non senso e in cellule epiteliali bronch…

2013

Circa il 10% dei pazienti affetti da fibrosi cistica (FC) presenta nel gene CFTR mutazioni non senso (o 'stop': UGA, UAG or UAA, mutazioni di classe I) che bloccano prematuramente la sintesi della proteina. Attualmente non esiste una cura per questo tipo di mutazioni ma si sta cercando di individuare delle molecole che siano in grado di indurre la traduzione di codoni di stop prematuri (readthrough) che, rispetto a molecole già note come il G418, abbiano effetti collaterali ridotti ed una maggiore specificità per uno specifico codone. Una piccola molecola che sembra possedere una tale attività è il PTC124 (Welch, 2007). Ad oggi però non c’è ancora un consenso generale sul meccanismo di azio…

The innovative role of the readthrough inducing drugs in the translation rescue of mRNAs characterized by premature stop codon (PTCs).

Integrated computational and experimental approaches for the identification of new molecules with readthrough activity on premature termination codon…

2015

Uno studio comparativo in silico sui possibili target di Ataluren e analoghi farmaci promotori di readthrough di codoni di stop prematuri

2019

E’ noto in letteratura che Ataluren (acido 5-(fluorofenil)-1,2,4-ossadiazolil-benzoico) sia in grado di sopprimere le mutazioni non senso favorendo il readthrough dei codoni di stop prematuri, anche se il suo meccanismo di azione non risulta ancora chiaro. La probabile interazione tra Ataluren e CTFR-mRNA è stata precedentemente studiata mediante dinamica molecolare. In questo studio1, abbiamo esteso il modeling del probabile meccanismo di azione di Ataluren mediante approcci computazionali completementari, quali Induced Fit Docking (IFD), Quantum Polarized Ligand Docking (QPLD), metodi MM-GBSA e mutagenesi computazionale. Oltre a considerare il CTFR-mRNA, sono stati presi in considerazione…

RESCUE OF LRBA GENE EXPRESSION IN PRIMARY HUMAN FIBROBLASTS CHARACTERISED BY NONSENSE MUTATION c. 5047 (C>T).

2021

Primary immunodeficiencies (PIDs) are rare genetic diseases characterized by susceptibility to infections, increased risk of autoimmunity, hypogammaglobulinemia, and lymphoproliferative syndromes. PIDs are associated to genetic alterations in about 400 known genes, among which, mutations of the LRBA gene. LRBA gene encodes a widely expressed multi-domain protein with highly conserved BEACH domain, involved in regulation of endosomal trafficking, particularly endocytosis of ligand-activated receptors. It was reported that stop mutations affect this gene leading to the loss of the protein expression. Recently, we identified three Translational Readthrough Inducing Drug (TRID), that showed hig…