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

Corrao, Federica; Zizzo, Maria Grazia; Tutone, Marco; Melfi, Raffaella; Fiduccia, Ignazio; Carollo, Pietro Salvatore; Leonardo, Aldo Di; Caldara, Gaetano Felice; Perriera, Riccardo; Pace, Andrea; Belmonte, Beatrice; Sammataro, Selene; Pibiri, Ivana; Lentini, Laura

doi:10.1016/j.biopha.2022.113886

Cited by 10 publications

(8 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NV848, NV914, and NV930 are synthetized molecules containing 1,2,4-oxadiazole [ 123 ]. In vitro testing showed a higher readthrough activity in CF model systems [ 123 , 124 ], NV848, NV914, and NV930 were evaluated in CF mouse models with a good tolerability and without any mortality at 2000 mg/kg of NV914 and 300 mg/kg of NV848 or NV930 [ 125 ]. Further studies are necessary to support these beneficial effects.…”

Section: Readthrough Mechanismmentioning

confidence: 99%

Readthrough Activators and Nonsense-Mediated mRNA Decay Inhibitor Molecules: Real Potential in Many Genetic Diseases Harboring Premature Termination Codons

Benslimane,

Loret,

Chazelas

et al. 2024

Pharmaceuticals

View full text Add to dashboard Cite

Nonsense mutations that generate a premature termination codon (PTC) can induce both the accelerated degradation of mutated mRNA compared with the wild type version of the mRNA or the production of a truncated protein. One of the considered therapeutic strategies to bypass PTCs is their “readthrough” based on small-molecule drugs. These molecules promote the incorporation of a near-cognate tRNA at the PTC position through the native polypeptide chain. In this review, we detailed the various existing strategies organized according to pharmacological molecule types through their different mechanisms. The positive results that followed readthrough molecule testing in multiple neuromuscular disorder models indicate the potential of this approach in peripheral neuropathies.

show abstract

Section: Readthrough Mechanismmentioning

confidence: 99%

Readthrough Activators and Nonsense-Mediated mRNA Decay Inhibitor Molecules: Real Potential in Many Genetic Diseases Harboring Premature Termination Codons

Benslimane,

Loret,

Chazelas

et al. 2024

Pharmaceuticals

View full text Add to dashboard Cite

show abstract

“…In this context, our research group has more than ten years of experience in this research field [10][11][12][13]. We have identified several compounds endowed with readthrough activity and three 1,2,4-oxadiazole derivatives (NV848, NV914, NV930) are undergoing in vivo studies [14] [15].…”

Section: Of 22mentioning

confidence: 99%

Investigating the Inhibition of FTSJ1 a Tryptophan tRNA-Specific 2′-O-Methyltransferase by NV TRIDs, as a Mechanism of Readthrough in Nonsense Mutated CFTR

Carollo¹,

Tutone²,

Culletta³

et al. 2023

Preprint

View full text Add to dashboard Cite

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 ribosome’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 investigate a possible mechanism of action (MOA) by which our recently synthesized TRIDs, namely NV848, NV914, and NV930, could exert their readthrough activity by in silico analysis and in vitro studies. Our results suggest a likely inhibition of FTSJ1, a tryptophan tRNA-specific 2’-O-methyltransferase.

show abstract

“…p53 is one of the best-characterized proteins in the research field since it is involved in cell cycle arrest, DNA repair, senescence, and apoptosis, all processes involved in cancer [32]. In order to exert its proper function, this protein has to undergo a series of important events: aggregation in tetramer form, phosphorylation of specific amino acidic NV molecules showed a good translational readthrough activity in cystic fibrosis in in vitro systems and a suitable tolerability in in vivo experiments [27,28]. Recently, we explored the possible MOA of these molecules to identify the interaction with specific proteins involved in the translation process.…”

Section: Evaluation Of P53 Molecular Weight Alteration After Dna Dama...mentioning

confidence: 99%

“…In the last few years, three new TRIDs were identified by our group and tested to validate their translational readthrough ability and tolerability in vivo [27][28][29]. These compounds, named NV848, NV914, and NV930 (also known as NV molecules; PTC Int.…”

Section: Introductionmentioning

confidence: 99%

“…WO 2019/101709 A1 20190531), present an oxadiazole-core chemical structure, like the Ataluren core, but with different functional groups (Scheme 1). NV molecules showed a good translational readthrough activity in cystic fibrosis in in vitro systems and a suitable tolerability in in vivo experiments [27,28]. Recently, we explored the possible MOA of these molecules to identify the interaction with specific proteins involved in the translation process.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Readthrough Approach Using NV Translational Readthrough-Inducing Drugs (TRIDs): A Study of the Possible Off-Target Effects on Natural Termination Codons (NTCs) on TP53 and Housekeeping Gene Expression

Perriera,

Vitale,

Pibiri

et al. 2023

IJMS

Self Cite

View full text Add to dashboard Cite

Nonsense mutations cause several genetic diseases such as cystic fibrosis, Duchenne muscular dystrophy, β-thalassemia, and Shwachman–Diamond syndrome. These mutations induce the formation of a premature termination codon (PTC) inside the mRNA sequence, resulting in the synthesis of truncated polypeptides. Nonsense suppression therapy mediated by translational readthrough-inducing drugs (TRIDs) is a promising approach to correct these genetic defects. TRIDs generate a ribosome miscoding of the PTC named “translational readthrough” and restore the synthesis of full-length and potentially functional proteins. The new oxadiazole-core TRIDs NV848, NV914, and NV930 (NV) showed translational readthrough activity in nonsense-related in vitro systems. In this work, the possible off-target effect of NV molecules on natural termination codons (NTCs) was investigated. Two different in vitro approaches were used to assess if the NV molecule treatment induces NTC readthrough: (1) a study of the translational-induced p53 molecular weight and functionality; (2) the evaluation of two housekeeping proteins’ (Cys-C and β2M) molecular weights. Our results showed that the treatment with NV848, NV914, or NV930 did not induce any translation alterations in both experimental systems. The data suggested that NV molecules have a specific action for the PTCs and an undetectable effect on the NTCs.

show abstract

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

Cited by 10 publications

References 24 publications

Readthrough Activators and Nonsense-Mediated mRNA Decay Inhibitor Molecules: Real Potential in Many Genetic Diseases Harboring Premature Termination Codons

Readthrough Activators and Nonsense-Mediated mRNA Decay Inhibitor Molecules: Real Potential in Many Genetic Diseases Harboring Premature Termination Codons

Investigating the Inhibition of FTSJ1 a Tryptophan tRNA-Specific 2′-O-Methyltransferase by NV TRIDs, as a Mechanism of Readthrough in Nonsense Mutated CFTR

Readthrough Approach Using NV Translational Readthrough-Inducing Drugs (TRIDs): A Study of the Possible Off-Target Effects on Natural Termination Codons (NTCs) on TP53 and Housekeeping Gene Expression

Contact Info

Product

Resources

About