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 6 publications

(2 citation statements)

References 24 publications

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“…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

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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.

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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

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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

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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.

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Readthrough compounds for nonsense mutations: bridging the translational gap

Spelier¹,

Doorn²,

Ent³

et al. 2023

Trends in Molecular Medicine

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

Cited by 6 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 compounds for nonsense mutations: bridging the translational gap

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