Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Readthrough approach by NV translational readthrough inducing drugs (TRIDs): a study of the possible off-target effects on natural termination codons (NTCs) on TP53 and housekeeping genes expression.

Riccardo Perriera
ORCID logo ,
Emanuele Vitale
,
Ivana Pibiri
* ORCID logo ,
Pietro Salvatore Carollo
,
Davide Ricci
,
Federica Corrao
,
Ignazio Fiduccia
,
Raffaella Melfi
ORCID logo ,
Maria Grazia Zizzo
,
Marco Tutone
ORCID logo ,
Andrea Pace
ORCID logo ,
Laura Lentini
* ORCID logo
Version 1 : Received: 11 August 2023 / Approved: 11 August 2023 / Online: 11 August 2023 (14:38:09 CEST)

A peer-reviewed article of this Preprint also exists.

Perriera, R.; Vitale, E.; Pibiri, I.; Carollo, P.S.; Ricci, D.; Corrao, F.; Fiduccia, I.; Melfi, R.; Zizzo, M.G.; Tutone, M.; Pace, A.; Lentini, L. 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. Int. J. Mol. Sci. 2023, 24, 15084. Perriera, R.; Vitale, E.; Pibiri, I.; Carollo, P.S.; Ricci, D.; Corrao, F.; Fiduccia, I.; Melfi, R.; Zizzo, M.G.; Tutone, M.; Pace, A.; Lentini, L. 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. Int. J. Mol. Sci. 2023, 24, 15084.

Abstract

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 that leads to the aberrant translation, 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 protein. The new oxadiazole-core TRIDs NV848, NV914, and NV930 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 molecules treatment induce NTCs readthrough: 1) A study of 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 do not induce any translation alterations in both experimental systems. Data suggested that NV molecules have a specific action for the PTCs and an undetectable effect on the NTCs.

Keywords

translational readthrough, nonsense, premature termination codons oxadiazole, precision medicine, genetic diseases.

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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