PMID- 37894764 OWN - NLM STAT- MEDLINE DCOM- 20231030 LR - 20231030 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 24 IP - 20 DP - 2023 Oct 11 TI - 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. LID - 10.3390/ijms242015084 [doi] LID - 15084 AB - Nonsense mutations cause several genetic diseases such as cystic fibrosis, Duchenne muscular dystrophy, beta-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 beta2M) 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. FAU - Perriera, Riccardo AU - Perriera R AUID- ORCID: 0000-0003-1127-0391 AD - Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Universita degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy. FAU - Vitale, Emanuele AU - Vitale E AD - Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Universita degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy. FAU - Pibiri, Ivana AU - Pibiri I AUID- ORCID: 0000-0001-5885-164X AD - Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Universita degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy. FAU - Carollo, Pietro Salvatore AU - Carollo PS AD - Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Universita degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy. FAU - Ricci, Davide AU - Ricci D AUID- ORCID: 0009-0000-8477-4182 AD - Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Universita degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy. FAU - Corrao, Federica AU - Corrao F AD - Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Universita degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy. FAU - Fiduccia, Ignazio AU - Fiduccia I AD - Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Universita degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy. FAU - Melfi, Raffaella AU - Melfi R AUID- ORCID: 0000-0003-4463-8156 AD - Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Universita degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy. FAU - Zizzo, Maria Grazia AU - Zizzo MG AD - Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Universita degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy. FAU - Tutone, Marco AU - Tutone M AUID- ORCID: 0000-0001-5059-8686 AD - Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Universita degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy. FAU - Pace, Andrea AU - Pace A AUID- ORCID: 0000-0003-1992-2024 AD - Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Universita degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy. FAU - Lentini, Laura AU - Lentini L AUID- ORCID: 0000-0002-1355-8252 AD - Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Universita degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy. LA - eng GR - Project PE_00000019/European Union - NextGenerationEU through the Italian Ministry of University and Research under PNRR - M4C2-I1.3 Project PE_00000019 "HEAL ITALIA" to Ivana Pibiri and Laura Lentini CUP B73C22001250006 (Dip. STEBICEF-University of Palermo)/ GR - FFC#06/2020/Italian Cystic Fibrosis Research Foundation/ PT - Journal Article DEP - 20231011 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Codon, Terminator) RN - 0 (Tumor Suppressor Protein p53) RN - 0 (Codon, Nonsense) SB - IM MH - Codon, Terminator MH - *Genes, Essential MH - *Tumor Suppressor Protein p53/genetics/metabolism MH - Protein Biosynthesis MH - Codon, Nonsense PMC - PMC10606485 OTO - NOTNLM OT - genetic diseases OT - nonsense OT - precision medicine OT - premature termination codons oxadiazole OT - translational readthrough COIS- The authors declare no conflict of interest. EDAT- 2023/10/28 11:42 MHDA- 2023/10/30 06:47 PMCR- 2023/10/11 CRDT- 2023/10/28 01:17 PHST- 2023/08/11 00:00 [received] PHST- 2023/09/11 00:00 [revised] PHST- 2023/10/08 00:00 [accepted] PHST- 2023/10/30 06:47 [medline] PHST- 2023/10/28 11:42 [pubmed] PHST- 2023/10/28 01:17 [entrez] PHST- 2023/10/11 00:00 [pmc-release] AID - ijms242015084 [pii] AID - ijms-24-15084 [pii] AID - 10.3390/ijms242015084 [doi] PST - epublish SO - Int J Mol Sci. 2023 Oct 11;24(20):15084. doi: 10.3390/ijms242015084.