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通读方法使用 NV 翻译通读诱导药物 (TRIDs)：对 TP53 和管家基因表达中自然终止密码子 (NTC) 的潜在非靶向效应的研究。

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.

机构信息

Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy.

出版信息

Int J Mol Sci. 2023 Oct 11;24(20):15084. doi: 10.3390/ijms242015084.

DOI:10.3390/ijms242015084
PMID:37894764
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10606485/
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, 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.

摘要

无义突变导致了多种遗传疾病，如囊性纤维化、杜氏肌营养不良症、β-地中海贫血和 Shwachman-Diamond 综合征。这些突变在内含子序列中诱导形成一个过早终止密码子（PTC），导致截短的多肽的合成。通过翻译通读诱导药物（TRIDs）介导的无义抑制疗法是纠正这些遗传缺陷的一种很有前途的方法。TRIDs 产生 PTC 的核糖体错读，称为“翻译通读”，并恢复全长和潜在功能蛋白的合成。新型的噁二唑核 TRIDs NV848、NV914 和 NV930（NV）在无义相关的体外系统中表现出翻译通读活性。在这项工作中，研究了 NV 分子对天然终止密码子（NTC）的可能的脱靶效应。使用两种不同的体外方法来评估 NV 分子处理是否诱导 NTC 通读：（1）研究翻译诱导的 p53 分子量和功能；（2）评估两种管家蛋白（Cys-C 和β2M）的分子量。我们的结果表明，在这两个实验系统中，NV848、NV914 或 NV930 的处理均未诱导任何翻译改变。这些数据表明，NV 分子对 PTC 具有特异性作用，对 NTC 几乎没有影响。

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3
Investigating the Inhibition of FTSJ1, a Tryptophan tRNA-Specific 2'-O-Methyltransferase by NV TRIDs, as a Mechanism of Readthrough in Nonsense Mutated CFTR.
DNMT1的长期缺失是一种可调节的细胞应激，它会触发细胞增殖停滞以防止主要的DNA甲基化丢失。
Cell Mol Life Sci. 2024 Dec 18;82(1):7. doi: 10.1007/s00018-024-05547-y.
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Mol Ther. 2024 Dec 4;32(12):4514-4523. doi: 10.1016/j.ymthe.2024.10.028. Epub 2024 Oct 28.
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