Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università Degli Studi di Palermo, Viale delle Scienze Ed. 16-17, 90128 Palermo, Italy.
Int J Mol Sci. 2019 Jul 6;20(13):3329. doi: 10.3390/ijms20133329.
This review focuses on the use of oxadiazoles as translational readthrough-inducing drugs (TRIDs) to rescue the functional full-length protein expression in mendelian genetic diseases caused by nonsense mutations. These mutations in specific genes generate premature termination codons (PTCs) responsible for the translation of truncated proteins. After a brief introduction on nonsense mutations and their pathological effects, the features of various classes of TRIDs will be described discussing differences or similarities in their mechanisms of action. Strategies to correct the PTCs will be presented, particularly focusing on a new class of Ataluren-like oxadiazole derivatives in comparison to aminoglycosides. Additionally, recent results on the efficiency of new candidate TRIDs in restoring the production of the cystic fibrosis transmembrane regulator (CFTR) protein will be presented. Finally, a prospectus on complementary strategies to enhance the effect of TRIDs will be illustrated together with a conclusive paragraph about perspectives, opportunities, and caveats in developing small molecules as TRIDs.
这篇综述重点介绍了恶二唑类化合物作为翻译通读诱导药物（TRIDs）的应用，以拯救由无义突变引起的孟德尔遗传疾病中的功能性全长蛋白表达。这些特定基因中的突变会产生导致截断蛋白翻译的无意义密码子（PTCs）。在简要介绍无义突变及其病理效应之后，将描述各种 TRIDs 类别的特征，讨论它们在作用机制上的差异或相似之处。将介绍校正 PTC 的策略，特别侧重于与氨基糖苷类药物相比的新型阿扎那韦样恶二唑衍生物。此外，还将介绍恢复囊性纤维化跨膜转导调节因子（CFTR）蛋白产生的新型候选 TRIDs 的最新研究结果。最后，将说明增强 TRIDs 效果的补充策略，并在开发小分子作为 TRIDs 的前景、机会和注意事项方面给出结论性段落。
