Strategies against Nonsense: Oxadiazoles as Translational Readthrough-Inducing Drugs (TRIDs)

International Journal of Molecular Sciences

Marco Tutone¹  Ambra Campofelice¹  Raffaella Melfi¹  Aldo Di Leonardo¹  Laura Lentini¹  Andrea Pace¹  Ivana Pibiri¹ 

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

关键词: premature termination codon;    nonsense mutation;    translational readthrough inducing drugs;    ataluren;    oxadiazoles;    cystic fibrosis;   

DOI  :  10.3390/ijms20133329

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown