Abstract
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.
Highlights
Protein synthesis is a crucial phase for any living organism; any phenomenon affecting any of the steps involved in such a crucial process could jeopardize life itself or cause severe disorders
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
This review illustrates the different classes of drugs that have been developed so far, in order to promote the readthrough of premature stop codons, focusing on oxadiazole derivatives, their proposed mechanism of action, and recent results in restoring the production of the full-length cystic fibrosis transmembrane regulator (CFTR) protein
Summary
Protein synthesis is a crucial phase for any living organism; any phenomenon affecting any of the steps involved in such a crucial process could jeopardize life itself or cause severe disorders. Drugs have been developed to target the translation phase and promote the bypass of the PTC, allowing the synthesis of full-length functional proteins, a strategy known as PTC “readthrough” [9,24,29,30]. This review illustrates the different classes of drugs that have been developed so far, in order to promote the readthrough of premature stop codons, focusing on oxadiazole derivatives, their proposed mechanism of action, and recent results in restoring the production of the full-length cystic fibrosis transmembrane regulator (CFTR) protein
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