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Review
. 2019 Jul 6;20(13):3329.
doi: 10.3390/ijms20133329.

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

Ambra Campofelice  1 , Laura Lentini  1 , Aldo Di Leonardo  1 , Raffaella Melfi  1 , Marco Tutone  1 , Andrea Pace  1 , Ivana Pibiri  2
Affiliations
Review

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

Ambra Campofelice et al. Int J Mol Sci. .

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.

Keywords: ataluren; cystic fibrosis; nonsense mutation; oxadiazoles; premature termination codon; translational readthrough inducing drugs.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Steps involved in protein synthesis in prokaryotic (left) and eukaryotic cells (right).
Figure 2
Figure 2
(A) Translation of premature termination codon (PTC)-containing mRNA in the absence of translational readthrough-inducing drugs (TRIDs); (B) ideal readthrough of PTC; (C) readthrough inserting a cognate amino acid; and (D) readthrough skipping amino acid insertion. Figure legend: mRNA, RNA messenger; tRNA, RNA transfer; 40S and 60S, small and large ribosome subunit, respectively; eEF1A, eukaryotic translation elongation factor 1A; eRF1 and eRF3, eukaryotic translation termination factor 1 and 3, respectively; and GTP, guanosine-5’-triphosphate.
Figure 3
Figure 3
Structures of some aminoglycoside antibiotics studied for readthrough ability.
Figure 4
Figure 4
Structure of ELX-02.
Figure 5
Figure 5
Structures of oxadiazoles.
Figure 6
Figure 6
Structure of Ataluren (also known as PTC124 or Translarna®) and its most active analogues.
Figure 7
Figure 7
(A) Histogram of luciferase activity shown by HeLa cells after treatment with some of the most active compounds compared with untreated cells and with Fluc used as positive control; (B) Immunofluorescence of IB3.1 cells untreated (Untr; negative control) or treated with PTC124 (Ataluren; positive control) and compounds 1–5 respectively. Cystic fibrosis transmembrane regulator (CFTR) protein was revealed by a specific antibody targeting its first external loop (secondary antibody in green, Alexa-488). Nuclei (blue) were DAPI (4′,6-diamidino-2-phenylindole) stained.
Figure 8
Figure 8
Structure of Amlexanox.
Figure 9
Figure 9
Structure of Clitocine.
Figure 10
Figure 10
Comparison between protein syntheses from: a normally coded gene (left), a nonsense-mutated gene through normal NMD and codon recognition (center-left), a nonsense-mutated gene through normal NMD and active readthrough (center-right), and a nonsense-mutated gene with inhibited NMD and active readthrough (right).
Figure 11
Figure 11
Structure of Lumacaftor.
Figure 12
Figure 12
Structure of Ivacaftor.
See this image and copyright information in PMC

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