Translational readthrough-inducing
drugs (TRIDs) rescue the functional
full-length protein expression in genetic diseases, such as cystic
fibrosis, caused by premature termination codons (PTCs). Small molecules
have been developed as TRIDs to trick the ribosomal machinery during
recognition of the PTC. Herein we report a computational study to
identify new TRID scaffolds. A pharmacophore approach was carried
out on compounds that showed readthrough activity. The pharmacophore
model applied to screen different libraries containing more than 87000
compounds identified four hit-compounds presenting scaffolds with
diversity from the oxadiazole lead. These compounds have been synthesized
and tested using the Fluc reporter harboring the UGA PTC. Moreover,
the cytotoxic effect and the expression of the CFTR protein were evaluated.
These compounds, a benzimidazole derivative (NV2899), a benzoxazole
derivative (NV2913), a thiazole derivative (NV2909), and a benzene-1,3-disulfonate
derivative (NV2907), were shown to be potential new lead compounds
as TRIDs, boosting further efforts to address the optimization of
the chemical scaffolds.
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 that leads to the aberrant translation, 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 protein. The new oxadiazole-core TRIDs NV848, NV914, and NV930 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 molecules treatment induce NTCs readthrough: 1) A study of 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 do not induce any translation alterations in both experimental systems. Data suggested that NV molecules have a specific action for the PTCs and an undetectable effect on the NTCs.
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