Advances in therapeutic use of a drug-stimulated translational readthrough of premature termination codons

Abstract

Premature termination codons (PTCs) in the coding regions of mRNA lead to the incorrect termination of translation and generation of non-functional, truncated proteins. Translational readthrough of PTCs induced by pharmaceutical compounds is a promising way of restoring functional protein expression and reducing disease symptoms, without affecting the genome or transcriptome of the patient. While in some cases proven effective, the clinical use of readthrough-inducing compounds is still associated with many risks and difficulties. This review focuses on problems directly associated with compounds used to stimulate PTC readthrough, such as their interactions with the cell and organism, their toxicity and bioavailability (cell permeability; tissue deposition etc.). Various strategies designed to overcome these problems are presented.

Keywords: Genetic diseases; Nonsense suppression; Premature termination codon; Stop codon suppression; Translational readthrough.

Fig. 1

PTC-RT process. a Ribosome encounters premature termination codon (PTC); the site is recognized by the translation termination machinery and the polypeptide elongation is prematurely terminated. b After addition of readthrough compound, translational machinery decodes PTC (PTC is recognized by nc- tRNAs), and translation continues until the normal termination codon (NTC). It allows translating a full-length protein. The NMD surveillance mechanism may detect and degrade PTC-bearing transcripts. If the NMD process is inhibited, very low levels of the full-length protein can be present even in the absence of stimulating agents, as the result of the endogeneous suppression of PTC

Fig. 2

Different problems associated with the drug-stimulated PTC-RT therapy. Upper part – problems associated with the PTC-RT- stimulating drugs. Lower part – problems associated with the biology of PTC-RT process