Internal ribosome entry site IRES

Fig. 10 Screening hit and higher affinity benzimidazoles for HCV RNA internal ribosome entry site (IRES) IIA subdomain...

Figure 38-10. Picornavimses disrupt the 4F complex. The 4E-4G complex (4F) directs the 40S ribosomal subunit to the typical capped mRNA (see text). 4G alone is sufficient for targeting the 40S subunit to the internal ribosomal entry site (IRES) of viral mRNAs. To gain selective advantage, certain viruses (eg, poliovirus) have a protease that cleaves the 4E binding site from the amino terminal end of 4G. This truncated 4G can direct the 40S ribosomal subunit to mRNAs that have an IRES but not to those that have a cap. The widths of the arrows indicate the rate of translation initiation from the AUG codon in each example.

Nutf CJ, Corey D. Intracellular inhibition of hepatitis C virus 35. (HCV) internal ribosomal entry site (IRES)-dependent translation by peptide nucleic acids (PNAs) and locked nucleic acids (LNAs)l. Nucleic Acids Res. 2004 32 3792-3798. 

L. Creancier, D. Morello, P. Mercier, and A.C. Prats, Fibroblast growth factor 2 internal ribosome entry site (IRES) activity ex vivo and in transgenic mice reveals a stringent tissue-specific regulation, J Cell Biol 150, 275-281 (2000). 

Internal ribosome entry site (IRES) 765 International biopharmaceutical reference material (IBRM) 1569 International conference on harmonization, see ICH... 

The eukaryotic protein-synthesizing machinery begins translation of most cellular mRNAs within about 100 nucleotides of the 5 capped end as just described. However, some cellular mRNAs contain an internal ribosome entry site (IRES) located far downstream of the 5 end. In addition, translation of some viral mRNAs, which lack a 5 cap, is initiated at IRESs by the host-cell machinery of infected eukaryotic cells. Some of the same translation initiation factors that assist in ribosome scanning from a 5 cap are required for locating an internal AUG start codon, but exactly how an IRES is recognized is less clear. Recent results indicate that some IRESs fold into an RNA structure that binds to a third site on the ribosome, the E site, thereby positioning a nearby internal AUG start codon in the P site. 

AUG codons in other positions, known as internal ribosome entry sites (IRES), 311,344 347 more rarely, non-AUG codons can also initiate translation with lower efficiency. Thus, mechanisms exist for synthesis of small amounts of proteins of varying lengths and of proteins that are encoded in any one of the three reading Even circular... 

Kikuchi, K., Umehara, T., Fukuda, K., Kuno, A., Hasegawa, T., Nishikawa, S. (2005). A hepatitis C virus (HCV) internal ribosome entry site (IRES) domain Ill-IV-targeted aptamer inhibits translation by binding to an apical loop of domain Illd. Nucleic Acids Res 33, 683-692. 

A second viral strategy to disrupt PKR function involves antagonistic viral nucleic adds. For example, the internal ribosome entry site (IRES) of Hepatitis C virus (HCV) has been shown to be able to bind to PKR in competition with dsRNA and prevent autophosphor tion and activation of PKR in vitro. EBV nucleic acid can also antagonise PKR, since fflV-encoded RNA1 (EBER-1) and EBER-2can bind PKR in vitro and EBER-1 can reverse the inhibitory eflfects of dsRNA on protein synthesis. AdV-encoded VAI RNA binds to PKR in competition with dsRNA but fails to lead to PKR autophosphorylation or activation. 

Figure 5, Primary screen far drugs targeted to the APP S untranslated region. In a screen of a library of 1,200 FDA-pre-approved compounds phenserine(ACHEi) and the potent intracellular iron chelator, desferrioxamine, were the validated positive control drugs that suppressed APP mRNA translation through APP 5 UTR sequences. In this transfection based screen several lead APP-5 UTR directed drugs were identified to limit luciferase gene expression driven by the APP 5 UTR. As an internal selectivity control for this screen, downstream dicistronic GFP gene expression (at the translational level by a viral internal ribosome entry site (IRES)) was unresponsive to drug action. Several leads (i,e, dimercaptopropanol) were identified to be chelators as described.

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