The eukaryotic translation initiation factor 4E is an indispensable component of the cap-dependent translation initiation process. eIF4E binds to the mRNA cap and recruits, with the rest of initiation factors, the mRNA to the ribosomes. Under normal physiological conditions, eIF4E is the least abundant element of the translation initiation machinery. However, it has become evident that eIF4E is overexpressed in numerous tumour types leading to a translation enhancement of the oncogenic mRNAs. Thus it contributes to the initiation as well as the progression of the disease. Although eIF4E has been validated as a cancer drug target for over two decades, no drug-like eIF4E inhibitor has been developed, apart from the antiviral drug ribavirin. In this project, a set of nucleotide-based eIF4E inhibitors was designed and synthesised to mimic the mRNA cap structure in order to block the eIF4E cap binding slot. These molecules have a modified m7GTP structure at the level of the phosphate moiety as well as the N7 substituents, sites that are directly linked to the ligand affinity for eIF4E. A series of competitive and functional assays was then developed and optimised with the aim of assessing the ability of these ligands to sequester eIF4E from binding to capped mRNAs. These assays examined the inhibitors at multiple levels including the binding to a recombinant eIF4E, the effect on eIF4E functional role and the cellular influence on protein synthesis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:659288 |
| Date | January 2013 |
| Creators | Soukarieh, Fadi |
| Publisher | University of Nottingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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