CARB 2 |
| In eukaryotes, the eIF4E protein plays a crucial role in initiation of the translation process through recognition of the 5'- terminal mRNA “Cap” structure, m7G(5')ppp(5')X (X= any nucleoside). For optimal effects during the initiation step, a strong binding between the 5'-cap and eIF4E protein is required. The eIF4E—Cap mRNA complex has been deemed as the rate limiting factor for translation initiation under for most circumstances and its up regulation has been associated with cell proliferation, tumorogenicity and deprivation of apoptosis. Previous studies in our group have demonstrated that aberrant activation of the cap-dependent protein synthesis machinery is required for the genesis and maintenace of human breast cancer, and we have recently discovered that 7-benzyl guanosine monophosphate is effective in blocking binding of eIF4E to 7-methyl GTP-5'-capped mRNA in cell free, but not in cell-based assay. A pronucleotide approach has thus been applied by developing synthetic methodology to generate a small library of water soluble, non-toxic stable phosphoramidates of 7- benzyl guanosine and its 7-methyl analog. Upto 90% inhibition of the cap-dependent translation was observed at 100µM level in a cell free system. IC50 value extracted from these data was shown to be ~ 10µM. In vivo experiments using Zebra fish as a model showed up to 46% inhibition of translation.
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Nucleosides, Nucleotides and Oligonucleotides
9:00 AM-11:40 AM, Sunday, 10 September 2006 Hilton San Francisco -- Yosemite C, Oral
Division of Carbohydrate Chemistry |