Modulation of viral Internal Ribosome Entry Segments (IRES)

Lead Research Organisation: University of Nottingham
Department Name: Sch of Pharmacy

Abstract

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Publications

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Title Synthetic methods and new 1-phenylethyl-3-pyrimidineguanidines 
Description We developed a convergent approach for the chemical synthesis of tripeptide-aminoanthraquinones (AAQ) conjugates. In brief, the cationic tripeptides, constructed by solid-phase chemistry on 1,3-diaminopropane chlorotrityl resin, were released by mild acidolysis to afford the partially protected peptides . The modified peptides were then selectively conjugated with the 6-bromohexanoyl-modified AAQ. The ten tripeptides-AAQ were obtained in good yields, but were of unacceptable aqueous solubility, even in the presence of DMSO; hence, we were unable to exploit these chemical tools to modulate HCV IRES function. Three 1-phenylethyl-3-pyrimidineguanidines (PPG) analogues, accessed via a 3-step synthetic strategy, were readily obtained and purified by reversed phase-HPLC. Novel PPG-AAQ conjugates were constructed. These are: (i) 3-(4-(2-(3-(4,6-dimethylpyrimidin-2-yl)guanidino)ethyl)phenoxy)-N-(9,10-dioxo-9,10-dihydroanthracen-1-yl)propanamide; and (ii) 6-(4-(2-(3-(4,6-dimethylpyrimidin-2-yl)guanidino)ethyl)phenoxy)-N-(9,10-dioxo-9,10-dihydroanthracen-1-yl)hexanamide. 
Type Of Material Technology assay or reagent 
Year Produced 2007 
Provided To Others? Yes  
Impact The impact is not obvious at the moment. 
 
Description Dicistronic construct comprising T7 driven Renilla luciferase and HCV IRES driven firefly luciferase 
Organisation University of Nottingham
Department School of Pharmacy
Country United Kingdom 
Sector Academic/University 
PI Contribution Design and synthesis of chemical reagents for IRES inhibition screens
Collaborator Contribution Provided research training and molecular tools to screen for HCV IRES inhibitors
Impact As part of the aims of the Discipline Hopping award, the PI obtained hands-on training in cellular and molecular biological techniques.
Start Year 2006