RNA viruses have been shown to be the causative agent in a variety of animal cancers, including human Adult T-cell Leukemia (ATL), caused by the Human T-cell Leukemia Virus (HTLV-I). We propose to develop agents inhibitory to HTLV based on their ability to interfere with the frameshift activity necessary to translate the gag/pro and gag/pro/pol mRNA into fusion proteins. It has been shown in related retroviruses that efficient frameshifting requires the formation of an RNA pseudoknot on the 3' side of the frameshift site. Furthermore, there is evidence that the mechanism by which such pseudoknot structures produce the frameshift may involve interaction with a protein or other soluble factor. We propose using the DOCK program to discover small molecules that can bind to the RNA pseudoknot structure and inhibit its frameshifting activity, thereby decreasing or eliminating expression of genes necessary for viral growth and reproduction. This is a novel application of structure-based drug design, targeting an RNA rather than a protein structure. CGL facilities are used to visualise and analyse molecular structures of RNA targets and their complexes with small ligands, generated by DOCK.
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