The long-term objectives of this research are to develop an intercalating agent which, when linked to backbone-modified nuclease-resistant oligonucleotide analogues, provides enhanced stability of triplex adducts in a highly specific manner, with regard to both the sequence of a double-stranded DNA target and, especially, undesired duplex adducts. Such intercalative oligonucleotide analogues would constitute a novel class of antigene drugs that could be targeted more efficiently and specifically to specific viral oncogenic double-stranded DNA targets, relative to the type of antigene compounds reported to date. This improved drug design strategy can be actively pursued in the future within context of Lynx's ongoing antiviral programs, especially for human immunodeficiency virus (HBV), infection by which is also a global problem of major proportion, and leads to liver cirrhosis and hepatocellular carcinoma.
Specific aims i n Phase I, which will build upon our recent discovery of several promising triplex-specific intercalators, synthesizing and testing more model triplexes and intercalator variations, examining phosphorotheioate backbone-modifications, and preliminary computer modeling to guide design of improved intercalators and linkages to the oligonucleotide.
