Intercalative Antigene Oligo Analogs as New Drugs

We will develop an intercalating agent which, when linked to backbone-modified nuclease-resis-tant 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 duplexadducts. Such intercalative oligonucleotide analogues would constitute a novel class of antigene drugsthat could be targeted more efficiently and specifically to specific viral oncogenic double-stranded DNAtargets, relative to the type of antigene compounds reported to date. This improved drug design strategycan be actively pursued in the future within context of Lynx's ongoing antiviral programs, especially forhuman immunodeficiency virus (HBV), infection which is also a global problem of major proportion, andleads to liver cirrhosis and hepatocellular carcinoma. Specific aims in Phase I, which will build upon ourrecent discovery of several promising triplex-specific intercalators, are synthesizing and testingmore model triplexes and intercalator variations, examining phosphorotheioate backbone-modifications,and preliminary computer modeling to guide design of improved intercalators and linkages to theoligonucleotide.