We will 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 oligonucleotlde 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, especialTy for human imml nodeficiency virus (HBV), infection which is also a global problem of major proportion, and leads to liver cirrhosis and hepatocellularcarcinoma. Specific aims in Phase 1, which will build upon our recent discovery of several promising triplex-specific intercalators, are 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.Awardee's statement of the potential commercial applications of the research:Antigene drug discovery is being pursued by Lynx as well as several new "start-up" companies, some in collaboration with existing pharmaceutical manufacturers. This technology has the potential for leading to a new class of antigene drugs for treatment of chronic infection by HIV- I and HBV. The technology has the potenttilal for broad applicability to other disease targets including cancer.National Institute of Allergy and Infectious Diseases (NIAID)
