ANTI-HCMV ACTIVITY OF TRIPLE HELIX-FORMING OLIGOS

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The aim of this project is to test the feasibility of using triple helix (triplex)-forming oligonucleotides as antiviral agents against human cytomegalovirus. Oligonucleotides have long been known to be capable of binding to duplex DNA to form triple helix complexes. Advances in triplex technology now allows the design of triplex-forming oligonucleotides capable of binding with complex DNA duplex sequences under physiological conditions. Binding by triplex-forming oligonucleotides to duplex DNA has been shown to disrupt binding to that duplex by site specific DNA binding proteins and to inhibit gene expression in several systems. We intend to test the ability of triplex-forming oligonucleotides to inhibit viral gene expression and virus growth in cell culture systems. Triplex-forming oligonuceotides will be designed to disrupt specific viral transcription initiation and/or elongation events as well as viral DNA replication events of human cytomegalovirus. These oligonculeotides will be synthesized and analyzed for the actual binding ability to synthetic target sequences in vitro, and then assayed as anti-viral agents in cell culture. Any triplex-forming oligonucleotide capable of inhibiting viral growth in cell culture assays will have passed the Phase I studies and proceed to further evaluation as an antiviral agent in an animal model system. The use of this technology for the development of antiviral agents is an innovative approach to the design of antiviral drugs.