The long-term goals of this project are to develop, optimize, and explore the scope of cyclic oligonucleotides as potential agents for the inhibition of replication of HIV-1 and other viruses. In the 2.5 years since the initial finding of this grant, several important milestones toward achieving these goals have been reached. The work has established a new strategy, binding of single strands by triplex formation, as a new and rapidly developing approach to nucleic acid recognition which is now being studied in several laboratories worldwide. The proposed studies are aimed at further characterization and development of these and related molecules for the binding and inhibition of viral nucleic acid sequences. Specific plans for the term covered by this proposal include: (1) Investigation of new strategies for synthesis of cyclic structures, including a convergent dimerization approach, and the use of template strands on solid support. (2) Full characterization of binding of RNAs by cyclic oligonucleotides having RNA, DNA, or chimeric backbone structure. (3) Kinetic and thermodynamic characterization of binding of duplex DNAs by strand displacement. (4) New studies aimed toward the incorporation of synthetically modified groups into cyclic structures to further improve properties. (5) In vitro testing of cyclic structures as inhibitors of cell-free translation. (6) In vitro testing of cyclic structures as inhibitors of transcription, reverse transcription, and DNA synthesis. (7) Collaborative studies to test first-generation molecules as viral inhibitors.
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