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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM046625-04
Application #
2184124
Study Section
AIDS and Related Research Study Section 4 (ARRD)
Project Start
1991-07-01
Project End
1997-06-30
Budget Start
1994-07-01
Budget End
1995-06-30
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Rochester
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Mohsen, Michael G; Kool, Eric T (2016) The Discovery of Rolling Circle Amplification and Rolling Circle Transcription. Acc Chem Res 49:2540-2550
Ohmichi, T; Kool, E T (2000) The virtues of self-binding: high sequence specificity for RNA cleavage by self-processed hammerhead ribozymes. Nucleic Acids Res 28:776-83
Xu, Y; Kool, E T (1999) High sequence fidelity in a non-enzymatic DNA autoligation reaction. Nucleic Acids Res 27:875-81
Xu, Y; Kool, E T (1998) Chemical and enzymatic properties of bridging 5'-S-phosphorothioester linkages in DNA. Nucleic Acids Res 26:3159-64
Wang, S; Xu, Y; Kool, E T (1997) Recognition of RNA by triplex formation: divergent effects of pyrimidine C-5 methylation. Bioorg Med Chem 5:1043-50
Kool, E T (1996) Circular oligonucleotides: new concepts in oligonucleotide design. Annu Rev Biophys Biomol Struct 25:1-28
Wang, S; Friedman, A E; Kool, E T (1995) Origins of high sequence selectivity: a stopped-flow kinetics study of DNA/RNA hybridization by duplex- and triplex-forming oligonucleotides. Biochemistry 34:9774-84
Wang, S; Kool, E T (1994) Circular RNA oligonucleotides. Synthesis, nucleic acid binding properties, and a comparison with circular DNAs. Nucleic Acids Res 22:2326-33
Booher, M A; Wang, S; Kool, E T (1994) Base pairing and steric interactions between pyrimidine strand bridging loops and the purine strand in DNA pyrimidine.purine.pyrimidine triplexes. Biochemistry 33:4645-51
Wang, S; Booher, M A; Kool, E T (1994) Stabilities of nucleotide loops bridging the pyrimidine strands in DNA pyrimidine.purine.pyrimidine triplexes: special stability of the CTTTG loop. Biochemistry 33:4639-44

Showing the most recent 10 out of 11 publications