The primary goal of this research project is the design and synthesis of RNA-DNA hybrid agent, which might inhibit the RNase activity of retroviral DNA polymerase. Thus, such a agent would be a possible therapeutic agent against human immunodeficiency virus (HIV). One characteristic function of the retroviruses, which is generally not found in normal eukaryotic cells, is production of a long RNA-DNA hybrid in the viral replication phase. If agents are designed which bind only to the RNA-DNA hybrid, but not to DNA or RNA, such agents will be able to inhibit specifically the RNase H activity of retroviral DNA polymerase, and therefore will suppress viral replication. Actinomycin analogue might be able to bind to an RNA-DNA hybrid. This hypothesis has been tested by a molecular mechanics calculation using a model structure of the complex between the actinomycin analogue and a small RNA-DNA hybrid. The results of the molecular mechanics calculation suggest that the analogue can bind to the RNA-DNA hybrid. Thus, this actinomycin analogue is a molecule which may stop the degradative activity of retroviral RNase H by binding preferentially to the RNA-DNA hybrid. This would suppress viral replication. The compound should therefore be investigated and tested as a possible therapeutic agent against AIDS.
| Takusagawa, F; Takusagawa, K T; Carlson, R G et al. (1997) Selectivity of F8-actinomycin D for RNA:DNA hybrids and its anti-leukemia activity. Bioorg Med Chem 5:1197-207 |
| Takusagawa, F; Wen, L; Chu, W et al. (1996) Physical and biological characteristics of the antitumor drug actinomycin D analogues derivatized at N-methyl-L-valine residues. Biochemistry 35:13240-9 |
| Shinomiya, M; Chu, W; Carlson, R G et al. (1995) Structural, physical, and biological characteristics of RNA.DNA binding agent N8-actinomycin D. Biochemistry 34:8481-91 |
