This proposal requests funds to synthesize anti-HTLV-III/LAV/HIV agents targeted to specific sequences on the retroviral RNA template. Specifically, dodecadeoxyribonucleotides will be synthesized and connected to nitidine (a benzophenanthridine alkaloid), via a polymethylene tether to the 5'-phosphate, to the 3'-phosphate, and to both the 5' and 3' phosphate group. The oligodeoxyribonucleotides are designed to target important sequences of the HTLV-III/LAV/HIV gene. Nitidine has antireverse transcriptase activity in its own right and, in addition, is expected to interact with this gene and stabilize the binding. The oligodeoxyribonucleotides and their nitidine conjugates will be tested against the HTLV-III/LAV/HIV virus. Model studies will be conducted to see if nitidine oligodeoxyribonucleotides inhibit the reverse transcriptase of rabbit beta-globin mRNA. Extensive physicochemical studies of the interaction of nitidine oligodeoxyribonucleotides with RNA and a model oligoribonucleotide will also be conducted. These studies are expected to result in novel anti-AIDS agents and provide information on the type of linkage which leads to the most activity. In addition, the different oligodeoxyribonucleotides will provide information on which gene in HIV is most succeptible to these agents. This project is of general significance since it will shed light on approaches to directing drugs and other agents to specific nucleic acid sequences (genes).
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