STRUCTURAL RNA MIMETICS - N3'-]P5' PHOSPHORAMIDATE DNA ANALOGS OF HIV-1 RRE AND TAR RNA FORM A-TYPE HELICES THAT BIND SPECIFICALLY TO REV AND TAT-RELATED PEPTIDES

An attractive strategy for the development of anti-retroviral drugs is the exploration of compounds that mimic RNA control regions of the vi ral genome and act as ''decoys'' to sequester viral gene regulatory pr oteins. Decoys consisting of RNA, however, are chemically unstable and readily degraded by cellular nucleases. DNA decoys, which are slightl y more stable, also might not be appropriate because of possible struc tural differences between RNA and DNA helices and the complexes they f orm with proteins. It was recently reported, however, that DNA analogs with modified N3' --> P5' phosphoramidate sugar-phosphate backbones a re stable and nuclease-resistant and exist predominately as A-form hel ices in solution [Gryaznov, S., et al. (1995) Proc. Natl. Acad. Sci. U .S.A. 92, 5798-5802]. We now report that oligonucleotide N3' --> P5' p hosphoramidate DNA analogs of HIV-1 RRE IIB and TAR RNA form stable du plexes that exist in the A form as judged by circular dichroism (CD). Moreover, gel shift assays demonstrate that these phosphoramidates can specifically bind to peptides derived from HIV-1 Rev and Tat proteins . Isosequential phosphodiester DNA duplexes, existing in the B form by CD, do not bind to the respective peptides under the experimental con ditions used. These results suggest the possibility that nuclease-resi stant oligonucleotide N3' --> P5' phosphoramidates might serve as RNA- like decoys and disrupt specific viral RNA/protein interactions such a s RRE/ReV and TAR/Tat in HIV-1.