Oligonucleotide analogue interference with the HIV-1 Tat protein-TAR RNA interaction

The HIV-1 Tat protein interaction with its RNA recognition sequence TAR is an important drug target and model system for the development of specific R NA-protein inhibitors. 2'-O-methyl oligoribonucleotides complementary to th e TAR apical stem-loop effectively block Tat binding in vitro. Substitution by 5-propynylC or 5-methylC LNA monomeric units into a 12-mer 2'-O-methyl oligoribonucleotide leads to stronger inhibition, as does a 12-mer PNA. 10- 16 mer 2'-O-methyl oligoribonucleotides give sequence- and dose-dependent i nhibition of Tat-dependent transcription of an HIV DNA template in HeLa cel l nuclear extract. Inhibition is maintained for the substituted 12-mer anal ogues but is poorer for PNA and is not correlated with TAR binding strength .