OLIGONUCLEOTIDE ANALOGUE INTERFERENCE WITH THE HIV-1 TAT PROTEIN-TAR RNA INTERACTION

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Abstract
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 RNA-protein inhibitors. 2′-O-methyl oligoribonucleotides complementary to the 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 inhibition of Tat-dependent transcription of an HIV DNA template in HeLa cell nuclear extract. Inhibition is maintained for the substituted 12-mer analogues but is poorer for PNA and is not correlated with TAR binding strength.