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 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.
Arzumanov
A
A
Medical Research Council, Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, U.K.
Walsh
A P
AP
Liu
X
X
Rajwanshi
V K
VK
Wengel
J
J
Gait
M J
MJ
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D015696:Gene Products, tat / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016325:HIV Long Terminal Repeat / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D009841:Oligonucleotides / Q000737:chemistry / Q000494:pharmacology*; D012367:RNA, Viral / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D019380:Anti-HIV Agents; D015696:Gene Products, tat; D009841:Oligonucleotides; D012367:RNA, Viral