title: Anti-HIV-1 activity by a triple-helix forming oligonucleotides targeted to polypurine tract on viral RNA.
abstract: Reverse transcription of HIV-1 into double-stranded DNA involves initiation of plus-strand DNA synthesis at the polypurine tract, PPT, by reverse transcriptase (RT). The PPT is a possible target for triple-helix formation. We show the effects of triple-helix formation by assays of RNase H cleavage inhibition in vitro using two systems (two-strand-system (FTFOs) or three-strand-system (TFOs)) targeted to the polypurine tract (PPT) of HIV-1. The two-stranded composition of a triple-helix is thermodynamically and kinetically superior to the three-strand-system. The FTFOs inhibited the RNase H activity in a sequence-specific manner, i.e., the triplex actually formed at the PPT and blocked the RNase H. The FTFOs containing the phosphorothioate groups at the antisense strand showed greater 3'-exonuclease resistance. In HIV-1 infected MT-4 cells, the FTFOs containing the phosphorothioate groups at the antisense strand and guanosine rich parts within the third Hoogsteen base pairing sequence inhibit the replication of HIV-1 more effectively than the antisense phosphorothioate oligonucleotides, indicating sequence-specific inhibition of HIV-1 replication.
authors.affiliation: Department of Industrial Chemistry and Chiba Institute of Technology, Tsudanuma, Narashino, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Hiratou
authors.forename: S
authors.initials: S
authors.lastname: Tsukahara
authors.forename: N
authors.initials: N
authors.lastname: Miyano-Kurosaki
authors.forename: K
authors.initials: K
authors.lastname: Takai
authors.forename: T
authors.initials: T
authors.lastname: Saito
authors.forename: N
authors.initials: N
authors.lastname: Yamamoto
authors.forename: H
authors.initials: H
authors.lastname: Takaku
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011687:Purines / Q000378:metabolism*; D012367:RNA, Viral / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D009841:Oligonucleotides; D011687:Purines; D012367:RNA, Viral