HIV-1 Integrase Complexes with DNA Dissociate in the Presence of Short Oligonucleotides Conjugated to Acridine

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• 作者：Marina Pinskaya ; Elena Romanova ; Evgenii Volkov ; Eric Deprez ; Hervé ; Leh ; Jean-Claude Brochon ; Jean-Franç ; ois Mouscadet ; and Marina Gottikh
• 刊名：Biochemistry
• 出版年：2004
• 出版时间：July 13, 2004
• 年：2004
• 卷：43
• 期：27
• 页码：8735 - 8743
• 全文大小：120K
• 年卷期：v.43,no.27(July 13, 2004)
• ISSN：1520-4995

文摘

The human immunodeficiency virus type 1 (HIV-1) integrase is an essential enzyme in thelife cycle of the virus and is therefore an attractive target for the development of new antiviral drugs.Among them, inhibitors which are capable of targeting the preassembled integrase/DNA complex are ofparticular interest, because they could suppress integrase activity in the context of the HIV-1 preintegrationcomplex. Here, we study the mechanism of action of 11-mer oligonucleotides, which are efficient inhibitorsof the catalytic activity of integrase, provided that they are conjugated to a hydrophobic compound, acridine.To understand the mechanism of the conjugate inhibitory action, we used a steady-state fluorescenceanisotropy assay, which allowed us to study the stability of the integrase/DNA complex in variousconditions. We found that oligonucleotide-acridine conjugates induced the efficient dissociation ofpreassembled integrase/DNA complexes. The simultaneous presence of both acridine and an oligonucleotidicmoiety is required for the inhibitory activity of conjugates. However, the dissociation effect is not dependenton the oligonucleotide sequence. Finally, our results suggest that the conjugates bind directly to integrasewithin its complex with DNA at a site different from the viral DNA binding site.