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JAC Advance Access originally published online on March 13, 2003
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Journal of Antimicrobial Chemotherapy (2003) 51, 813-819
© 2003 The British Society for Antimicrobial Chemotherapy

Inhibition of human immunodeficiency virus 1 replication in vitro by a self-stabilized oligonucleotide with 2'-O-methyl-guanosine-uridine quadruplex motifs

Tomoyuki Kuwasaki1, Masasi Hatta1, Hiroaki Takeuchi2 and Hiroshi Takaku1,3,*

1 Department of Industrial Chemistry and 3 High Technology Research Center, Chiba Institute of Technology, 2-17-1 Tsudanuma, Narashino, Chiba 275-0016; 2 Department of Virology, Tohoku University, School of Medicine, 2-1 Seiryo 113-8519, Japan

Received 5 November 2002; returned 16 December 2002; revised 17 January 2003; accepted 20 January 2003

Objectives: Given that the guanosine-quadruplex may have a role in blocking the interaction between gp120 and CD4, we describe here the design of a highly nuclease-resistant dimeric hairpin guanosine-quadruplex, [Gm3Um4Gm3-s], containing the 2'-O-methyl groups on the nucleoside and sulphur groups on the internucleotidic bonds, and its anti-HIV-1 activity in cultured cells.

Methods: The unmodified and modified oligonucleotides were chemically synthesized. The anti-HIV activities of test compounds on HIV-1 infection were determined by protection against HIV-1-induced cytopathic effects. The mechanism of action of the oligonucleotides was determined by virus binding and detection [anti-CD4 monoclonal antibody (MAb) and anti-V3 MAb] assays.

Results: Gm3Um4Gm3-s was highly nuclease resistant, had significantly higher anti-HIV-1 activity than dG3T4G3-s, dG10-s and Gm10-s, and blocked the interaction between gp120 and CD4.

Conclusion: The anti-HIV-1 activity of this oligonucleotide was increased when the phosphodiester and 2'-hydroxyl groups on the oligonucleotide backbones were replaced with a phosphorothioate and 2'-O-methyl backbone; thus Gm3Um4Gm3-s may inhibit HIV-1 infection, at least in part, by blocking the interaction between gp120 and CD4.

Keywords: HIV-1, phosphorothioate group, 2'-O-methyl nucleoside, dimeric hairpin guanosine-quadruplex, nuclease resistant

* Corresponding author. Tel: +81-474-78-0407; Fax: +81-474-71-8764; E-mail: takaku{at}ic.it-chiba.ac.jp


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