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

Abstract

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. 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. 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. 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.