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


CONCLUSIONS
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.
Kuwasaki
Tomoyuki
T
Department of Industrial Chemistry, Chiba Institute of Technology, 2-17-1 Tsudanuma, Narashino, Chiba 275-0016, Japan.
Hatta
Masasi
M
Takeuchi
Hiroaki
H
Takaku
Hiroshi
H
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D015704:CD4 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D017931:DNA Primers / Q000138:chemical synthesis / Q000494:pharmacology; D005092:Exonucleases / Q000378:metabolism; D005434:Flow Cytometry; D006151:Guanosine / Q000031:analogs & derivatives*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects; D006801:Humans; D023282:Nuclease Protection Assays; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D014529:Uridine; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; D015704:CD4 Antigens; D017931:DNA Primers; D015699:HIV Envelope Protein gp120; D009841:Oligonucleotides; D006151:Guanosine; D005092:Exonucleases; C024900:2'-O-methylguanosine; D014529:Uridine