An oligonucleotide with a dimeric hairpin guanosine quadruplex (basket type structure) (dG3T4G3-s), containing phosphorothioate groups, was able to inhibit human immunodeficiency virus type 1 (HIV-1)-induced syncytium formation and virus production (as measured by p24 core antigen expression) in peripheral blood mononuclear cells. This oligonucleotide lacks primary sequence homology with the complementary (antisense) sequences to the HIV-1 genome. Furthermore, this oligonucleotide may have increased nuclease resistance. The activity of this oligonucleotide was increased when the phosphodiester backbone was replaced with a phosphorothioate backbone. In vivo results showed that dG3T4G3-s was capable of blocking the interaction between gp120 and CD4. We also found that dG3T4G3-s specifically inhibits the entry of T-cell line-tropic HIV-1 into cells. This compound is a viable candidate for evaluation as a therapeutic agent against HIV-1 in humans.

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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.

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SummaryA new type of hairpin antisense oligodeoxyribonucleotide, containing 2'-methoxynucleosides with base-pairing in the stem region at the 3'-end, was tested for 3'-exonuclease resistance and anti-HIV activity. An increased resistance to nuclease degradation has been observed by incubation of the hairpin oligo-nucleotides with DNA polymerase and foetal bovine serum. Of particular interest is the hairpin antisense oligonucleotide containing 2'_ methoxynucleosides with base-pairing in the stem region at the 3'·end, which has increased nuclease resistance and hybridizes effectively with a complementary RNA. Furthermore, these compounds were assayed for inhibition of virus replication in HIV-1 infected MT-4 cells. In the anti-HIV activity test, the hairpin oligonucleotide phosphorothioate derivatives showed higher anti-HIV activities compared to their linear counterparts.