Newly Designed Six-membered Azasugar-Containing Phosphorothioate Oligonucleotide as a Potent AIDS Therapeutic Drug

A series of modified oligonucleotides containing a phosphorothioate (P=S) backbone and a six-membered azasugar (6-AZS) as a sugar substitute in a nucleotide were synthesized and tested for their ability to inhibit the human immunodeficiency virus type l(H IV -l) in vitro without the aid of any transfecting agents. While P=S oligonucleotides with natural nucleotides had little anti-HIV-1 activity, the six-membered azasugar nucleotide (6-AZN)-containing P=S oligonucleotides (AZPSONs) potently inhibited the HIV-l/SHIV replication and syncytium formation (EC 50 = 0.02-0.2 ]xM) without cytotoxicity up to 100 |iM. DBM-2198, the most effective in anti-HIV-1 activity among the AZPSONs, consists of random sequence and five 6-AZNs evenly distributed in 18 nucleotides. DBM-2198 showed strong antiviral activity against, not only laboratory strains, but also primary isolates and even drug-resistant strains of HIV-1. DBM-2198 was much more effective than ddl or ddC in its anti-HIV-1 activity in vitro. Particularly noteworthy is that the anti-HIV-1 activity of DBM-2198 was better than that of AZT with respect to its long-lasting efficacy after a single treatment. Nevertheless, the antiviral activity of the AZPSONs was very specific to HIV-1. Poliovirus, or even simian immunodeficiency virus (SIV), was not inhibited by the AZPSONs. Taken together, our results strongly suggest that AZPSON can be used as a safe and effective AIDS-therapeutic drug against a broad spectrum of HIV-1 strains.