Anti-human immunodeficiency virus type 1 activity of R-95288, a phosphodiester hexadeoxyribonucleotide modified by dibenzyloxybenzyl and hydroxyethyl residues at the 5'- and 3'-ends

The phosphodiester hexadeoxyribunocleotide R-95288 is a potent anti-human immunodeficiency virus type 1 (HIV-1) agent in vitro which consists of a TGGGAG nucleoside sequence with dibenzyloxybenzyl and hydroxyethyl substituents at the 5'- and 3'-ends, respectively. In this study, the antiviral activity of R-95288 against various strains of HIV-1 in vitro was assessed and its mechanism of action was analysed. R-95288 inhibited replication of all strains of HIV-1 used including laboratory strains with the syncytium-inducing (SI) phenotype and clinical isolates with both SI and non-SI (NSI) phenotypes. The 50% inhibitory concentrations (IC(50)s) were 0.62-18 mu g mL(-1) (0.21-6.2 mu M). R-95288 inhibited the binding and fusion of HIV-1-infected T cells with CD4(+) cells: In addition, R-95288 specifically blocked the binding of monoclonal antibodies, recognizing the anti-VS loop or the CD4-binding site of the virus envelope glycoprotein gp120. Furthermore, the target site of R-95288 within the V3 loop was found in the putative heparin-binding region by binding inhibition assays using various anti-V3 loop antibodies. These results suggest that R-95288 can inhibit various strains of HIV-1, possibly by specific interaction with gp120.