Extension of the polyanionic cosalane pharmacophore as a strategy for increasing anti-HIV potency

The anti-HIV agent cosalane inhibits both the binding of gp120 to CD4 as we ll as an undefined postattachment event prior to reverse transcription. Sev eral cosalane analogues having an extended polyanionic "pharmacophore" were designed based on a hypothetical model of the binding of cosalane to CD4. The analogues were synthesized, and a number of them displayed anti-HIV act ivity. One of the new analogues was found to possess enhanced potency as an anti-HIV agent relative to cosalane itself. Although the new analogues inh ibited both HIV-1 and HTV-2, they were more potent as inhibitors of HIV-1 t han HIV-2. Mechanism of action studies indicated that the most potent of th e new analogues inhibited fusion of the viral envelope with the cell membra ne at lower concentrations than it inhibited attachment, suggesting inhibit ion of fusion as the primary mechanism of action.