NONPEPTIDIC ANTI-AIDS AGENTS - INHIBITION OF HIV-1 PROTEINASE BY DISULFONATES

Based upon an earlier observation that sodium docosanedioate (NaO2C-(CH2)20-CO2Na) weakly inhibits HIV-1 proteinase (IC5012μM), we have identified a class of more potent inhibitors (sulfonic acids) of this enzyme which are likewise dianionic at pH 5-6.5. Many of the compounds were moderately strong inhibitors of the enzyme (IC5040nM-10μM) and some have previously been shown to have anti-HIV activity in lymphocytes. Proteinase inhibition was dependent on the separation between sulfonate/carboxylate substituents, consistent with the hypothesis that negative charged ends of an inhibitor might form ionic bonds with Arg 8 and Arg 108 located at either end of the substrate-binding groove of the enzyme. The binding mode remains to be established by structure elucidation. Results for enzyme inhibition are presented along with structure-activity relationships and evidence for pH dependent inhibition. The general observations reported here may be useful for developing more potent and selective non-peptidic proteinase inhibitors. © 1992.