Non-peptidic 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 (IC50 12 microM), 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 (IC50 40nM-10 microM) 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.
Brinkworth
R I
RI
Centre for Drug Design and Development, University of Queensland, Brisbane, Australia.
Fairlie
D P
DP
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D001665:Binding Sites; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D014961:X-Ray Diffraction
D017320:HIV Protease Inhibitors; D013451:Sulfonic Acids