INHIBITION OF HIV-1 PROTEINASE BY NONPEPTIDE CARBOXYLATES

Some simple dicarboxylates are among the first reported non-peptide inhibitors of HIV-1 proteinase. Only weak inhibition (IC50 ≥ 10μM) was observed but this may be significant since only two potential enzyme-binding groups are present. Dixon plots and preliminary kinetic data are reported and a possible mechanism for the inhibition is discussed. The dicarboxylates are long enough to engage the carboxylate side chains of Arg 8 and Arg 108 at either end of the 24Å long substrate-binding groove. This mode of binding has not been proven but other molecules with similarly separated charged ends are equally effective inhibitors, perhaps indicating a common mechanism of inhibition. There is evidence that placing other functional groups on the inhibitor enables alternative interactions with the enzyme which can reduce inhibitor potency. We propose that incorporation of ionic binding groups in more elaborate and selective non-peptides may potentiate inhibition of HIV-1 proteinase. © 1991.