POTENCY AND SELECTIVITY OF INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUSPROTEASE BY A SMALL NONPEPTIDE C4 CYCLIC UREA, DMP-323

DMP 323 is a potent inhibitor of the protease of human immunodeficienc y virus (HIV), with antiviral activity against both HIV type 1 and HIV type 2. This compound is representative of a class of small, novel, n onpeptide cyclic urea inhibitors of HIV protease that were designed on the basis of three-dimensional structural information and three-dimen sional database searching. We report here studies of the kinetics of D MP 323 inhibition of the cleavage of peptide and HIV-1 gag polyprotein substrates. DMP 323 acts as a rapidly binding, competitive inhibitor of HIV protease. DMP 323 is as potent against both peptide and viral p olyprotein substrates as A-80987, Q8024, and Ro-31-8959, which are amo ng the most potent inhibitors of HIV protease described in the literat ure to date. Incubation with human plasma or serum did not decrease th e effective potency of DMP 323 for HIV protease, suggesting that plasm a protein binding is of a low affinity relative to that of HIV proteas e. DMP 323 was also assessed for its ability to inhibit the mammalian proteases renin, pepsin, cathepsin D, cathepsin G, and chymotrypsin. N o inhibition of greater than 12% was observed for any of these enzymes at concentrations of DMP 323 that were 350 to 40,000 times higher tha n that required to inhibit the viral protease 50%.