COMPETITIVE-INHIBITION OF HIV-1 PROTEASE BY BIPHENYL CARBOXYLIC-ACIDS

A novel series of nonpeptidic compounds that contain a biphenyl carbox ylic acid group have been shown to inhibit HIV-1 protease, The active compounds, most of which are highly soluble, have IC50 values in the r ange of 3.4-74 mu-M. The structure-inhibitory activity relationship de monstrates the necessity of the biphenyl carboxylic acid group for inh ibition, which is enhanced by the presence of a sulfone group and by h alogenation of an adjacent phenyl group, A double reciprocal plot of i nhibition data on two of the compounds clearly shows that the inhibiti on occurs in a competitive manner, with K-i values of 1.1 and 3.4 mu M . Inhibition by several of the compounds was found to be reversible an d fast-binding, while one of the biphenyl carboxylic acids inhibits in a reversible slow-binding manner. Time-dependent inhibition studies w ere conducted on this compound, and it was determined to have the kine tic values of k(on) = 0.18 mu M(-1)min(-1), k(off) = 9.7 X 10(-2)min(- 1), and K-i = 0.14 mu M. Thus, the slow-binding inhibitor is the most potent in the series. Molecular modeling has provided information on a possible binding mode for two different biphenyl carboxylic acid inhi bitors of HIV-1 protease. 1995 Academic Press, Inc.