STRUCTURE-ACTIVITY-RELATIONSHIPS FOR MACROCYCLIC PEPTIDOMIMETIC INHIBITORS OF HIV-1 PROTEASE

A rational approach to developing inhibitors of proteolytic enzymes is the systematic modification of their peptide substrates to proteolyti cally stable, low molecular weight, nonpeptidic inhibitors. Replacing the scissile amide bond with a noncleavable transition state isostere usually gives potent protease inhibitors, but the remaining hydrolysab le amide bonds render the inhibitors unstable to peptidases generally. Attempts to replace them with retention of inhibitor potency has prov ed difficult(1,2) due to the unpredictable cooperative influences of s uch variations on the conformations of both neighbouring inhibitor gro ups and enzyme residues. We recently described a method(3) for regiose lectively fixing the conformation of inhibitor components and now show effects on activity of varying both the 'free' and 'fixed' components .