MACROCYCLIC INHIBITORS OF PENICILLOPEPSIN - 1 - DESIGN, SYNTHESIS, AND EVALUATION OF AN INHIBITOR BRIDGED BETWEEN P1 AND P3

The macrocyclic peptidyl phosphonate 1-L was designed on the basis of the conformation of an acyclic analogue (4) bound to the aspartic prot ease penicillopepsin. This material and the two acyclic comparison com pounds 2-L and 3 were synthesized and evaluated as inhibitors; their b inding affinity was found to be inversely related to the degree of con formational flexibility across the series: 3 (K-i = 110 mu M), 2-L (K- i = 7.6 mu M), 1-L (K-i = 0.80 mu M). NMR methods in conjunction with molecular modeling were used to assign the stereochemical configuratio ns of the precursor 16-L and its diastereomer 16-D and to determine th e solution conformations of the macrocyclic ring systems. The conforma tion of the peptide backbone in 1-L closely approximates that desired for a mimic of the lead inhibitor 4, and it appears that the low-energ y conformation of 1-L can be accommodated in the pencillopepsin active site without significant distortion.