Inhibition of Achromobacter Protease I by Lysinal Derivatives

Abstract

Z-Val-, Z-Pro-, Z-Leu-Leu-, and Z-Leu-Pro-lysinals and Bz-DL-lysinal were chemically synthesized and tested as novel inhibitors for Achromobacter protease I (API), a lysine-specific serine protease. Among the lysinal derivatives tested, Z-Val-lysinal was the most potent competitive inhibitor, its K_i being estimated as 6.5 nM in an esterolytic assay with Tos-Lys-OMe. In an amidolytic assay, Z-Leu-Leu-lysinal was the most potent inhibitor and the apparent mode of inhibition was non-competitive. The K_is of the other lysinal derivatives in both esterolytic and amidolytic assays were more than 10³ times lower than that of leupeptin. Z-Val-lysinol, lacking the aldehyde group, was a poor competitive inhibitor. These results suggest that acyl-, aclyaminoacyl-, and acylpeptidyllysinals function as a transition-state inhibitor for Achromobacter protease I.