Peptidyl Ammonium Methyl Ketones as Substrate Analog Inhibitors of Proline-Specific Peptidases

摘要: AbstractProlyl endopeptidase (PEP) and dipeptidyl peptidase IV (DP IV) are serine enzymes cleaving highly specific prolyl peptide bonds. Both were found to be inhibited by newly designed peptidyl ammonium pyridinium methyl ketones acting as slow binding inhibitors. The most potent inhibitor of PEP is Z-Pro-Pro-CH2N+C5H5 exhibiting a K*i value 1.8 nM with first-order rate constant kon 0.0022 s−1 for the formation tight enzyme-inhibitor complex. DP H-Pro-Pro-CH2N+(CH3)3 form an enzyme-inhibitor-complex apparent second order 2713M−1s−1. In contrast very stable N-terminal protected Z-Pro-Pro-CH2N+ (CH3)3, deblocked derivative decomposes rapidly in aqueous solution.