Inhibition of aminopeptidases by amastatin and bestatin derivatives. Effect of inhibitor structure on slow-binding processes

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Abstract
Amastatin [(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl-L-valyl-L-valyl-L-aspartic acid] and bestatin[(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-L-leucine] [immunologic and antineoplastic drugs] are slow-binding, competitive inhibitors of aminopeptidase M (AP-M) with net Ki of 1.9 .times. 10-8 and 4.1 .times. 10-6 M, respectively. The effect of inhibitor structure on net Ki and on slow-binding inhibition was evaluated for analogs of both inhibitors on [porcine kidney] AP-M and leucine aminopeptidase (LAP). The (2S)-hydroxyl group contributes to the stabilization of a collision complex [EI], which is formed rapidly. In contrast, increasing the peptide chain length of the inhibitor produces more potent inhibitors as a consequence of a slower binding process. A statine analog of amastatin [(3S,4S)-Sta-Val-Val-Asp] stimulated rather than inhibited LAP. AP-M binds tri- and tetrapeptide inhibitors more strongly than dipeptide inhibitors; LAP binds dipeptide inhibitors more strongly. The difference in binding can be used to distinguish cytosolic from membrane-bound aminopeptidases.