Small-molecule inhibitor: apstatin

Name

History: Apstatin was synthesised by Prechel et al. (1995).
Peptidases inhibited: Apstatin is a specific, though not highly potent, inhibitor of prolyl aminopeptidases. It inhibits membrane-bound aminopeptidase P2 from various sources in the low micromolar range. It also inhibits the bacterial aminopeptidase P: Maggiora et al., 1999). The soluble homologue of mammalian aminopeptidase P2, aminopeptidase P1, was completely inhibited by 100 micromolar apstatin (Cottrell et al., 2000). Apstatin did not inhibit a variety of other membrane-bound peptidases tested (Maggiora et al., 1999).
Mechanism: Inhibition of aminopeptidase P2 is reversible, K_i about 3 micromolar (Prechel et al., 1995; Maggiora et al., 1999). The N-terminal, 3-amino-2-hydroxy-4-phenyl-butanoic acid residue is present also in bestatin (Powers & Harper (1986)).
Pharmaceutical relevance: Apstatin has a bradykinin-sparing effect in vivo (Prechel et al., 1995), and has been shown to reduce myocardial infarct size by a kinin-dependent pathway (Ersahin et al., 1999; Wolfrum et al., 2001).
DrugBank: DB04092

Structure
Chemical/biochemical name: N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]-L-prolyl-L-prolyl-L-alaninamide
Related inhibitors: An analogue in which the N-terminal residue was a (2S,3R)-3-amino-2-hydroxy-5-methyl-hexanoyl group was a more potent inhibitor than apstatin itself (Maggiora et al., 1999).