Small-molecule inhibitor: Cpp-Ala-Ala-Phe-pAb

Name

History: Cpp-A-A-F-pAB was described by Chu & Orlowski (1984) as an inhibitor of a soluble netallopeptidase of rat brain that later came to be known as thimet oligopeptidase.
Peptidases inhibited: Thimet oligopeptidase is inhibited with K_i = 31 nM (Knight & Barrett, 1991). Neurolysin is inhibited much more weakly (K_i = 600 nM: Steer et al., 2002).
Mechanism: Inhibition is reversible. Structure/function relationships for inhibition of thimet oligopeptidase were investigated by Knight & Barrett (1991).

Structure
Chemical/biochemical name: N-1-(R,S)carboxy-3-phenylpropyl-Ala-Ala-Phe-p-carboxyanilide
Related inhibitors: The related Cpp-Ala-Pro-Phe-pAb has K_i = 7 nM for thimet oligopeptidase (Knight & Barrett, 1991).

Inhibitor class: This is a compound in the carboxylate class of reversible metallopeptidase inhibitors. In these, the active site zinc of the enzyme is generally coordinated by a carboxylate of the inhibitor, and this interaction contributes to inhibitory potency. Reviewed by Patchett & Cordes (1985) and Powers & Harper (1986), pp. 268 - 277 (who provide a table of K_i values).
Comment: Cpp-Ala-Pro-Phe-pAb can be converted by the action of neprilysin to Cpp-Ala-Ala, which is a potent inhibitor of angiotensin-converting enzyme compound peptidase, and this occurs in vivo. Not all of the pharmacological effects of Cpp-Ala-Ala-Phe-pAB are therefore directly attributable to inhibition of thimet oligopeptidase (Cardozo & Orlowski, 1993; Williams et al., 1993). A compound modified from Cpp-Ala-Ala-Phe-pAB that is more stable under biological conditions is JA-2.