Small-molecule inhibitor: CA074

Name

History: Inhibition of cathepsin B by CA074 was first described in 1991 (Murata et al., 1991; Towatari et al., 1991).
Peptidases inhibited: This is a selective inhibitor of cathepsin B and cathepsin X: Klemencic et al., 2000). The cathepsin B-like CPC peptidase also is inhibited Mottram et al., 2004. Half-times (s) for inhibition at 10 micromolar inhibitor (Salvesen & Nagase, 2001): >5000 (papain), 0.6 (cathepsin B), >5000 (cathepsin H), >5000 (cathepsin L).
Mechanism: Irreversible inhibition is by a mechanism similar to that of E64, but specificity for cathepsin B is conferred by an interaction between the inhibitor and the 'occluding loop' of the enzyme (Turk et al., 1995; Yamamoto et al., 2000). In contrast to the complexes of E64 with papain and most other family C1 peptidases, complexes of CA074 and analogues with cathepsin B show binding of the inhibitor in the prime-side subsites (Matsumoto et al., 1998).

Structure
Chemical/biochemical name: N-(L-3-trans-propylcarbamoyloxirane-2-carbonyl)-L-isoleucyl-L-proline
Related inhibitors: CA030 (an analogue of CA074 in which an n-propylamide group is replaced by an ethyl ester).

Inhibitor class: This compound is of the epoxysuccinate class of inhibitors, which affect primarily cysteine peptidases in clan CA. The compounds inhibit irreversibly by S-alkylation of the catalytic cysteine, which results in opening of the epoxide ring. A thioester bond is formed by nucleophilic attack at C2 or C3 of the epoxide ring. Powers et al. (2002) (pp. 4664-4675) provide an authoritative review of epoxysuccinyl peptides as peptidase inhibitors.
Comment: The methyl ester acts as a proinhibitor effective against intracellular cathepsin B (Buttle et al., 1992).