Small-molecule inhibitor: Ep475

Name

History: Ep475 was amongst the first synthetic analogues of E64 to be described (Hanada et al., 1978).
Peptidases inhibited: Ep475 rapidly inactivates papain and indeed a wide range of peptidases in family C1, as E64 does.
Mechanism: Similar to E64 (Kim et al., 1992).

Structure
Chemical/biochemical name: L-3-carboxy-2,3-trans-epoxypropionyl-leucylamido(3-methyl)butane; L->trans-epoxysuccinyl-leucylamido(3-methyl)butane

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: Being less hydrophilic than E64, Ep-475 permeates cells more readily, and the ethyl ester proinhibitor Ep475 is even more permeant.